WO2012079000A1 - Use of chimeric antigen receptor-modified t cells to treat cancer - Google Patents

Use of chimeric antigen receptor-modified t cells to treat cancer Download PDF

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Publication number
WO2012079000A1
WO2012079000A1 PCT/US2011/064191 US2011064191W WO2012079000A1 WO 2012079000 A1 WO2012079000 A1 WO 2012079000A1 US 2011064191 W US2011064191 W US 2011064191W WO 2012079000 A1 WO2012079000 A1 WO 2012079000A1
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WIPO (PCT)
Prior art keywords
cells
cell
car
antigen
acid sequence
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PCT/US2011/064191
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English (en)
French (fr)
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WO2012079000A4 (en
Inventor
Carl H. June
Bruce L. Levine
David L. Porter
Michael D. Kalos
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University of Pennsylvania Penn
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University of Pennsylvania Penn
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Priority to PH1/2013/501201A priority Critical patent/PH12013501201A1/en
Application filed by University of Pennsylvania Penn filed Critical University of Pennsylvania Penn
Priority to EP17153799.6A priority patent/EP3214091B1/en
Priority to BR122021026173-3A priority patent/BR122021026173B1/pt
Priority to ES11846757.0T priority patent/ES2641870T3/es
Priority to BR112013014265A priority patent/BR112013014265B8/pt
Priority to JP2013543380A priority patent/JP5947311B2/ja
Priority to CA2820681A priority patent/CA2820681C/en
Priority to MA36089A priority patent/MA34813B1/fr
Priority to BR122021026169-5A priority patent/BR122021026169B1/pt
Priority to TR2018/20015T priority patent/TR201820015T4/tr
Priority to EP11846757.0A priority patent/EP2649086B1/en
Priority to LTEP11846757.0T priority patent/LT2649086T/lt
Priority to EA201390847A priority patent/EA027153B1/ru
Priority to SG2013043229A priority patent/SG190997A1/en
Priority to AU2011338200A priority patent/AU2011338200B2/en
Priority to KR1020237030855A priority patent/KR20230133410A/ko
Priority to AP2013006918A priority patent/AP2013006918A0/xx
Priority to MX2013006570A priority patent/MX347078B/es
Priority to US13/992,622 priority patent/US9499629B2/en
Priority to CN201711345686.8A priority patent/CN108103085B/zh
Priority to KR1020217011458A priority patent/KR102417796B1/ko
Priority to PL11846757T priority patent/PL2649086T3/pl
Priority to KR1020137017546A priority patent/KR102062407B1/ko
Priority to PL17153799T priority patent/PL3214091T3/pl
Priority to SI201131301T priority patent/SI2649086T1/en
Priority to CN201180067173.XA priority patent/CN103492406B/zh
Priority to HRP20171577TT priority patent/HRP20171577T1/hr
Priority to MX2016013253A priority patent/MX385933B/es
Priority to RS20171041A priority patent/RS56453B1/sr
Priority to DK11846757.0T priority patent/DK2649086T3/en
Priority to KR1020227022607A priority patent/KR20220101745A/ko
Priority to NZ612512A priority patent/NZ612512A/en
Priority to EP19199404.5A priority patent/EP3660029A1/en
Publication of WO2012079000A1 publication Critical patent/WO2012079000A1/en
Publication of WO2012079000A4 publication Critical patent/WO2012079000A4/en
Priority to IL226694A priority patent/IL226694B/en
Priority to CL2013001645A priority patent/CL2013001645A1/es
Priority to CR20130269A priority patent/CR20130269A/es
Priority to TNP2013000246A priority patent/TN2013000246A1/fr
Anticipated expiration legal-status Critical
Priority to CU2013000079A priority patent/CU20130079A7/es
Priority to ZA2013/04470A priority patent/ZA201304470B/en
Priority to US13/938,923 priority patent/US8911993B2/en
Priority to US13/938,947 priority patent/US8906682B2/en
Priority to EC2013012739A priority patent/ECSP13012739A/es
Priority to US14/107,302 priority patent/US9328156B2/en
Priority to US14/465,952 priority patent/US8975071B1/en
Priority to US14/466,096 priority patent/US8916381B1/en
Priority to US14/567,426 priority patent/US9102760B2/en
Priority to US14/568,569 priority patent/US9102761B2/en
Priority to US14/568,195 priority patent/US9101584B2/en
Priority to US14/984,371 priority patent/US9481728B2/en
Priority to US14/997,042 priority patent/US9518123B2/en
Priority to US14/996,953 priority patent/US9464140B2/en
Priority to US14/997,136 priority patent/US9540445B2/en
Priority to US15/353,899 priority patent/US20170283775A1/en
Priority to AU2017203087A priority patent/AU2017203087B2/en
Priority to US15/696,584 priority patent/US20180258391A1/en
Priority to AU2017225161A priority patent/AU2017225161C1/en
Priority to CY20171101020T priority patent/CY1119760T1/el
Priority to FR19C1006C priority patent/FR19C1006I2/fr
Priority to NL300967C priority patent/NL300967I2/nl
Priority to LTPA2019502C priority patent/LTC2649086I2/lt
Priority to LTPA2019503C priority patent/LTPA2019503I1/lt
Priority to NO2019007C priority patent/NO2019007I1/no
Priority to LUC00104 priority patent/LUC00104I2/fr
Priority to CY2019008C priority patent/CY2019008I1/el
Priority to CY2019007C priority patent/CY2019007I1/el
Priority to NO2019006C priority patent/NO2019006I1/no
Priority to AU2020200767A priority patent/AU2020200767C1/en
Priority to AU2022201895A priority patent/AU2022201895A1/en
Ceased legal-status Critical Current

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Definitions

  • CLL chronic lymphocytic leukemia
  • CD 19 is an attractive tumor target. Expression of CD 19 is restricted to normal and malignant B cells (Uckun, et al. Blood, 1988, 71 : 13-29), so that CD 19 is a widely accepted target to safely test CARs, While CARs can trigger T-cell activation in a manner similar to an endogenous T-cell receptor, a major impediment to the clinical application of this technology to date has been limited in vivo expansion of CAR+ T cells, rapid disappearance of the cells after infusion, and disappointing clinical activity (Jena, et al., Blood;, 2010, 1 16: 1035- 1044; Uckun, et al, Blood, 1988, 71 : 13-29).
  • the present invention provides an isolated nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the CD3 zeta signaling domain comprises the amino acid sequence of SEQ ID NO: 24.
  • CAR chimeric antigen receptor
  • the nucleic acid sequence encodes a CAR comprising the amino acid sequence of SEQ ID NO: 12.
  • the nucleic acid sequence encoding a CAR comprises the nucleic acid sequence of SEQ ID NO: 8.
  • the antigen binding domain in the CAR is an antibody or an antigen-binding fragment thereof.
  • the antigen-binding fragment is a Fab or a scFv.
  • the antigen binding domain in the CAR binds to a tumor antigen.
  • the tumor antigen is associated with a hematologic malignancy.
  • the tumor antigen is associated with a solid tumor.
  • the tumor antigen is selected from the group consisting of CD 19, CD20, CD22, ROR1, mesothelin, CD33/IL3Ra, c-Met ; PSMA, Glycolipid F77, EGFRvllI, GD-2, NY-ESO- 1 TCR, MAGE A3 TCR, and any combination thereof.
  • the costimulatory signaling region in the CAR comprises the intracellular domain of a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD- 1, ICOS, lymphocyte function-associated antigen- 1 (LFA- 1), CD2, CD 7, LIGHT, NKG2C, B7- H3, a ligand that specifically binds with CD83, and any combination thereof.
  • a costimulatory molecule selected from the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD- 1, ICOS, lymphocyte function-associated antigen- 1 (LFA- 1), CD2, CD 7, LIGHT, NKG2C, B7- H3, a ligand that specifically binds with CD83, and any combination thereof.
  • the CD3 zeta signaling domain in the CAR is encoded by the nucleic acid sequence of SEQ ID NO: 18.
  • the invention also provides an isolated CAR comprising an antigen binding domain, a transmembrane domain, a costimuiatory signaling region, and a CD3 zeta signaling domain, wherein the CD3 zeta signaling domain comprises the amino acid sequence of SEQ ID NO: 24.
  • the invention also provides a cell comprising a nucleic acid sequence encoding a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO: 24.
  • the cell comprising the CAR is selected from the group consisting of a T cell, a Natural Killer (NK) cell, a cytotoxic T lymphocyte (CTL), and a regulatory T cell.
  • NK Natural Killer
  • CTL cytotoxic T lymphocyte
  • the cell comprising the CAR exhibits an antitumor immunity when the antigen binding domain of the CAR binds to its corresponding antigen
  • the invention also provides a vector comprising a nucleic acid sequence encoding a CAR, wherein the CAR comprises an antigen binding domain, a costimulatory signaling region, and a CD3 zeta signaling domain, wherein the CD3 zeta signaling domain comprises the amino acid sequence of SEQ ID NO: 24.
  • the invention also provides a method for stimulating a T cell-mediated immune response to a target cell population or tissue in a mammal,
  • the method comprises administering to a mammal an effective amount of a cell genetically modified to express a CAR wherein the CAR comprises an antigen binding domain, a costimulatory signaling region, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO: 24, wherein the antigen binding domain is selected to specifically recognize the target cell population or tissue.
  • the invention also provides a method of providing an anti-tumor immunity in a mammal.
  • the method comprises administering to a mammal an effective amount of a cell genetically modified to express a CAR wherein the CAR comprises an antigen binding domain, a costimulatory signaling region, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO: 24, thereby providing an anti-tumor immunity in the mammal.
  • the invention also includes a method of treating a mammal having a disease, disorder or condition associated with an elevated expression of a tumor antigen.
  • the method comprises administering to a mammal an effective amount of a cell genetically modified to express a CAR wherein the CAR comprises an antigen binding domain, a costimulatory signaling region, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO: 24, thereby treating the mammal.
  • the cell is an autologous T cell
  • the tumor antigen is selected from the group consisting of CD 19, CD20, CD22, ROR1 , raesothelin, CD33/IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvlll, GD-2, NY-ESO- 1 TCR, MAGE A3 TCR, and any combination thereof.
  • the invention also provides a method of treating a human with chronic lymphocytic leukemia.
  • the method comprises administering to a human a T cell genetically engineered to express a CAR wherein the CAR comprises an antigen binding domain, a costimulatory signaling region, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO: 24.
  • the human is resistant to at least one chemotherapeutic agent
  • the chronic lymphocytic leukemia is refractory CD 19+ leukemia and lymphoma.
  • the invention also includes a method of generating a persisting population of genetically engineered T cells in a human diagnosed with cancer.
  • the method comprises administering to a human a T cell genetically engineered to express a CAR wherein the CAR comprises an antigen binding domain, a costimulatory signaling region, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO: 24, wherein the persisting population of genetically engineered T cells persists in the human for at least one month after administration.
  • the persisting population of genetically engineered T cells comprises at least one cell selected from the group consisting of a T cell that was administered to the human, a progeny of a T cell that was administered to the human, and a combination thereof.
  • the persisting population of genetically engineered T ceils comprises a memory T cell.
  • the persisting population of genetically engineered T cells persists in the human for at least three months after administration. In another embodiment, the persisting population of genetically engineered T cells persists in the human for at least four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, two years, or three years after administration.
  • the chronic lymphocytic leukemia is treated.
  • the invention also provides a method of expanding a population of genetically engineered T cells in a human diagnosed with cancer. In one
  • the method comprises administering to a human a T cell genetically engineered to express a CAR wherein the CAR comprises an antigen binding domain, a costimulatory signaling region, and a CD3 zeta signaling domain comprising the amino acid sequence of SEQ ID NO: 24, wherein the administered genetically engineered T cell produces a population of progeny T cells in the human,
  • the progeny T cells in the human comprise a memory T cell
  • the T cell is an autologous T cell.
  • the human is resistant to at least one chemotherapeutic agent
  • the cancer is chronic lymphocytic leukemia.
  • the chronic lymphocytic leukemia is refractory CD 19+ leukemia and lymphoma.
  • the population of progeny T cells persists in the human for at least three months after administration.
  • the population of progeny T ceils persist in the human for at least four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, two years, or three years after administration,
  • the cancer is treated.
  • Figure 1 is a series of images of the schematic representations of the gene-transfer vector and transgene, gene modified T cell manufacturing and clinical protocol design
  • Figure 1A depicts the lentiviral vectors and transgene that show the major functional elements.
  • FIG. 1 depicts T cell manufacturing. Autologous cells were obtained via an apheresis, and T cells were enriched by mononuclear cell ehitriation, washed and residual leukemia cells depleted by addition of anti-CD3/CD28 coated paramagnetic beads for positive selection and activation of T cells. Lentiviral vector was added at the time of cell activation and was washed out on day 3 post culture initiation.
  • FIG. 1 C depicts the clinical protocol design. Patients were given lymphodepleting chemotherapy as described, followed by CART19 infusion # 1 by i.v. gravity flow drip over a period of 15-20 minutes. The infusion was given using a split dose approach over 3 days (10%, 30%, 60%) beginning 1 to 5 days after completion of chemotherapy. Endpoint assays were conducted on study week 4. At the conclusion of active monitoring, subjects were transferred to a destination protocol for long term follow up as per FDA guidance.
  • Figure 2 comprising Figures 2A through 2F, is a series of images demonstrating sustained in vivo expansion and persistence in blood and marrow of CART19 cells.
  • Each data point represents the average of triplicate measurements on 100-200 ng genomic DNA, with maximal % CV less than 1.56%, Pass/fail parameters for the assay included pre-established ranges for slope and efficiency of amplification, and amplification of a reference sample.
  • the lower limit of quantification for the assay established by the standard curve range was 2 copies transgene/microgram genomic DNA; sample values below that number are considered estimates and presented if at least 2/3 replicates generated a Ct value with % CV for the values 15%.
  • CART 19 cells were infused at day 0, 1, and 2 for UPN 01 and UPN 03, and days 0, 1, 2 and 1 1 for UPN 02.
  • Figure 3 is a series of images demonstrating serum and bone marrow cytokines before and after CAR T cell infusion; longitudinal measurements of changes in serum cytokines, chemokines and cytokine receptors in UPN 01 as depicted in Figure 3A, UPN 02 as depicted in Figure 3B and UPN 03 as depicted in Figure 3C, on the indicated day after CART19 ceil infusion and serial assessments of the same analytes in the bone marrow from UPN 03 as depicted in Figure 3D, Samples were subjected multiplex analysis using Luminex bead array technology and pre-assembled and validated multiplex kits.
  • Absolute values for each analyte at each time-point were derived from a recombinant protein-based standard curve over a 3-fold 8-point dilution series, with upper and lower limits of quantification (ULOQ, LLOQ) determined by the 80- 120% observed/expected cutoff values for the standard curves.
  • UAOQ, LLOQ upper and lower limits of quantification
  • Standard curve ranges for analytes and baseline (day 0) values (listed in parentheses sequentially for UPNO l , 02 and 03), all in pg/ml: IL l -Ra: 35.5-29,3 18 (689, 301 , 287); IL-6: 2.7-4,572 (7, 10.1 , 8.7); IFN- ⁇ : 1 1 .2-23,972 (2.8, ND, 4.2 ); CXCL10: 2.1 -5,319 (481 , 1 15, 287 ); IP- 1 ⁇ : 3.3-7,233 (99.7, 371 , 174 ); MCP-1 : 4.8-3,600 (403, 560, 828); CXCL9: 48.2- 3,700 (1,412, 126, 177); 1L2-Ra: 13.4-34,210 (4,319, 9,477, 610); IL-8: 2.4-5,278
  • Figure 4 is a series of images depicting prolonged surface CART19 expression and establishment of functional memory CARs vivo.
  • Figure 4A depicts detection of CAR-expressing CD3+ lymphocytes and absence of B cells in periphery and marrow.
  • Freshly processed peripheral blood or marrow mononuclear cells obtained from UPN 03 at day 169 post-CARTl 9 cell infusion were evaluated by flow-cytometry for surface expression of CAR 19 (top) or presence of B cells (bottom); as a control, PBMC obtained from a healthy donor ND365 were stained.
  • the gating strategy for the CD3+ and B cell populations is presented in Figure 9.
  • samples were co-stained with antibodies to CD I -PE-Cy7 and CD16- PE-Cy7 (dump channel) and CD3-FITC, positively gated on CD3+, and evaluated for CAR19 expression in the CD8+ and CD8-lymphocyte compartments by co-staining with CD8a-PE and the anti-CAR 19 idiotype antibody conjugated to Alexa-647. Data in plots are gated on the dump channet-negative/CD3-positive cell population.
  • the gating strategy involved an initial gating on dump channel (CD 14, CD 16, Live/Dead Aqua)-negative and CD3- positive cells, followed by positive gates on CD4+ and CD8+ cells, Gates and quadrants were established using FMO controls (CAR, CD45RA, PD-1 , CD25, CD127, CCR7) or by gating on positive cell populations (CD3, CD4, CD8) and clearly delineated subsets (CD27, CD28, CD57); data were displayed after bi- exponentiai transformation for objective visualization of events.
  • Figure 4D depicts functional competence of persisting CAR ceils, Frozen peripheral blood samples from UPN 03 obtained by apheresis at day 56 and 169 post T cell infusion were rested overnight in culture medium with no added factors, washed, and evaluated directly ex- vtvo for the ability to recognize CD 19-expressing target cells using CD 107 degranulation assays. Following a two-hour incubation in the presence of anti-CD28, anti-CD49d, and CD107-FITC, cell mixtures were harvested, washed, and subjected to multi-parametric flow cytometric analysis to evaluate the ability of CART 19 cells to de-granulate in response to CD19-expressing targets.
  • the gating strategy involved an initial gate on dump channels (CD I 4-PE-Cy7, CD16-PE-Cy7, Live/Dead Aq a)- negative and CD3-PE-positive cells, followed by gating on CD8-PE-Texas Red- positive cells; presented data is for the CD8+ gated population, in all cases, negative gate quadrants were established on no-stain controls.
  • Figure 5 is series of images depicting the results of experiments evaluating clinical responses after infusion of CART1 cells
  • Figure 5A depicts that UPN 02 was treated with two cycles of rituximab and bendamustine with minimal response (R/B, arrow), CART19 T cells were infused beginning 4 days after bendamustine only (B, arrow).
  • the rituximab and bendamustine-resistant leukemia was rapidly cleared from blood, as indicated by a decrease in the absolute lymphocyte count (ALC) from 60,600/ul to 200/ ⁇ within 18 days of the infusion. Corticosteroid treatment was started on day 18 post infusion due to malaise and non-infectious febrile syndrome.
  • ALC absolute lymphocyte count
  • FIG. 5B depicts the results of example experiments staining sequential bone marrow biopsy or clot specimens from patient UPN 01 and 03 for CD20. Pretreatment infiltration with leukemia present in both patients was absent on post treatment specimens accompanied by normalization of cellufarity and trilineage hematopoiesis.
  • UPN 01 has not had any CLL cells detected as assessed by flow cytometry, cytogenetics and fluorescence in-situ hybridization or normal B cells detected by flow cytometry in bone marrow or blood, UPN 03 had 5% residual normal CD5-negative B cells confirmed by flow cytometry on day +23, which also showed them to be polyclonal; no normal B cells were detected at day +176.
  • FIG. 5C depicts the results of experiments using sequential CT imaging to assess the rapid resolution of chemotherapy-resistant generalized lymphadenopathy.
  • Figure 6 is a series of images depicting absolute lymphocyte counts and total CART19+ cells in circulation for UPN 01, 02, 03.
  • Total CART19+ cells in circulation is plotted for all 3 subjects using the absolute lymphocyte count from CBC values, and assuming a 5.0 L volume of blood,
  • the total number of CART! 9 cells in circulation was calculated by using the tandem CBC values with absolute lymphocyte counts and the Q-PCR marking values as depicted in Figure 2, converting copies/ng DNA to average % marking as described elsewhere herein.
  • the Q-PCR % marking was found to correlate closely ( ⁇ 2 fold variation) with the flow cytometric characterization of the infusion products and with data from samples where concomitant flow cytometry data was available to directly enumerate CART19 cells by staining,
  • Figure 7, comprising Figures ' 7A through 7D is a series of images depicting experiments involving the direct ex vivo detection of CART1 -positive cells in UPN-01 PBMC 71 days post-T cell infusion
  • UPN-01 PBMC collected either fresh post-apheresis on day71 day post infusion, or frozen at the time of apheresis for manufacture of the T cell prodiict(baseiine) and viably thawed prior to the staining, were subjected to fiow-cytometric analysis to detect the presence ofCART19 cells that express the CAR 19 moiety on the surface.
  • fiow-cytometric analysis to detect the presence ofCART19 cells that express the CAR 19 moiety on the surface.
  • samples were co-stained with CD3-PE and the anti-CAR I 9 idiotype antibody conjugated to Alexa-647, or co-stained with CD3-PE alone (FMO for
  • Figure 7A depicts that an initial lymphocyte gate was established based on forward and side scatter (FSC vs SSC), followed by gating on CD3+ ceils.
  • Figure 7B depicts CD3+ lymphocyte gate;
  • Figure 7C depicts CAR idiotype stain;
  • Figure 7D depicts CAR idiotype FMO.
  • the CAR19-positive gate was established on the CAR19 FMO samples,
  • Figure 8 is a series of images depicting the gating strategy to identify CART19 expression by using polychromatic flow cytometry in UPN 03 blood specimens.
  • the gating strategy for Figure 8C is shown for the UPN 03 Day 56 sample and is representative of the strategy used on the UPN 03 Day 169 sample, Figure 8A depicts primary gate: Dump (CD 14, CD 16,
  • Figure 8B depicts secondary gates: CD4- positive, CD8positive.
  • Figure 8C depicts tertiary gates: CAR19-positive and CAR19- negative, established on CAR FMO samples (right-most panels).
  • Figure 9 depicts the gating strategy to directly identify CART 1 expression and B cells in blood and marrow specimens
  • the gating strategy for Figure 4A which shows detection of CAR-expressing CD3+ lymphocytes and absence of B cells in periphery and marrow: Leftplot: Cell gate; Upper panel: positive gate for CD3+ cells, Lower panel: negative gate (CD 14-negative, CD3-negative) for B cells, NC365, peripheral blood control cells from a healthy donor
  • Figure 10 is an image summarizing the patient demographics and response.
  • Figure 1 1 depicts the manufacturing process of CART-19 cells Figure 12, comprising Figures 12A through 12D ⁇ is a series of images depicting the clinical response in a patient.
  • Figure 32A shows the lentivirai vector used to infect T ceils from the patient.
  • a pseudotyped, clinical-grade lentiviral vector of vesicular stomatitis virus protein G (pELPs ! 9-BB-z) directing expression of anti- CD] 9 scFv derived from FMC63 murine monoclonal antibody, human CD8a hinge and transmembrane domain, and human 4-1BB and CD3 ⁇ signaling domains was produced, Details of the CAR19 transgene, at the bottom of Figure 12A, show the major functional elements. The figure is not to scale.
  • 3'LTR denotes 3' long terminal repeat; 5'LTR, 5' long terminal repeat; Amp R, ampiciilin resistance gene; Bovine GH Poly A, bovine growth hormone with polyadenylation tail; cPPT/CTS, central polypurine tract with central termination sequence; EF- l ct, elongation factor 1 -alpha; env, envelope; gag, grou -specific antigen; pol, HIV gene encoding polymerase and reverse transcriptase; R, repeat; RRE, rev response element; scFv, single-chain variable fragment; TM, transmembrane; and WPRE, woodchuck hepatitis virus post- transcriptional regulatory element.
  • Figure 12B shows serum creatinine, uric acid, and lactate dehydrogenase (LDH) levels from day 1 to day 28 after the first CART19-cell infusion. The peak levels coincided with hospitalization for the tumor lysis syndrome.
  • Figure 12C shows bone marrow-biopsy specimens obtained 3 days after
  • the baseline specimen shows hyperceliular bone marrow (60%) with trilineage hematopoiesis, infiltrated by predominantly interstitial aggregates of small, mature lymphocytes that account for 40% of total eel hilarity.
  • the specimen obtained on day 23 shows residual lymphoid aggregates ( 10%) that were negative for chronic lymphoid leukemia (CLL), with a mixture of T cells and CD5-negative B cells.
  • CLL chronic lymphoid leukemia
  • the specimen obtained 6 months after infusion shows trilineage hematopoiesis, without lymphoid aggregates and continued absence of CLL.
  • Figure 12D shows contrast-enhanced CT scans obtained before the patient was enrolied in the study and 31 days and 104 days after the first infusion.
  • the preinfusion CT scan reveals l -to-3-cm bilateral masses. Regression of axillary lymphadenopathy occurred within 1 month after infusion and was sustained, Arrows highlight various enlarged lymph nodes before therapy and lymph-node responses on comparable CT scans after therapy,
  • Figure 13 is a series of images depicting serum and bone marrow cytokines before and after chimeric antigen receptor T-celi infusion.
  • Serial measurements of the cytokine interferon-y Figure I 3A
  • the interfei n-y-stimulated chemokines C-X-C motif chemokine 10 Figure 13B
  • CX-C motif !igand 9 Figure 13C
  • interleukin-6 Figure 13D
  • interferon- ⁇ 1 1.2 to 23,972 pg per milliliter (1.4 pg per milliliter); CXCL10, 2, 1 to 53 19 pg per milliliter (274 pg per milliliter); CXCL9, 48,2 to 3700 pg per milliliter ( 177 pg per milliliter); interleukin-6, 2.7 to 4572 pg per milliliter (8,3 pg per milliliter); tumor necrosis factor a (TNF-a), 1 ,9 to 4005 pg per milliliter (not detectable); and soluble interleukin-2 receptor, 13,4 to 34,210 pg per milliliter (644 pg per milliliter).
  • TNF-a tumor necrosis factor a
  • Figure 13E shows the induction of the immune response in bone marrow.
  • the cytokines TNF-a, interleukin-6, interferon- ⁇ , chemokine CXCL9, and soluble interleukin-2 receptor were measured in supernatant fluids obtained from bone marrow aspirates on the indicated days before and after CART19-cel! infusion, The increases in levels of interleukin-6, interferon- ⁇ , CXCL9, and soluble interleukin-2 receptor coincided with the tumor lysis syndrome, peak chimeric antigen receptor T- cel! infiltration, and eradication of the leukemic infiltrate,
  • Figure 14 is a series of images depicting expansion and persistence of chimeric antigen receptor T cells in vivo.
  • Genomic DNA gDNA was isolated from samples of the patient's whole blood ( Figure 14 A) and bone marrow aspirates ( Figure 14B) collected at serial time points before and after chimeric antigen receptor T-celi infusion and used for quantitative real-time polymerase-chain-reaction (PCR) analysis.
  • PCR quantitative real-time polymerase-chain-reaction
  • Peak levels of chimeric antigen receptor T cells were temporally correlated with the tumor lysis syndrome, A blood sample obtained on day 0 and a bone marrow sample obtained on day 1 had no PCR signal at baseline, Flow-cytometric analysis of bone marrow aspirates at baseline (Figure 14C) shows predominant infiltration with CD 19+CD5+ cells that were clonal, as assessed by means of immunoglobulin kappa light-chain staining, with a paucity of T cells. On day 3 1 after infusion, CD5+ T cells were present, and no normal or malignant B cells were detected. The numbers indicate the relative frequency of cells in each quadrant. Both the x axis and the y axis show a log 10 scale.
  • the gating strategy involved an initial gating on CD 1.9+ and CD5+ cells in the boxes on the left, and the subsequent identification of immunoglobulin kappa and lambda expression on the CD 19+CD5+ subset (boxes on the right)
  • the invention relates to compositions and methods for treating cancer including but not limited to hematologic malignancies and solid tumors.
  • the present invention relates to a strategy of adoptive cell transfer of T cells transduced to express a chimeric antigen receptor (CAR).
  • CARs are molecules that combine antibody- based specificity for a desired antigen (e.g., tumor antigen) with a T cell receptor- activating intracellular domain to generate a chimeric protein that exhibits a specific anti-tumor cellular immune activity,
  • the present invention relates generally to the use of T cells genetically modified to stably express a desired CAR.
  • T cells expressing a CAR are referred to herein as CAR T cells or CAR modified T cells.
  • the cell can be genetically modified to stably express an antibody binding domain on its surface, conferring novel antigen specificity that is MHC independent.
  • the T cell is genetically modified to stably express a CAR that combines an antigen recognition domain of a specific antibody with an intracellular domain of the CD3- zeta chain or FcyRI protein into a single chimeric protein.
  • the CAR of the invention comprises an extracellular domain having an antigen recognition domain, a transmembrane domain, and a cytoplasmic domain.
  • the transmembrane domain that naturally is associated with one of the domains in the CAR is used.
  • the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins to minimize interactions with other members of the receptor complex.
  • the transmembrane domain is the CD8 hinge domain.
  • the CAR of the invention can be designed to comprise the CD28 and/or 4- I BB signaling domain by itself or be combined with any other desired cytoplasmic domain(s) useful in the context of the CAR of the invention.
  • the cytoplasmic domain of the CAR can be designed to further comprise the signaling domain of CD3-zeta.
  • the cytoplasmic domain of the CAR can include but is not limited to CD3-zeta, 4- IBB and CD28 signaling modules and combinations thereof. Accordingly, the invention provides CAR T cells and methods of their use for adoptive therapy.
  • the CAR T ceils of the invention can be generated by introducing a lentiviral vector comprising a desired CAR, for example a CAR comprising anti-CD19, CD8a hinge and transmembrane domain, and human 4- 1BB and CD3zeta signaling domains, into the ceils.
  • a desired CAR for example a CAR comprising anti-CD19, CD8a hinge and transmembrane domain, and human 4- 1BB and CD3zeta signaling domains.
  • the CAR T cells of the invention are able to replicate in vivo resulting in long-term persistence that can lead to sustained tumor control.
  • the invention relates to administering a genetically modified T cell expressing a CAR for the treatment of a patient having cancer or at risk of having cancer using lymphocyte infusion.
  • lymphocyte infusion is used in the treatment.
  • Autologous lymphocyte infusion is used in the treatment.
  • Autologous PBMCs are collected from a patient in need of treatment and T cells are activated and expanded using the methods described herein and known in the art and then infused back into the patient.
  • the invention relates generally to the treatment of a patient at risk of developing CLL.
  • the invention also includes treating a malignancy or an autoimmune disease in which chemotherapy and/or
  • the invention includes using T cells expressing an anti-CD19 CAR including both CD3-zeta and the 4-1 BB costinnilatoiy domain (also referred to as CART19 T cells).
  • the CART 19 T cells of the invention can undergo robust in vivo T cell expansion and can establish CD 19-specific memory cells that persist at high levels for an extended amount of time in blood and bone marrow,
  • the CART19 T cells of the invention infused into a patient can eliminate leukemia cells in vivo in patients with advanced chemotherapy-resistant CLL.
  • the invention is not limited to CART19 T cells, Rather, the invention includes any antigen binding moiety fused with one or more intracellular domains selected from the group of a CD I 37 (4-1BB) signaling domain, a CD28 signaling domain, a CD3zeta signal domain, and any combination thereof.
  • a CD I 37 (4-1BB) signaling domain selected from the group of a CD I 37 (4-1BB) signaling domain, a CD28 signaling domain, a CD3zeta signal domain, and any combination thereof.
  • an element means one element or more than one element
  • Activation refers to the state of a T cell that has been sufficiently stimulated to induce detectable cellular proliferation. Activation can also be associated with induced cytokine production, and detectable effector functions.
  • the term “activated T cells” refers to, among other things, T cells that are undergoing cell division.
  • antibody refers to an immunoglobulin molecule which specifically binds with an antigen.
  • Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources and can be immunoreactive portions of intact immunoglobulins. Antibodies are typically tetramers of immunoglobulin molecules.
  • the antibodies in the present invention may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab and F(ab)2, as well as single chain antibodies and humanized antibodies (Harlow et al,, 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, in: Antibodies: A
  • antibody fragment refers to a portion of an intact antibody and refers to the antigenic determining variable regions of an intact antibody.
  • antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, scFv antibodies, and muitispecific antibodies formed from antibody fragments.
  • an “antibody heavy chain,” as used herein, refers to the larger of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations,
  • antibody light chain refers to the smaller of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations, ⁇ and ⁇ light chains refer to the two major antibody light chain isotypes.
  • synthetic antibody an antibody which is generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage as described herein.
  • the term should also be construed to mean an antibody which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology which is available and well known in the art.
  • antigen or "Ag” as used herein is defined as a molecule that provokes an immune response, This immune response may involve either antibody production, or the activation of specific immunoiogicaily-competent cells, or both.
  • antigens can be derived from recombinant or genomic DNA.
  • any DNA which comprises a nucleotide sequences or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encodes an "antigen" as that term is used herein.
  • an antigen need not be encoded solely by a full length nucleotide sequence of a gene. It is readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to elicit the desired immune response. Moreover, a skilled artisan will understand that an antigen need not be encoded by a "gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a biological fluid.
  • anti-tumor effect refers to a biological effect which can be manifested by a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in the number of metastases, an increase in life expectancy, or amelioration of various physiological symptoms associated with the cancerous condition.
  • An "anti-tumor effect” can also be manifested by the ability of the peptides, polynucleotides, cells and antibodies of the invention in prevention of the occurrence of tumor in the first place.
  • auto-antigen means, in accordance with the present invention, any self-antigen which is mistakenly recognized by the immune system as being foreign.
  • Auto-antigens comprise, but are not limited to, cellular proteins, phosphoproteins, cellular surface proteins, cellular lipids, nucleic acids, glycoproteins, including cell surface receptors.
  • autoimmune disease as used herein is defined as a disorder that results from an autoimmune response.
  • An autoimmune disease is the result of an inappropriate and excessive response to a self-antigen.
  • autoimmune diseases include but are not limited to, Addision's disease, alopecia greata, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, Crohn's disease, diabetes (Type 1), dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barr syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, psoriasis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, thyroid
  • autologous is meant to refer to any material derived from the same individual to which it is later to be re-introduced into the individual.
  • Allogeneic refers to a graft derived from a different animal of the same species
  • Xenogeneic refers to a graft derived from an animal of a different species.
  • cancer as used herein is defined as disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body, Examples of various cancers include but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer and the like.
  • Co-stimulatory ligand includes a molecule on an antigen presenting cell (e.g., an aAPC, dendritic cell, B cell, and the like) that specifically binds a cognate co-stimulatory molecule on a T cell, thereby providing a signal which, in addition to the primary signal provided by, for instance, binding of a TCR/CD3 complex with an MHC molecule loaded with peptide, mediates a T DCi response, including, but not limited to, proliferation, activation, differentiation, and the like.
  • an antigen presenting cell e.g., an aAPC, dendritic cell, B cell, and the like
  • a co-stimulatory ligand can include, but is not iimited to, CD7, B7-1 (CD80), B7-2 (CD86), PD-L 1 , PD-L2, 4-1BBL, OX40L, inducible costiinulatory ligand (ICOS-L), intercellular adhesion molecule (rCAM), CD30L, CD40, CD70, CD83, HLA-G, MICA, MICB, HVEM, lymphotoxin beta receptor,
  • an antibody that specifically binds with a co-stimulatory molecule present on a T cell such as, but not limited to, CD27, CD28, 4- IBB, OX40, CD30, CD40, PD-1, 1COS, lymphocyte function-associated antigen- 1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83.
  • a co-stimulatory molecule present on a T cell such as, but not limited to, CD27, CD28, 4- IBB, OX40, CD30, CD40, PD-1, 1COS, lymphocyte function-associated antigen- 1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83.
  • a "co-stimulatory molecule” refers to the cognate binding partner on a T cell that specifically binds with a co-stimulatory Hgand, thereby mediating a co- stimulatory response by the T cell, such as, but not limited to, proliferation, Co- stimulatory molecules include, but are not Iimited to an MHC class I molecule, BTLA and a Toll ligand receptor.
  • a “co-stimulatory signal”, as used herein, refers to a signal, which in combination with a primary signal, such as TCR/CD3 ligation, leads to T cell proliferation and/or upregulation or downregulation of key molecules,
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.
  • an “effective amount” as used herein means an amount which provides a therapeutic or prophylactic benefit.
  • Encoding refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom, Thus, a gene encodes a protein if transcription and translation of mRNA
  • Both the coding strand the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.
  • endogenous refers to any material from or produced inside an organism, cell, tissue or system.
  • exogenous refers to any material introduced from or produced outside an organism, cell, tissue or system.
  • expression is defined as the transcription and/or translation of a particular nucleotide sequence driven by its promoter.
  • “Expression vector” refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed.
  • An expression vector comprises sufficient cis- acting elements for expression; other elements for expression can be supplied by the host eel! or in an in vitro expression system.
  • Expression vectors include all those known in the ait, such as cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g. , lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide,
  • “Homologous” refers to the sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. When a position in both of the two compared sequences is occupied by the same base or amino acid monomer subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous at that position, The percent of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared X 100. For example, if 6 of 10 of the positions in two sequences are matched or homologous then the two sequences are 60% homologous. By way of example, the DNA sequences ATTGCC and TATGGC share 50% homology. Generally, a comparison is made when two sequences are aligned to give maximum homology,
  • immunoglobulin or "Ig,” as used herein is defined as a class of proteins, which function as antibodies, Antibodies expressed by B cells are sometimes referred to as the BCR (B cell receptor) or antigen receptor.
  • BCR B cell receptor
  • the Five members included in this class of proteins are IgA, IgG, IgM, IgD, and IgE.
  • IgA is the primary antibody that is present in body secretions, such as saliva, tears, breast milk, gastrointestinal secretions and mucus secretions of the respiratory and genitourinary tracts.
  • IgG is the most common circulating antibody.
  • IgM is the main immunoglobulin produced in the primary immune response in most subjects, It is the most efficient immunoglobulin in agglutination, complement fixation, and other antibody responses, and is important in defense against bacteria and viruses.
  • IgD is the immunoglobulin that has no known antibody function, but may serve as an antigen receptor.
  • IgE is the immunoglobulin that mediates immediate hypersensitivity by causing release of mediators from mast cells and basophils upon exposure to allergen.
  • an "instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the compositions and methods of the invention.
  • the instructional material of the kit of the invention may, for example, be affixed to a container which contains the nucleic acid, peptide, and/or composition of the invention or be shipped together with a container which contains the nucleic acid, peptide, and/or composition.
  • the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
  • isolated means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not
  • isolated but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated.”
  • An isolated nucleic acid or protein can exist in substantially purified form, or can exist i a non-native environment such as, for example, a host cell.
  • the following abbreviations for the commonly occurring nucleic acid bases are used. "A” refers to adenosine, “C” refers to cytosme, “G” refers to guanosine, “T” refers to thymidine, and “U” refers to uridine.
  • nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence.
  • the phrase nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s).
  • a "lentivirus” as used herein refers to a genus of the Retroviridae family. Lentiviruses are unique among the retroviruses in being able to infect non- dividing cells; they can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, S1V, and FIV are all examples of lentiviruses. Vectors derived from lentiviruses offer the means to achieve significant levels of gene transfer in vivo.
  • moduleating mediating a detectable increase or decrease in the level of a response in a subject compared with the level of a response in the subject in the absence of a treatment or compound, and/or compared with the level of a response in an otherwise identical but untreated subject.
  • the term encompasses perturbing and/or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, preferably, a human.
  • nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. Nucleotide sequences that encode proteins and RNA may include introns.
  • operbiy linked refers to functional linkage between a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter.
  • a first nucleic acid sequence is operabiy linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence.
  • a promoter is operabiy linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence.
  • operabiy linked DNA sequences are contiguous and, where necessary to join two protein coding regions, in the same reading frame.
  • tumor antigen or overexpression of the tumor antigen is intended to indicate an abnormal level of expression of the tumor antigen in a cell from a disease area like a solid tumor within a specific tissue or organ of the patient relative to the level of expression in a normal cell from that tissue or organ.
  • Patients having solid tumors or a hematological malignancy characterized by overexpression of the tumor antigen can be determined by standard assays known in the art,
  • parenteral administration of an immunogenic composition includes, e.g., subcutaneous (s.c), intravenous (i.v.), intramuscular (i.m.) > or intrastemal injection, or infusion techniques.
  • patient refers to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
  • the patient, subject or individual is a human.
  • nucleic acid as used herein is defined as a chain of nucleotides.
  • nucleic acids are polymers of nucleotides.
  • nucleic acids and polynucleotides as used herein are interchangeable.
  • nucleic acids are polynucleotides, which can be hydrolyzed into the monomelic "nucleotides.”
  • the monomeric nucleotides can be hydrolyzed into nucleosides.
  • polynucleotides include, but are not limited to, all nucleic acid sequences which are obtained by any means available in the ait, including, without limitation, recombinant means, i.e., the cloning of nucleic acid sequences from a recombinant library or a cell genome, using ordinary cloning technology and PCRTM, and the like, and by synthetic means.
  • recombinant means i.e., the cloning of nucleic acid sequences from a recombinant library or a cell genome, using ordinary cloning technology and PCRTM, and the like, and by synthetic means.
  • peptide As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds.
  • a protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein's or peptide's sequence.
  • Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds, As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types, "Polypeptides" include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.
  • promoter as used herein is defined as a DNA sequence recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence.
  • promoter/regulatory sequence means a nucleic acid sequence which is required for expression of a gene product operably linked to the promoter/reg latory sequence.
  • this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product.
  • the promoter/reg latory sequence may, for example, be one which expresses the gene product in a tissue specific manner.
  • a “constitutive" promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell under most or all physiological conditions of the cell.
  • an “inducible” promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell substantially only when an inducer which corresponds to the promoter is present in the cell,
  • tissue-specific promoter is a nucleotide sequence which, when operably linked with a polynucleotide encodes or specified by a gene, causes the gene product to be produced in a ceil substantially only if the ceil is a cell of the tissue type corresponding to the promoter.
  • an antibody which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample.
  • an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more species, but, such cross-species reactivity does not itself alter the classification of an antibody as specific, in another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen, However, such cross reactivity does not itself alter the classification of an antibody as specific.
  • the terms “specific binding” or “specifically binding,” can be used in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope "A”, the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled "A” and the antibody, will reduce the amount of labeled A bound to the antibody,
  • stimulation is meant a primary response induced by binding of a stimulatory molecule (e.g., a TCR/CD3 complex) with its cognate ligand thereby mediating a signal transduction event, such as, but not limited to, signal transduction via the TCR/CD3 complex, Stimulation can mediate altered expression of certain molecules, such as downregulation ofTGF- ⁇ , and/or reorganization of cytoskeletal structures, and the like.
  • a stimulatory molecule e.g., a TCR/CD3 complex
  • signal transduction event such as, but not limited to, signal transduction via the TCR/CD3 complex
  • Stimulation can mediate altered expression of certain molecules, such as downregulation ofTGF- ⁇ , and/or reorganization of cytoskeletal structures, and the like.
  • a "stimulatory molecule,” as the term is used herein, means a molecule on a T cell that specifically binds with a cognate stimulatory ligand present on an antigen presenting cell.
  • a “stimulatory ligand,” as used herein, means a ligand that when present on an antigen presenting cell (e.g., an aAPC, a dendritic cell, a B-cell, and the like) can specifically bind with a cognate binding partner (referred to herein as a "stimulatory molecule") on a T cell, thereby mediating a primary response by the T cell, including, but not limited to, activation, initiation of an immune response, proliferation, and the like.
  • an antigen presenting cell e.g., an aAPC, a dendritic cell, a B-cell, and the like
  • a cognate binding partner referred to herein as a "stimulatory molecule”
  • Stimulatory ligands are well-known in the art and encompass, inter alia, an MHC Class I molecule loaded with a peptide, an anti-CD3 antibody, a superagonist anti-CD28 antibody, and a superagonist anti-CD2 antibody.
  • subject is intended to include living organisms in which an immune response can be elicited ⁇ e.g., mammals), Examples of subjects include humans, dogs, cats, mice, rats, and transgenic species thereof.
  • substantially purified cell is a cell that is essentially free of other cell types.
  • a substantially purified ceil also refers to a cell which has been separated from other cell types with which it is normally associated in its naturally occurring state.
  • a population of substantially purified cells refers to a homogenous population of cells. In other instances, this term refers simply to cell that have been separated from the cells with which they are naturally associated in their natural state, in some embodiments, the cells are cultured in vitro. In other embodiments, the cells are not cultured in vitro.
  • terapéutica as used herein means a treatment and/or prophylaxis.
  • a therapeutic effect is obtained by suppression, remission, or eradication of a disease state.
  • therapeutically effective amount refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, or subject that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the signs or symptoms of the disorder or disease being treated.
  • the therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc, of the subject to be treated.
  • a disease as the term Is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject.
  • transfected or “transformed” or “transduced” as used herein refers to a process by which exogenous nucleic acid is transferred or introduced into the host cell.
  • a “transfected” or “transformed” or “transduced” cell is one which has been transfected, transformed or transduced with exogenous nucleic acid.
  • the cell includes the primary subject cell and its progeny.
  • under transcriptional control or "operatively linked” as used herein means that the promoter is in the correct location and orientation in relation to a polynucleotide to control the initiation of transcription by RNA polymerase and expression of the polynucleotide.
  • a “vector” is a composition of matter which comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell.
  • vectors are known in the art including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses.
  • the term “vector” includes an autonomously replicating plasmid or a virus.
  • the term should also be construed to include non-plasmid and non-viral compounds which facilitate transfer of nucleic acid into cells, such as, for example, polylysine compounds, liposomes, and the like.
  • viral vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, and the like.
  • ranges throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1 , 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. Description
  • the present invention provides compositions and methods for treating cancer among other diseases.
  • the cancer may be a hematological malignancy, a solid tumor, a primary or a metatastizing tumor.
  • the cancer is a hematological malignancy, and more preferably, the cancer is Chronic Lymphocytic Leukemia (CLL).
  • CLL Chronic Lymphocytic Leukemia
  • Other diseases treatable using the compositions and methods of the invention include viral, bacterial and parasitic infections as well as autoimmune diseases.
  • the invention provides a cell (e.g., T cell) engineered to express a CAR wherein the CAR T cell exhibits an antitumor property.
  • the CAR of the invention can be engineered to comprise an extracellular domain having an antigen binding domain fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (e.g., CD3 zeta).
  • the CAR of the invention when expressed in a T cell is able to redirect antigen recognition based on the antigen binding specificity.
  • An exemplary antigen is CD19 because this antigen is expressed on malignant B cells.
  • the invention is not limited to targeting CD 1 , Rather, the invention includes any antigen binding moiety that when bound to its cognate antigen, affects a tumor cell so that the tumor cell fails to grow, is prompted to die, or otherwise is affected so that the tumor burden in a patient is diminished or eliminated,
  • the antigen binding moiety is preferably fused with an intracellular domain from one or more of a costimulatory molecule and a zeta chain.
  • the antigen binding moiety is fused with one or more intracellular domains selected from the group of a CD! 37 (4-1 BB) signaling domain, a CD28 signaling domain, a CD3zeta signal domain, and any combination thereof.
  • the CAR of the invention comprises a CD 137 (4- I BB) signaling domain.
  • CD137 (4- I BB) signaling domain is partly based on the discovery that CAR-mediated T-cell responses can be further enhanced with the addition of costimulatory domains.
  • inclusion of the CD137 (4- 1BB) signaling domain significantly increased anti-tumor activity and in vivo persistence of CAR T cells compared to an otherwise identical CAR T cell not engineered to express CD137 (4-1BB).
  • the present invention provides chimeric antigen receptor (CAR) comprising an extracellular and intracellular domain.
  • the extracellular domain comprises a target-specific binding element otherwise referred to as an antigen binding moiety.
  • the intracellular domain or otherwise the cytoplasmic domain comprises, a costimulatory signaling region and a zeta chain portion.
  • the costimulatory signaling region refers to a portion of the CAR comprising the intracellular domain of a costimulatory molecule.
  • Costimulatory molecules are cell surface molecules other than antigens receptors or their ligands that are required for an efficient response of lymphocytes to antigen.
  • spacer domain generally means any oligo- or polypeptide that functions to link the transmembrane domain to, either the extracellular domain or, the cytoplasmic domain in the polypeptide chain, A spacer domain may comprise up to 300 amino acids, preferably 10 to 100 amino acids and most preferably 25 to 50 amino acids.
  • Antigen binding moiety generally means any oligo- or polypeptide that functions to link the transmembrane domain to, either the extracellular domain or, the cytoplasmic domain in the polypeptide chain.
  • a spacer domain may comprise up to 300 amino acids, preferably 10 to 100 amino acids and most preferably 25 to 50 amino acids.
  • the CAR of the invention comprises a target- specific binding element otherwise referred to as an antigen binding moiety.
  • the choice of moiety depends upon the type and number of ligands that define the surface of a target cell.
  • the antigen binding domain may be chosen to recognize a ligand that acts as a cell surface marker on target cells associated with a particular disease state.
  • celi surface markers that may act as ligands for the antigen moiety domain in the CAR of the invention include those associated with viral, bacterial and parasitic infections, autoimmune disease and cancer cells,
  • the CAR of the invention can be engineered to target a tumor antigen of interest by way of engineering a desired antigen binding moiety that specifically binds to an antigen on a tumor cell.
  • tumor antigen or “hyperporoliferative disorder antigen” or “antigen associated with a hyperproliferative disorder” refers to antigens that are common to specific hyperproliferative disorders such as cancer.
  • the antigens discussed herein are merely included by way of example. The list is not intended to be exclusive and further examples will be readily apparent to those of skill in the art.
  • Tumor antigens are proteins that are produced by tumor cells that elicit an immune response, particularly T-cell mediated immune responses.
  • the selection of the antigen binding moiety of the invention will depend on the particular type of cancer to be treated, Tumor antigens are well known in the art and include, for example, a glioma-associated antigen, carcinoembryonic antigen (CEA), ⁇ -human chorionic gonadotropin, alphafetoprotein (AFP), lectin-reactive AFP, thyroglobulm, RAGE-1 , MN-CA IX, human telomerase reverse transcriptase, RU1 , RU2 (AS), intestinal carboxyi esterase, mut hsp70-2, M-CSF, prostase, prostate-specific antigen (PSA), PAP, NY-ESO- 1 , LAGE-la, p53, prostein, PSMA, Her2/neu, survivin and telomerase, prostate-carcinoma tumor antigen-
  • the tumor antigen comprises one or more antigenic cancer epitopes associated with a malignant tumor.
  • Malignant tumors express a number of proteins that can serve as target antigens for an immune attack. These molecules include but are not limited to tissue-specific antigens such as MART-1 , tyrosinase and GP 100 in melanoma and prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) in prostate cancer.
  • Other target molecules belong to the group of transformation-related molecules such as the oncogene HER- 2/Neu ErbB-2.
  • Yet another group of target antigens are onco-fetal antigens such as carcinoembryonic antigen (CEA).
  • B-cell lymphoma the tumor-specific idiotype immunoglobulin constitutes a truly tumor-specific immunoglobulin antigen that is unique to the individual tumor.
  • B-cell differentiation antigens such as CD I 9, CD20 and CD37 are other candidates for target antigens in B-cell lyjnphoma. Some of these antigens (CEA, HER-2, CD19, CD20, idiotype) have been used as targets for passive immunotherapy with monoclonal antibodies with limited success.
  • the type of tumor antigen referred to in the invention may also be a tumor-specific antigen (TSA) or a tumor-associated antigen (TAA).
  • TSA tumor-specific antigen
  • TAA associated antigen is not unique to a tumor cell and instead is also expressed on a normal cell under conditions that fail to induce a state of immunologic tolerance to the antigen.
  • the expression of the antigen on the tumor may occur under conditions that enable the immune system to respond to the antigen.
  • TAAs may be antigens that are expressed on normal cells during fetal development when the immune system is immature and unable to respond or they may be antigens that are normally present at extremely low levels on normal cells but which are expressed at much higher levels on tumor cells.
  • TSA or TAA antigens include the following: Differentiation antigens such as MART-l/MelanA (MART-1), g l OO (Pmel 17), tyrosinase, TRP-1 , TRP-2 and tumor-specific multilineage antigens such as MAGE-1, MAGE-3, BAGE, GAGE- 1 , GAGE-2, pi 5; overexpressed embryonic antigens such as CEA; overexpressed oncogenes and mutated tumor-suppressor genes such as p53, Ras, HER-2/neu; unique tumor antigens resulting from chromosomal translocations; such as BCR-ABL, E2A-PRL, H4-RET, 1GH-IGK, MYL-RAR; and viral antigens, such as the Epstein Barr virus antigens EBVA and the human papillomavirus (HPV) antigens E6 and E7.
  • Differentiation antigens such as MART-l/Melan
  • the antigen binding moiety portion of the CAR targets an antigen that includes but is not limited to CD19, CD20, CD22, ROR l , Mesothelin, CD33/lL3Ra, c-Met, PSMA, Glycoiipid F77, EGFRvIII, GD-2, MY- ESO- 1 TCR, MAGE A3 TCR, and the like.
  • the CAR of the invention can be engineered to include the appropriate antigen bind moiety that is specific to the desired antigen target.
  • the desired antigen target For example, if CD19 is the desired antigen that is to be targeted, an antibody for CD 19 can be used as the antigen bind tnoiety for incorporation into the CAR of the invention.
  • the antigen binding moiety portion of the CAR of the invention targets CD 19.
  • the antigen binding moiety portion in the CAR of the invention is anti-CD 19 scFV, wherein the nucleic acid sequence of the anti-CD19 scFV comprises the sequence set forth in SEQ ID: 1 4.
  • the anti-CD 19 scFV comprise the nucleic acid sequence that encodes the amino acid sequence of SEQ ID NO: 20.
  • the anti-CD 19 scFV portion of the CAR of the invention comprises the amino acid sequence set forth in SEQ ID NO: 20.
  • the CAR can be designed to comprise a transmembrane domain that is fused to the extracellular domain of the CAR.
  • the transmembrane domain that naturally is associated with one of the domains in the CAR is used.
  • the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins to minimize interactions with other members of the receptor complex.
  • the transmembrane domain may be derived either from a natural or from a synthetic source. Where the source is natural, the domain may be derived from any membrane-bound or transmembrane protein.
  • Transmembrane regions of particular use in this invention may be derived from (i.e. comprise at least the transmembrane region(s) of) the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CDS, CD9, CD 16, CD22, CD33, CD37, CD64, CD80, CD86, CD 134, CD137, CD 154.
  • the transmembrane domain may be synthetic, in which case it will comprise predominantly hydrophobic residues such as leucine and valine.
  • a triplet of phenylalanine, tryptophan and valine will be found at each end of a synthetic transmembrane domain.
  • a short oligo- or polypeptide linker preferably between 2 and 10 amino acids in length may form the linkage between the transmembrane domain and the cytoplasmic signaling domain of the CAR.
  • a glycine-serine doublet provides a particularly suitable linker.
  • the transmembrane domain in the CAR of the invention is the CDS transmembrane domain.
  • the CD8 transmembrane domain comprises the nucleic acid sequence of SEQ ID NO: 16.
  • the CD8 transmembrane domain comprises the nucleic acid sequence that encodes the amino acid sequence of SEQ ID NO: 22, In another embodiment, the CDS transmembrane domain comprises the amino acid sequence of SEQ ID NO: 22.
  • the transmembrane domain of the CAR of the invention comprises the CD8 hinge domain
  • the CD8 hinge domain comprises the nucleic acid sequence of SEQ ID NO: 15.
  • the CD8 hinge domain comprises the nucleic acid sequence that encodes the amino acid sequence of SEQ ID NO: 21.
  • the CD8 hinge domain comprises the amino acid sequence of SEQ ID NO: 21.
  • the cytoplasmic domain or otherwise the intracellular signaling domain of the CAR of the invention is responsible for activation of at least one of the normal effector functions of the immune cell in which the CAR has been placed in.
  • effector function refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines.
  • intracellular signaling domain refers to the portion of a protein which transduces the effector function signal and directs the cell to perform a specialized function. While usually the entire intracellular signaling domain can be employed, in many cases it is not necessary to use the entire chain.
  • intracellular signaling domain is thus meant to include any truncated portion of the intracellular signaling domain sufficient to transduce the effector function signal.
  • intracellular signaling domains for use in the CAR of the invention include the cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivative or variant of these sequences and any synthetic sequence that has the same functional capability.
  • T cell activation can be said to be mediated by two distinct classes of cytoplasmic signaling sequence: those that initiate antigen- dependent primary activation through the TCR (primary cytoplasmic signaling sequences) and those that act in an antigen-independent manner to provide a secondary or co-stimulatory signal (secondary cytoplasmic signaling sequences).
  • Primary cytoplasmic signaling sequences regulate primary activation of the TCR complex either in a stimulatory way, or in an inhibitory way.
  • Primary cytoplasmic signaling sequences that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or ITAMs.
  • Examples of 1TAM containing primary cytoplasmic signaling sequences that are of particular use in the invention include those derived from TCR zeta, FcR gamma, FcR beta, CD3 gamma , CD3 delta , CD3 epsilon, CDS, CD22, CD79a, CD79b, and CD66d. It is particularly preferred that cytoplasmic signaling molecule in the CAR of the invention comprises a cytoplasmic signaling sequence derived from CD3 zeta.
  • the cytoplasmic domain of the CAR can be designed to comprise the CD3-zeta signaling domain by itseif or combined with any other desired cytoplasmic domain(s) useful in the context of the CAR of the invention.
  • the cytoplasmic domain of the CAR can comprise a CD3 zeta chain portion and a costhnulatory signaling region.
  • the costimuiatory signaling region refers to a portion of the CAR comprising the intracellular domain of a costimuiatory molecule,
  • a costimuiatory molecule is a cell surface molecule other than an antigen receptor or their ligands that is required for an efficient response of lymphocytes to an antigen.
  • Examples of such molecules include CD27, CD28, 4- I BB (CD 137), OX40, CD30, CD40, PD- 1 , ICOS, lymphocyte function-associated antigen- 1 (LFA-1 ), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, and the like.
  • 4- 1BB as the co-stimulatory signaling element
  • other costimulatory elements are within the scope of the invention.
  • cytoplasmic signaling sequences within the cytoplasmic signaling portion of the CAR of the invention may be finked to each other in a random or specified order.
  • a short oiigo- or polypeptide linker preferably between 2 and 10 amino acids in length may form the linkage.
  • a glycine-serine doublet provides a particularly suitable linker.
  • the cytoplasmic domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD28. In another embodiment, the cytoplasmic domain is designed to comprise the signaling domain of CD3 ⁇ zeta and the signaling domain of 4- IBB, In yet another embodiment, the cytoplasmic domain is designed to comprise the signaling domain of CD3-zeta and the signaling domain of CD28 and 4-1BB.
  • the cytoplasmic domain in the CAR of the invention is designed to comprise the signaling domain of 4- I BB and the signaling domain of CD3-zeta, wherein the signaling domain of 4-1BB comprises the nucleic acid sequence set forth in SEQ TD NO: 17 and the signaling domain of CD3-zeta comprises the nucleic acid sequence set forth in SEQ ID NO; 18.
  • the cytoplasmic domain in the CAR of the invention is designed to comprise tiie signaling domain of 4- I BB and the signaling domain of CD3-zeta, wherein the signaling domain of 4- IBB comprises the nucleic acid sequence that encodes the amino acid sequence of SEQ ID NO: 23 and the signaling domain of CD3-zeta comprises the nucleic acid sequence that encodes the amino acid sequence of SEQ ID NO: 24.
  • the cytoplasmic domain in the CAR of the invention is designed to comprise the signaling domain of 4- I BB and the signaling domain of CD3-zeta, wherein the signaling domain of 4- IBB comprises the amino acid sequence set forth in SEQ ID NO: 23 and the signaling domain of CD3-zeta comprises the amino acid sequence set forth in SEQ ID NO: 24.
  • the present invention encompasses a DNA construct comprising sequences of a CAR, wherein the sequence comprises the nucleic acid sequence of an antigen binding moiety operably linked to the nucleic acid sequence of an intracellular domain.
  • An exemplary intracellular domain that can be used in the CAR of the invention includes but is not limited to the intracellular domain of CD3-zeta, CD28, 4- IBB, and the like, in some instances, the CAR can comprise any combination of CD3-zeta, CD28, 4- 1 BB, and the like.
  • the CAR of the invention comprises anti-CD 19 scFv, human CD8 hinge and transmembrane domain, and human 4- I BB and CD3zeta signaling domains.
  • the CAR of the invention comprises the nucleic acid sequence set forth in SEQ ID NO: 8.
  • the CAR of the invention comprises the nucleic acid sequence that encodes the amino acid sequence of SEQ ID NO: 12.
  • the CAR of the invention comprises the amino acid sequence set forth in SEQ ID NO: 12.
  • nucleic acid sequences coding for the desired molecules can be obtained using recombinant methods known in the art, such as, for example by screening libraries from cells expressing the gene, by deriving the gene from a vector known to include the same, or by isolating directly from cells and tissues containing the same, using standard techniques.
  • the gene of interest can be produced synthetically, rather than cloned.
  • the present invention also provides vectors in which a DNA of the present invention is inserted.
  • Vectors derived from retroviruses such as the lentivirus are suitable tools to achieve long-term gene transfer since they allow long-term, stable integration of a transgene and its propagation in daughter cells.
  • Lentiviral vectors have the added advantage over vectors derived from onco-retrovi ruses such as murine leukemia viruses in that they can transduce non-proliferating cells, such as hepatocytes. They also have the added advantage of low immunogenicity.
  • the expression of natural or synthetic nucleic acids encoding CARs is typically achieved by operably linking a nucleic acid encoding the CAR polypeptide or portions thereof to a promoter, and incorporating the construct into an expression vector.
  • the vectors can be suitable for replication and integration eukaryotes.
  • Typical cloning vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence.
  • the expression constructs of the present invention may also be used for nucleic acid immu ization and gene therapy, using standard gene delivery protocols. Methods for gene delivery are known in the art. See, e.g., U.S, Pat. Nos. 5,399,346, 5,580,859, 5,589,466, incorporated by reference herein in their entireties.
  • the invention provides a gene therapy vector,
  • the nucleic acid can be cloned into a number of types of vectors.
  • the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid.
  • Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors,
  • the expression vector may be provided to a cell in the form of a viral vector.
  • Viral vector technology is well known in the art and is described, for example, in Sambrook et al, (2001 , Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and in other virology and molecular biology manuals.
  • Viruses, which are useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno- associated viruses, herpes viruses, and lentiviruses.
  • a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endomiclease sites, and one or more selectable markers, (e.g., WO 01/96584; WO 01/29058; and U.S, Pat. No. 6,326, 193).
  • retroviruses provide a convenient platform for gene delivery systems.
  • a selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art.
  • the recombinant virus can then be isolated and delivered to ceils of the subject either in vivo or ex vivo.
  • retroviral systems are known in the art.
  • adenovirus vectors are used.
  • a number of adenovirus vectors are known in the art.
  • lentivirus vectors are used.
  • promoter elements e.g., enhancers
  • promoters regulate the frequency of transcriptional initiation.
  • these are located in the region 30-1 10 bp upstream of the start site, although a number of promoters have recently been shown to contain functional elements downstream of the start site as well.
  • the spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another, In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline.
  • tk thymidine kinase
  • a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto.
  • CMV immediate early cytomegalovirus
  • Another example of a suitable promoter is Elongation Growth Factor - 1 a (EF- 1 a).
  • constitutive promoter sequences may also be used, including, but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the hemoglobin promoter, and the creatine kinase promoter.
  • SV40 simian virus 40
  • MMTV mouse mammary tumor virus
  • HSV human immunodeficiency virus
  • LTR long terminal repeat
  • MoMuLV promoter MoMuLV promoter
  • an avian leukemia virus promoter an Epstein-Barr virus immediate early promoter
  • Rous sarcoma virus promoter as well as human gene promoters such as
  • inducible promoters are also contemplated as part of the invention.
  • the use of an inducible promoter provides a molecular switch capable of turning on expression of the polynucleotide sequence which it is operatively linked when such expression is desired, or turning off the expression when expression is not desired.
  • inducible promoters include, but are not limited to a meta!lothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter.
  • the expression vector to be introduced into a ceil can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected through viral vectors, in other aspects, the selectable marker may be carried on a separate piece of DNA and used in a co- transfection procedure. Both selectable markers and reporter genes may be flanked with appropriate regulatory sequences to enable expression in the host cells. Useful selectable markers include, for example, antibiotic-resistance genes, such as neo and the like.
  • Reporter genes are used for identifying potentially transfected cells and for evaluating the functionality of regulatoiy sequences.
  • a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and that encodes a polypeptide whose expression is manifested by some easily detectable property, e.g., enzymatic activity. Expression of the reporter gene is assayed at a suitable time after the DNA has been introduced into the recipient cells.
  • Suitable reporter genes may include genes encoding luciferase, beta-galactosidase, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or the green fluorescent protein gene (e.g., Ui-Tei et al., 2000 FEBS Letters 479: 79-82).
  • Suitable expression systems are well known and may be prepared using known techniques or obtained commercially.
  • the construct with the minimal 5' flanking region showing the highest level of expression of reporter gene is identified as the promoter.
  • Such promoter regions may be linked to a reporter gene and used to evaluate agents for the ability to mod late promoter- driven transcription.
  • the vector can be readily introduced into a host cell, e.g., mammalian, bacterial, yeast, or insect cell by any method in the art.
  • the expression vector can be transferred into a host cell by physical, chemical, or biological means.
  • Physical methods for introducing a polynucleotide into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electioporation, and the like. Methods for producing cells comprising vectors and/or exogenous nucleic acids are well-known in the art. See, for example, Sambrook et ai. (2001 , Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). A preferred method for the introduction of a polynucleotide into a host cell is calcium phosphate transfection.
  • Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors.
  • Viral vectors, and especially retroviral vectors have become the most widely used method for inserting genes into mammalian, e.g., human cells.
  • Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, and the like. See, for example, U.S. Pat, Nos. 5,350,674 and 5,585,362.
  • Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes,
  • nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes.
  • An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle).
  • an exemplary delivery vehicle is a liposome.
  • the use of lipid formulations is contemplated for the introduction of the nucleic acids into a host cell ⁇ in vitro, ex vivo or in vivo).
  • the nucleic acid may be associated with a lipid.
  • the nucleic acid associated with a lipid may be encapsulated in the aqueous interior of a liposome, interspersed within the lipid bilayer of a liposome, attached to a liposome via a linking molecule that is associated with both the liposome and the oligonucleotide, entrapped in a liposome, complexed with a liposome, dispersed in a solution containing a lipid, mixed with a lipid, combined with a lipid, contained as a suspension in a lipid, contained or complexed with a micelle, or otherwise associated with a lipid.
  • Lipid, lipid/DNA or lipid/expression vector associated compositions are not limited to any particular structure in solution.
  • Lipids are fatty substances which may be naturally occurring or synthetic lipids.
  • lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.
  • Lipids suitable for use can be obtained from commercial sources.
  • DMPC dimyristyi phosphatidylcholine
  • DCP dicetyl phosphate
  • Choi cholesterol
  • DMPG dimyristyi phosphatidylglycerol
  • Stock solutions of lipids in chloroform or chloroform/methanol can be stored at about -20°C.
  • Liposome is a generic term encompassing a variety of single and multilamellar lipid vehicles formed by the generation of enclosed lipid bilayers or aggregates. Liposomes can be characterized as having vesicular structures with a phospholipid bilayer membrane and an inner aqueous medium. Multilamellar liposomes have multiple lipid layers separated by aqueous medium. They form spontaneously when phospholipids are suspended in an excess of aqueous solution.
  • compositions that have different structures in solution than the norma! vesicular structure are also encompassed.
  • the lipids may assume a micellar structure or merely exist as nonuniform aggregates of lipid molecules.
  • lipofectamine- nucleic acid complexes are also contemplated.
  • assays include, for example, "molecular biological” assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR; "biochemical” assays, such as detecting the presence or absence of a particular peptide, e.g., by immunological means (ELlSAs and Western blots) or by assays described herein to identify agents falling within the scope of the invention.
  • T cells Prior to expansion and genetic modification of the T cells of the invention, a source of T cells is obtained from a subject.
  • T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors.
  • any number of T cell lines available in the art may be used.
  • T cells can be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan, such as FicollTM separation.
  • cells from the circulating blood of an individual are obtained by apheresis.
  • the apheresis product typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets, in one embodiment, the cells collected by apheresis may be washed to remove the plasma fraction and to place the cells in an appropriate buffer or media for subsequent processing steps.
  • the cells are washed with phosphate buffered saline (PBS).
  • the wash solution lacks calcium and may lack magnesium or may lack many if not all divalent cations. Again, surprisingly, initial activation steps in the absence of calcium lead to magnified activation.
  • a washing step may be accomplished by methods known to those in the art, such as by using a semi-automated "flow- through” centrifuge (for example, the Cobe 2991 ceil processor, the Baxter CytoMate, or the Haemonetics Cell Saver 5) according to the manufacturer's instructions.
  • a semi-automated "flow- through" centrifuge for example, the Cobe 2991 ceil processor, the Baxter CytoMate, or the Haemonetics Cell Saver 5
  • the cells may be resuspended in a variety of biocompatible buffers, such as, for example, Ca 3+ -free, Mg 2+ -free PBS, PlasmaLyte A, or other saline solution with or without buffer, Alternatively, the undesirable components of the apheresis sample may be removed and the cells directly resuspended in culture media.
  • T cells are isolated from peripheral blood lymphocytes by lysing the red blood cells and depleting the monocytes, for example, by centriftigation through a PERCOLLTM gradient or by counterflow centrifugal elutriation.
  • a specific subpopulation of T cells such as CD3 + , CD28 + , CD4 + , CD8 + , CD45RA + , and CD45RO + T cells, can be further isolated by positive or negative selection techniques.
  • T cells are isolated by incubation with anti-CD3/anti-CD28 (i.e., 3x28)-conjugated beads, such as
  • the time period is about 30 minutes. In a further embodiment, the time period ranges from 30 minutes to 36 hours or longer and all integer values there between. In a further embodiment, the time period is at least 1 , 2, 3, 4, 5, or 6 hours. In yet another preferred embodiment, the time period is 10 to 24 hours. In one preferred embodiment, the incubation time period is 24 hours. For isolation of T cells from patients with leukemia, use of longer incubation times, such as 24 hours, can increase ceil yield.
  • TIL tumor infiltrating lymphocytes
  • CD3/CD28 beads and/or by increasing or decreasing the ratio of beads to T cells can be preferentially selected for or against at culture initiation or at other time points during the process, Additionally, by increasing or decreasing the ratio of anti-CD3 and/or anti-CD28 antibodies on the beads or other surface, subpopulations of T cells can be preferentially selected for or against at culture initiation or at other desired time points.
  • multiple rounds of selection can also be used in the context of this invention. In certain embodiments, it may be desirable to perform the selection procedure and use the "unseiected" cells in the activation and expansion process. "Unseiected" cells can also be subjected to further rounds of selection.
  • Enrichment of a T cell population by negative selection can be accomplished with a combination of antibodies directed to surface markers unique to the negativeiy selected cells.
  • One method is cell sorting and/or selection via negative magnetic immunoadherence or flow cytometry that uses a cocktail of monoclonal antibodies directed to cell surface markers present on the cells negatively selected.
  • a monoclonal antibody cocktail typically includes antibodies to CD 14, CD20, CD1 l b, CD 16, HLA-DR, and CD8,
  • it may be desirable to enrich for or positively select for regulatory T cells which typically express CD4 + S CD25 + , CD62L 1 ", GITR + , and FoxP3 + .
  • T regulatory cells are depleted by anti-C25 conjugated beads or other similar method of selection.
  • the concentration of cells and surface can be varied.
  • a concentration of 2 billion cells/ml is used.
  • a concentration of 1 billion cells/ml is used.
  • greater than 100 million cells/ml is used.
  • a concentration of cells of 10, 15, 20, 25, 30, 35, 40, 45, or 50 million cells/ml is used.
  • a concentration of ceils from 75, 80, 85, 90, 95, or 100 million cells/ml is used.
  • concentrations of 125 or 150 million cells/ml can be used.
  • Using high concentrations can result in increased cell yield, cell activation, and cell expansion.
  • use of high cell concentrations allows more efficient capture of cells that may weakly express target antigens of interest, such as CD28-negative T cells, or from samples where there are many tumor ceils present ⁇ i.e., leukemic blood, tumor tissue, etc.). Such populations of cells may have therapeutic value and would be desirable to obtain.
  • using high concentration of cells allows more efficient selection of CD8 + T cells that normally have weaker CD28 expression.
  • concentrations of cells By significantly diluting the mixture of T cells and surface (e.g., particles such as beads), interactions between the particles and cells is minimized. This selects for cells that express high amounts of desired antigens to be bound to the particles, For example, CD4 + T cells express higher levels of CD28 and are more efficiently captured than CD8 + T cells in dilute concentrations.
  • the concentration of cells used is 5 X 10 6 /mi. In other embodiments, the concentration used can be from about 1 X 10 5 /ml to 1 X 10 6 /ml, and any integer value in between,
  • the cells may be incubated on a rotator for varying lengths of time at varying speeds at either 2-10°C or at room temperature.
  • T ceils for stimulation can also be frozen after a washing step.
  • the freeze and subsequent thaw step provides a more uniform product by removing granulocytes and to some extent monocytes in the cell population.
  • the cells may be suspended in a freezing solution.
  • a freezing solution many freezing solutions and parameters are known in the art and will be useful in this context, one method involves using PBS containing 20% DMSO and 8% human serum albumin, or culture media containing 10% Dextran 40 and 5% Dextrose, 20% Human Serum Albumin and 7.5% DMSO, or 31.25% Plasmaiyte-A, 3 1.25% Dextrose 5%, 0.45% NaCl, 10% Dextran 40 and 5% Dextrose, 20% Human Serum Albumin, and 7.5% DMSO or other suitable ceil freezing media containing for example, Hespan and PlasmaLyte A, the cells then are frozen to -80°C at a rate of 1° per minute and stored in the vapor phase of a liquid nitrogen storage tank. Other methods of controlled freezing may be used
  • cryopreserved cells are thawed and washed as described herein and allowed to rest for one hour at room temperature prior to activation using the methods of the present invention.
  • a blood sample or an apheresis product is taken from a generally healthy subject.
  • a blood sample or an apheresis is taken from a generally healthy subject who is at risk of developing a disease, but who has not yet developed a disease, and the cells of interest are isolated and frozen for later use.
  • the T cells may be expanded, frozen, and used at a later time.
  • samples are collected from a patient shortly after diagnosis of a particular disease as described herein but prior to any treatments.
  • the ceils are isolated from a blood sample or an apheresis from a subject prior to any number of relevant treatment modalities, including but not limited to treatment with agents such as natal izumab, efalizumab, antiviral agents,
  • immunosuppressive agents such as cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies
  • immunoablative agents such as CAMPATH, anti-CD3 antibodies, Cytoxan, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, and irradiation.
  • These drugs inhibit either the calcium dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit the p70S6 kinase that is important for growth factor induced signaling (rapamycin) (Liu et a!., Cell 66:807-815, 1991 ;
  • the cells are isolated for a patient and frozen for later use in conjunction with (e.g., before, simultaneously or following) bone marrow or stem cell transplantation, T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, or antibodies such as O T3 or CAMPATH.
  • T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, or antibodies such as O T3 or CAMPATH.
  • the cells are isolated prior to and can be frozen for later use for treatment following B-cell ablative therapy such as agents that react with CD20, e.g., Rituxan.
  • T cells are obtained from a patient directly following treatment.
  • the quality of T cells obtained may be optimal or improved for their ability to expand ex vivo.
  • these cells may be in a preferred state for enhanced eiigraftment and in vivo expansion.
  • mobilization for example, mobilization with GM-CSF
  • conditioning regimens can be used to create a condition in a subject wherein repopulation, recirculation, regeneration, and/or expansion of particular cell types is favored, especially during a defined window of time foiiowing therapy.
  • Illustrative ceil types include T cells, B ceils, dendritic ceils, and other cells of the immune system.
  • the T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 6,352,694; 6,534,055; 6,905,680;
  • the T cells of the invention are expanded by contact with a surface having attached thereto an agent that stimulates a CD3 TCR complex associated signal and a ligand that stimulates a co-stimulatory molecule on the surface of the T cells
  • T cell populations may be stimulated as described herein, such as by contact with an antt-CD3 antibody, or antigen-binding fragment thereof, or an anti-CD2 antibody immobilized on a surface, or by contact with a protein kinase C activator (e.g., bryostatin) in conjunction with a calcium ionophore,
  • a ligand that binds the accessory molecule is used for co- stimulation of an accessory molecule on the surface of the T cells.
  • a population of T cells can be contacted with an anti-CD3 antibody and an anti-CD28 antibody, under conditions appropriate for stimulating proliferation of the T cells, to stimulate proliferation of either CD4 + T cells or CD8 + T cells, an anti-CD3 antibody and an anti-CD28 antibody.
  • an anti-CD28 antibody include 9.3, B-T3, XR-CD28 (Diacione, Besancon, France) can be used as can other methods commonly known in the art (Berg et al., Transplant Proc. 30(8):3975-3977, 1998; Haanen et al., J. Exp. Med. 190(9): 13191328, 1999; Garland et al., J. Immunol Meth. 227( 1 -2):53-63, 1999).
  • the primary stimulatory signal and the co- stimulatory signal for the T cell may be provided by different protocols.
  • the agents providing each signal may be in solution or coupled to a surface. When coupled to a surface, the agents may be coupled to the same surface ⁇ i.e., in "cis” formation) or to separate surfaces ⁇ i.e., in "trans” formation), Alternatively, one agent may be coupled to a surface and the other agent in solution.
  • the agent providing the co-stimulatory signal is bound to a cell surface and the agent providing the primary activation signal is in solution or coupled to a surface. In certain embodiments, both agents can be in solution.
  • the agents may be in soluble form, and then cross-linked to a surface, such as a cell expressing Fc receptors or an antibody or other binding agent which will bind to the agents.
  • a surface such as a cell expressing Fc receptors or an antibody or other binding agent which will bind to the agents.
  • the two agents are immobilized on beads, either on the same bead, i.e., "cis," or to separate beads, i.e., "trans.”
  • the agent providing the primary activation signal is an anti-CD3 antibody or an antigen-binding fragment thereof and the agent providing the co-stimulatory signal is an anti-CD28 antibody or antigen-binding fragment thereof; and both agents are co- immobilized to the same bead in equivalent molecular amounts.
  • a 1 : 1 ratio of each antibody bound to the beads for CD4 + T cell expansion and T cell growth is used.
  • a ratio of anti CD3:CD28 antibodies bound to the beads is used such that an increase in T cell expansion is observed as compared to the expansion observed using a ratio of 1 : 1. In one particular embodiment an increase of from about 1 to about 3 fold is observed as compared to the expansion observed using a ratio of 1 : 1 , In one embodiment, the ratio of CD3:CD28 antibody bound to the beads ranges from 100: 1 to 1 : 100 and all integer values there between. In one aspect of the present invention, more anti-CD28 antibody is bound to the particles than anti-CD3 antibody, i.e., the ratio of CD3:CD28 is less than one.
  • the ratio of anti CD28 antibody to anti CD3 antibody bound to the beads is greater than 2: 1.
  • a 1 : 100 CD3;CD28 ratio of antibody bound to beads is used.
  • a 1 :75 CD3:CD28 ratio of antibody bound to beads is used.
  • a 1 :50 CD3:CD28 ratio of antibody bound to beads is used.
  • a 1 :30 CD3 :CD28 ratio of antibody bound to beads is used.
  • a 1 : 10 CD3:CD28 ratio of antibody bound to beads is used.
  • a 1 :3 CD3 :CD28 ratio of antibody bound to the beads is used.
  • a 3: 1 CD3:CD28 ratio of antibody bound to the beads is used.
  • Ratios of particles to cells from 1 :500 to 500: 1 and any integer values in between may be used to stimulate T cells or other target cells.
  • the ratio of particles to cells may depend on particle size relative to the target cell. For example, small sized beads could only bind a few cells, while larger beads could bind many,
  • the ratio of cells to particles ranges from 1 : 100 to 100: 1 and any integer values in-between and in further embodiments the ratio comprises 1 :9 to 9: 1 and any integer values in between, can also be used to stimulate T cells.
  • the ratio of anti-CD3- and anti-CD28-coupled particles to T ceils that result in T cell stimulation can vaiy as noted above, however certain preferred values include 1 : 100, 1 :50, 1 :40, 1 :30, 1 :20, 1 : 10, 1 :9, 1 :8, 1 :7, 1 :6, 1 :5, 1 :4, 1 :3, 1 :2, 1 : 1, 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1 , 9: 1 , 10: 1 , and 15: 1 with one preferred ratio being at least 1 : 1 particles per T cell. In one embodiment, a ratio of particles to cells of 1 : 1 or less is used.
  • a preferred particle: cell ratio is 1 :5.
  • the ratio of particles to cells can be varied depending on the day of stimulation.
  • the ratio of particles to cells is from 1 : 1 to 10: 1 on the first day and additional particles are added to the cells every day or every other day thereafter for up to 10 days, at final ratios of from 1 : 1 to 1 : 10 (based on cell counts on the day of addition),
  • the ratio of particles to cells is 1 : 1 on the first day of stimulation and adjusted to 1 :5 on the third and fifth days of stimulation.
  • particles are added on a daily or every other day basis to a final ratio of 1 : 1 on the first day, and 1 :5 on the third and fifth days of stimulation, In another embodiment, the ratio of particles to cells is 2: 1 on the first day of stimulation and adjusted to 1 : 10 on the third and fifth days of stimulation. Tn another embodiment, particles are added on a daily or every other day basis to a final ratio of 1 : 1 on the first day, and 1 : 10 on the third and fifth days of stimulation,
  • ratios will vary depending on particle size and on cell size and type.
  • the cells such as T cells
  • the beads and the cells are subsequently separated, and then the cells are cultured
  • the agent-coated beads and cells prior to culture, are not separated but are cultured together.
  • the beads and cells are first concentrated by application of a force, such as a magnetic force, resulting in increased ligation of cell surface markers, thereby inducing cell stimulation,
  • cell surface proteins may be ligated by allowing paramagnetic beads to which anti-CD3 and anti-CD28 are attached (3x28 beads) to contact the T cells.
  • the cells for example, 10 4 to 10 9 T cells
  • beads for example, DYNABEADS® M-450 CD3/CD28 T paramagnetic beads at a ratio of 1 : 1
  • a buffer preferably PBS (without divalent cations such as, calcium and magnesium).
  • the target cell may be very rare in the sample and comprise only 0.01 % of the sample or the entire sample (i.e., 100%) may comprise the target cell of interest.
  • any cell number is within the context of the present invention.
  • it may be desirable to significantly decrease the volume in which particles and cells are mixed together i.e., increase the concentration of cells
  • a concentration of about 2 billion cells/ml is used, In another embodiment, greater than 100 million cells/ml is used.
  • a concentration of cells of 10, 15, 20, 25, 30, 35, 40, 45, or 50 million cells/ml is used.
  • a concentration of cells from 75, 80, 85, 90, 95, or 100 million cells/ml is used, In further embodiments,
  • concentrations of 125 or 150 million cells/ml can be used. Using high concentrations can result in increased cell yield, cell activation, and cell expansion, Further, use of high cell concentrations allows more efficient capture of ceils that may weakly express target antigens of interest, such as CD28-negative T cells. Such populations of cells may have therapeutic value and would be desirable to obtain in certain embodiments. For example, using high concentration of cells allows more efficient selection of CD8+ T cells that normally have weaker CD28 expression,
  • the mixture may be cultured for several hours (about 3 hours) to about 14 days or any hourly integer value in between. In another embodiment, the mixture may be cultured for 21 days. In one embodiment of the invention the beads and the T cells are cultured together for about eight days. In another embodiment, the beads and T cells are cultured together for 2-3 days, Several cycles of stimulation may also be desired such that culture time of T cells can be 60 days or more.
  • Conditions appropriate for T ceil culture include an appropriate media (e.g., Minimal Essential Media or RPM1 Media 1640 or, X-vivo 15, (Lonza)) that may contain factors necessary for proliferation and viability, including serum (e.g., fetal bovine or human serum), interletikin-2 (IL-2), insulin, IFN- ⁇ , IL-4, IL-7, GM-CSF, IL- 10, IL- 12, IL-15, TGFp, and TNF- or any other additives for the growth of cells known to the skilled artisan.
  • serum e.g., fetal bovine or human serum
  • interletikin-2 IL-2
  • insulin IFN- ⁇
  • IL-4 interletikin-2
  • IL-7 interletikin-2
  • IL- 10 interletikin-2
  • TGFp TGFp
  • TNF- or any other additives for the growth of cells known to the skilled artisan e.g., TGFp, TNF- or any other additives for the growth of cells
  • kits for the growth of ceils include, but are not limited to, surfactant, piasmanate, and reducing agents such as N-acetyl-cysteine and 2-mercaptoethanol
  • Media can include RPMI 1640, AIM-V, DMEM, MEM, a-MEM, F-12, X-Vivo 1 5, and X-Vivo 20, Optimizer, with added amino acids, sodium pyruvate, and vitamins, either serum-free or supplemented with an appropriate amount of serum (or plasma) or a defined set of hormones, and/or an amount of cytokine(s) sufficient for the growth and expansion of T cells.
  • Antibiotics e.g., penicillin and streptomycin
  • the target cells are maintained under conditions necessary to support growth, for example, an appropriate temperature (e.g., 37° C) and atmosphere (e.g., air plus 5% C0 2 ).
  • T cells that have been exposed to varied stimulation times may exhibit different characteristics, For example, typical blood or apheresed peripheral blood mononuclear cell products have a helper T cell population (T H , CD4 + ) that is greater than the cytotoxic or suppressor T cell population (T c , CD8 + ).
  • T H , CD4 + helper T cell population
  • T c , CD8 + cytotoxic or suppressor T cell population
  • Ex vivo expansion of T cells by stimulating CD3 and CD28 receptors produces a population of T cells that prior to about days 8-9 consists predominately of T H cells, while after about days 8-9, the population of T cells comprises an increasingly greater population of T c cells. Accordingly, depending on the purpose of treatment, infusing a subject with a T cell population comprising predominately of TH cells may be advantageous.
  • an antigen-specific subset of T c cells has been isolated it may be beneficial to expand this subset to a greater degree.
  • phenotyptc markers vary significantly, but in large part, reproducibly during the course of the cell expansion process. Thus, such reproducibility enables the ability to tailor an activated T ceil product for specific purposes.
  • the present invention encompasses a cell (e.g., T cell) transduced with a lentiviral vector (LV).
  • a cell e.g., T cell
  • LV lentiviral vector
  • the LV encodes a CAR that combines an antigen recognition domain of a specific antibody with an intracellular domain of CD3 ⁇ zeta, CD28, 4-1BB, or any combinations thereof. Therefore, in some instances, the transduced T cell can elicit a CAR-mediated T-cell response.
  • the invention provides the use of a CAR to redirect the specificity of a primary T cell to a tumor antigen
  • the present invention also provides a method for stimulating a T cell-mediated immune response to a target cell population or tissue in a mammal comprising the step of administering to the mammal a T cell that expresses a CAR, wherein the CAR comprises a binding moiety that specifically interacts with a predetermined target, a zeta chain portion comprising for example the intracellular domain of human CD3zeta, and a costimulatory signaling region,
  • the present invention includes a type of cellular therapy where T cells are genetically modified to express a CAR and the CAR T cell is infused to a recipient in need thereof.
  • the infused cell is able to kill tumor cells in the recipient.
  • CAR T cells are able to replicate in vivo resulting in long-term persistence that can lead to sustained tumor control,
  • the CAR T cells of the invention can undergo robust in vivo T cell expansion and can persist for an extended amount of time.
  • the CAR T cells of the invention evolve into specific memory T cells that can be reactivated to inhibit any additional tumor formation or growth.
  • CART1 cells of the invention can undergo robust in vivo T cell expansion and persist at high levels for an extended amount of time in blood and bone marrow and form specific memory T cells.
  • CAR T ceils may differentiate in vivo into a central memory-like state upon encounter and subsequent elimination of target cells expressing the surrogate antigen.
  • the anti-tumor immunity response elicited by the CAR-modified T cells may be an active or a passive immune response.
  • the CAR mediated immune response may be part of an adoptive immunotherapy approach in which CAR-modified T cells induce an immune response specific to the antigen binding moiety in the CAR.
  • a CART19 cells elicits an immune response specific against cells expressing CD19.
  • the invention should be construed to include any number of variations for each of the components of the construct as described elsewhere herein. That is, the invention includes the use of any antigen binding moiety in the CAR to generate a CAR-mediated T-cell response specific to the antigen binding moiety.
  • the antigen binding moiety in the CAR of the invention can target a tumor antigen for the purposes of treat cancer.
  • Cancers that may be treated include tumors that are not vascularized, or not yet substantially vascularized, as well as vascularized tumors,
  • the cancers may comprise non-solid tumors (such as hematological tumors, for example, leukemias and lymphomas) or may comprise solid tumors.
  • Types of cancers to be treated with the CARs of the invention include, but are not limited to, carcinoma, blastoma, and sarcoma, and certain leukemia or lymphoid malignancies, benign and malignant tumors, and malignancies e.g., sarcomas, carcinomas, and melanomas.
  • Adult tumors/cancers and pediatric tumors/cancers are also included,
  • Hematologic cancers are cancers of the blood or bone marrow.
  • hematological (or hematogenous) cancers include leukemias, including acute leukemias (such as acute lymphocytic leukemia, acute myelocytic leukemia, acute myelogenous leukemia and myeloblasts, promyeiocytic, myelomonocytic, monocytic and erythroleukemia), chronic leukemias (such as chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (indolent and high grade forms), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myeiodysplastic syndrome, hairy cell leukemia and myelodysplasia.
  • acute leukemias such as acute lymphocytic leukemia, acute mye
  • Solid tumors are abnormal masses of tissue that usually do not contain cysts or liquid areas. Solid tumors can be benign or malignant. Different types of solid tumors are named for the type of cells that form them (such as sarcomas, carcinomas, and lymphomas). Examples of solid tumors, such as sarcomas and carcinomas, include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer, lung cancers, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous eel!
  • carcinoma basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, pheochromocytomas sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, Wilms' tumor, cervical cancer, testicular tumor, seminoma, bladder carcinoma, melanoma, and CNS tumors (such as a glioma (such as brainstem glioma and mixed gliomas), glioblastoma (also known as glioblastoma multiforme) astrocytoma, CNS lymphoma, germinoma, medu!loblastoma, Schwannoma craniopharyogioma, ependymoma, pineaioma, hemangioblastoma, acoustic
  • the antigen bind moiety portion of the CAR of the invention is designed to treat a particular cancer.
  • the CAR designed to target CD19 can be used to treat cancers and disorders including but are not limited to pre-B ALL (pediatric indication), adult ALL, mantle cell lymphoma, diffuse large B- ceil lymphoma, salvage post allogenic bone marrow transplantation, and the like.
  • the CAR can be designed to target CD22 to treat diffuse large B-cell lymphoma
  • cancers and disorders include but are not limited to pre-B ALL (pediatric indication), adult ALL, mantle cell lymphoma, diffuse large B-cell lymphoma, salvage post allogenic bone marrow transplantation, and the like can be treated using a combination of CARs that target CD 19, CD20, CD22, and RORL
  • the CAR can be designed to target mesothelin to treat mesothelioma, pancreatic cancer, ovarian cancer, and the iike,
  • the CAR can be designed to target CD33/IL3Ra to treat acute myelogenous leukemia and the like.
  • the CAR can be designed to target c-Met to treat triple negative breast cancer, non-small ceil l ng cancer, and the like.
  • the CAR can be designed to target PSMA to treat prostate cancer and the like.
  • the CAR can be designed to target Giycolipid F77 to treat prostate cancer and the like. In one embodiment, the CAR can be designed to target EGFRvIlI to treat gliobastoma and the like,
  • the CAR can be designed to target GD-2 to treat neuroblastoma, melanoma, and the like.
  • the CAR can be designed to target NY-ESO- 1
  • TCR to treat myeloma, sarcoma, melanoma, and the like.
  • the CAR can be designed to target MAGE A3 TCR to treat myeloma, sarcoma, melanoma, and the like.
  • the invention should not be construed to be limited to solely to the antigen targets and diseases disclosed herein. Rather, the invention should be construed to include any antigenic target that is associated with a disease where a CAR can be used to treat the disease.
  • the CAR-modified T cells of the invention may also serve as a type of vaccine for ex vivo immunization and/or in vivo therapy in a mammal, Preferably, the mammal is a human.
  • cells are isolated from a mammal (preferably a human) and genetically modified (i.e., transduced or transfected in vitro) with a vector expressing a CAR disclosed herein.
  • the CAR-modified cell can be administered to a mammalian recipient to provide a therapeutic benefit.
  • the mammalian recipient may be a human and the CAR-modified cell can be autologous with respect to the recipient, Alternatively, the cells can be allogeneic, syngeneic or xenogeneic with respect to the recipient.
  • ex vivo culture and expansion of T cells comprises: (1 ) collecting CD34+ hematopoietic stem and progenitor cells from a mammal from peripheral blood harvest or bone marrow explants; and (2) expanding such cells ex vivo.
  • ex vivo culture and expansion of T cells comprises: (1 ) collecting CD34+ hematopoietic stem and progenitor cells from a mammal from peripheral blood harvest or bone marrow explants; and (2) expanding such cells ex vivo.
  • other factors such as flt3-L, IL-1 , IL-3 and c-kit ligand, can be used for culturing and expansion of the cells,
  • the present invention also provides compositions and methods for in vivo immunization to elicit an immune response directed against an antigen in a patient.
  • the cells activated and expanded as described herein may be utilized in the treatment and prevention of diseases that arise in individuals who are immunocompromised.
  • the CAR-modified T cells of the invention are used in the treatment of CCL.
  • the cells of the invention are used in the treatment of patients at risk for developing CCL.
  • the present invention provides methods for the treatment or prevention of CCL comprising administering to a subject in need thereof, a therapeutically effective amount of the CAR-modified T cells of the invention.
  • compositions of the present invention may comprise a target cell population as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients.
  • Such compositions may comprise buffers such as neutral buffered saline, phosphate buffered saline and the like; carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol; proteins; polypeptides or amino acids such as glycine;
  • compositions of the present invention are preferably formulated for intravenous administration.
  • compositions of the present invention may be administered in a manner appropriate to the disease to be treated (or prevented).
  • the quantity and frequency of administration will be determined by such factors as the condition of the patient, and the type and severity of the patient's disease, although appropriate dosages may be determined by clinical trials.
  • an immunologically effective amount When “an immunologically effective amount”, “an anti-tumor effective amount”, “an tumor-inhibiting effective amount”, or “therapeutic amount” is indicated, the precise amount of the compositions of the present invention to be administered can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject). It can generally be stated that a pharmaceutical composition comprising the T cells described herein may be administered at a dosage of 10 4 to 10 9 cells/kg body weight, preferably 10 5 to 10 6 cells/kg body weight, including all integer values within those ranges. T cell compositions may also be administered multiple times at these dosages.
  • the cells can be administered by using infusion techniques that are commonly known in immunotherapy (see, e.g., Rosenberg et al uncomfortable Eng. J. of Med. 319: 1676, 1988).
  • immunotherapy see, e.g., Rosenberg et al uncomfortable Eng. J. of Med. 319: 1676, 1988.
  • the optimal dosage and treatment regime for a particular patient can readily be determined by one skilled in the art of medicine by monitoring the patient for signs of disease and adjusting the treatment accordingly.
  • T cells can be activated from blood draws of from 1 Occ to 400cc.
  • T cells are activated from blood draws of 20cc, 30cc, 40cc, 50cc, 60cc, 70cc, 80cc, 90cc, or 1 OOcc, Not to be bound by theory, using this multiple blood draw/multiple reinfusion protocol may serve to select out certain populations of T cells.
  • compositions described herein may be administered to a patient subcutaneously, intradermaliy, mtratumora!ly, intranodally, intramedullary, intramuscularly, by intravenous (/.v.) injection, or intraperitoneally.
  • the T cell compositions of the present invention are administered to a patient by intradermal or subcutaneous injection.
  • the T cell compositions of the present invention are preferably administered by i. v. injection.
  • the compositions of T cells may be injected directly into a tumor, lymph node, or site of infection.
  • ceils activated and expanded using the methods described herein, or other methods known in the art where T cells are expanded to therapeutic levels are administered to a patient in conjunction with (e.g., before, simultaneously or following) any number of relevant treatment modalities, including but not limited to treatment with agents such as antiviral therapy, cidofovir and interleukin-2, Cytarabine (also known as ARA-C) or natal izitmab treatment for MS patients or efaiizumab treatment for psoriasis patients or other treatments for PML patients.
  • the T cells of the invention may be used in combination with chemotherapy, radiation,
  • immunosuppressive agents such as cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAM PATH, anti ⁇ CD3 antibodies or other antibody therapies, cytoxin, fliidaribine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation,
  • These drugs inhibit either the calcium dependent phosphatase calcineurin (cyclosporine and F 506) or inhibit the p70S6 kinase that is important for growth factor induced signaling (rapamycin) (Liu et al., Cell 66:807-815, 1991 ; Henderson et al., Immun.
  • the cell compositions of the present invention are administered to a patient in conjunction with (e.g., before, simultaneously or following) bone marrow transplantation, T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH.
  • the cell compositions of the present invention are administered following B-cell ablative therapy such as agents that react with CD20, e.g., Rituxan.
  • subjects may undergo standard treatment with high dose chemotherapy followed by peripheral blood stem cell transplantation.
  • subjects receive an infusion of the expanded immune cells of the present invention.
  • expanded cells are administered before or following surgery.
  • the dosage of the above treatments to be administered to a patient will vary with the precise nature of the condition being treated and the recipient of the treatment.
  • the scaling of dosages for human administration can be performed according to art-accepted practices,
  • the dose for CAMPATH for example, will generally be in the range 1 to about 100 mg for an adult patient, usually administered daily for a period between 1 and 30 days,
  • the preferred daily dose is 1 to 10 mg per day although in some instances larger doses of up to 40 mg per day may be used (described in U.S. Patent No. 6, 120,766), EXPERIMENTAL EXAMPLES
  • Example 1 T cells expressing chimeric receptors establish memory and potent antitumor effects in patients with advanced leukemia
  • Lymphocytes engineered to express chimeric antigen receptors have demonstrated minimal in vivo expansion and antitumor effects in previous clinical trials.
  • CARs chimeric antigen receptors
  • the results presented herein demonstrate that that CAR T cells containing CD 137 have potent non-cross resistant clinical activity following infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL), The engineered T cells expanded more than a thousand-fold in vivo, trafficked to bone marrow and continued to express functional CARs at high levels for at least 6 months, On average, each infused CAR+ T cell eradicated at least 1000 CLL cells.
  • a CD 19 specific immune response was demonstrated in the blood and bone marrow, accompanied by complete remission in two of three patients. A portion of the cells persist as memory CAR+ T cells, indicating the potential of this non-MHC restricted approach for the effective treatment of B cell malignancies.
  • FIG. 1 Patients with CD 1 positive hematologic malignancy with persistent disease following at least two prior treatment regimens and who were not eligible for allogeneic stem cell transplantation were eligible for the trial. Following tumor restaging, peripheral blood T cells for CART19 manufacturing were collected by apheresis and the subjects given a single course of chemotherapy as specified in Figure 10 during the week before infusion, CART 19 cells were administered by intravenous infusion using a 3 day split dose regimen ( 10%, 30% and 60%) at the dose indicated in Figure 10 and if available, a second dose was administered on day 10; only patient UPN 02 had sufficient cells for a second infusion. Subjects were assessed for toxicity and response at frequent intervals for at least 6 months. The protocol was approved by the US Food and Drug Administration, the Recombinant DNA Advisory Committee and the Institutional Review Board of the University of Pennsylvania. The first day of infusion was set as study Day 0.
  • Patient UPN 01 was first diagnosed with stage ⁇ B cell CLL at age 55. The patient was asymptomatic and observed for approximately 1 - 1/2 years until requiring therapy for progressive lymphocytosis, thrombocytopenia, adenopathy, and splenomegaly. Over the course of time, the patient received prior lines of therapy. The most recent therapy was 2 cycles of pentostatin,
  • Patient UPN 02 was first diagnosed with CLL at age 68 when the patient was presented with fatigue and leukocytosis. The patient was relatively stable for 4 years when the patient developed progressive leukocytosis (195,000/ ⁇ 1), anemia and thrombocytopenia requiring therapy, Kaiyotypic analysis showed that the CLL cells had deletion of chromosome 17p. Because of progressive disease, the patient was treated with alemtiizumab with a partial response but within one and a half years the patient had progressive disease. The patient was retreated with alemtiizumab for 18 weeks with a partial response and a 1 year progression free interval. The patient then received 2 cycles of bendamustine with rit ximab without a significant response (Figure 5A). The patient received single agent bendamustine as lymphodepleting chemotherapy prior to CART- 19 cell infusion.
  • Patient UPN 03 presented at age 50 with asymptomatic stage I CLL and was followed with observation for years.
  • the patient had progressive leukocytosis (white blood count 92,000/ ⁇ ) and progressive adenopathy requiring therapy.
  • the patient received 2 cycles of rituximab with fhidarabine that resulted in normalization of blood counts and significant improvement though not complete resolution in adenopathy.
  • the patient had an approximately 3 year progression free interval, Kaiyotypic testing showed cells to contain deletion of chromosome 17p with FISH demonstrating a TP 53 deletion in 170 of 200 cells.
  • the CD19-BB-Z transgene (GeMCRIS 0607-793) was designed and constructed as described (Milone et al., 2009, ol Ther. 17: 1453-1464).
  • Lentiviral vector was produced according to current good manufacturing practices using a three- plasmid production approach at Lentigen Corporation as described (Zufferey et al., ⁇ 997, Nature biotechnol 15:871 -875),
  • CLL burden at baseline was estimated as shown in Figure 10.
  • the amount of CLL cells were calculated in bone marrow, blood, and secondaiy lymphoid tissues as described below.
  • Bone marrow in healthy adults, the bone marrow represents approximately 5% of totai body weight (Woodard et al., 1960, Phys Med Biol, 5:57- 59; Bigle et al., 1976, Health Phys 31 :213-218).
  • the bone marrow in iliac crest samples has an increasing percentage of inactive (fatty) marrow with age, rising from 20% of the total marrow at age 5 to about 50% by age 35, when it remains stable until age 65, and then rises to about 67% inactive marrow by age 75 (Hartsock et al., 1965, Am J Clin Path 43:326-33 1 ).
  • the international reference value for the total skeletal weight of active (red) and inactive (fatty) marrow for males at age 35 is currently set at 1 170g and 2480g, respectively (Basic anatomical and physiological data for use in radiological protection: The Skeleton in Annals of the ICRP, Vol, 25 (ed. Smith, H.) 58-68 (A report of a Task Group of Committee 2 of the International Commission on Radiological Protection, Oxford, 1995)).
  • lymphadenopathy and splenomegaly The volume of lymphadenopathy and splenomegaly was quantified on axial CT scans using FDA-approved software. The volumes are for chest, abdomen and pelvis only. Masses from the T l vertebral body to the level of the bifurcation of the common femoral artery were measured in all patients, and in some, the nodes in the inguinal area were also included.
  • the tumor volumes in secondary lymphoid tissues in the three patients are shown below in Table 2 as calculated from the available CT scans.
  • the baseline CT scan for patient UPN 01 was performed 8 days after 2 cycles of pentostatin/ cyclophosphamide/ rituximab, and showed no response to this chemotherapy regimen compared to the previous CT scan.
  • the patient had one cycle of bendamustine before CART 19, and thus, the change in tumor volume from Day - 37 to Day +3 1 for UPN 01 cannot exclude the potential contribution of the bendamustine as well as CART 19.
  • the change in tumor volume for UPN 03 reflects the combined effect of 1 cycle of pentastatin/ cyclophosphamide and CART19.
  • Samples peripheral blood, marrow were collected in lavender top (K2EDTA,) or red top (no additive) vacutainer tubes (Becton Dickinson) and delivered to the TCSL within 2 hours of draw. Samples were processed within 30 minutes of receipt according to established laboratory SOP.
  • Peripheral blood and marrow mononuclear cells were purified via Ficoll density gradient centrifugation using Ficoll-Paque (GE Health care, 1 7- 1440-03) and frozen in RPM1 (Gibco 1 1875- 135) supplemented with 4% human serum albumin (Gemini Bio-Products, 800-120), 2% Hetastarch (Novaplus, NDC0409-7248-49), and 10% DMSO (Sigma, D2650) using 5100 Cryo 1 0 freezing containers; after 24-72 hours at -80° C, cells were transferred to liquid Nitrogen for long-term storage.
  • K562 (CML, CD19-negative) was obtained from ATCC (CCL-243), K.562/CD19, a generous gift of Carmine Carpenito, and is K562 lentivirally transduced at 100% frequency to express the CD19 molecule, NALM-6, a CD 19- positive non-T, non-B ALL precursor B cell line (Hurwitz et al., 1979, Tnt J Cancer 23: 174- 180), and confirmed to express the CD 19 antigen was a generous gift of Laurence Cooper.
  • the above cell lines were maintained in R10 medium (RPMI 1640 (Gibco, 1 1875) supplemented with 10% fetal bovine serum (Hycione), and 1 % Pen- Strep (Gibco, 1 140-122).
  • Peripheral mononuclear ceils (ND365) from a healthy donor were obtained by apheresis from the Human Immunology Core at the
  • Pass/fail parameter ranges including standard curve slope and r 2 values, ability to accurately quantify a reference sample (1000 copies/plasmid spike) and no amplification in healthy donor DNA sample were calculated from the qualification studies and pre-established acceptance ranges.
  • Primer/probes for the CD 19 CAR transgene were as described (Milone et al., 2009, Mol Ther 17: 1453- 1464).
  • To determine copy number/unit DNA an 8-point standard curve was generated consisting of 10 6 -5 copies lentivirus plasmid spiked into 100 ng non-transduced control genomic DNA. Each data-point (samples, standard curve, reference samples) was evaluated in triplicate with average values reported.
  • a parallel amplification reaction to control for the quality of interrogated DNA was performed using 12-20 ng input genomic DNA, a primer/probe combination specific for non-transcribed genomic sequence upstream of the
  • CDKN 1 A gene (GENEBANK: Z85996 ) (sense primer:
  • Quantification of soluble cytokine factors was performed using Lummex bead array technology and kits purchased from Life technologies
  • TCM by measuring CD107 degranulation in response to target cells.
  • Degranulation assays were performed using I x 10 6 PBMC and 0.25 x 10 6 target cells in a final volume of 500 ⁇ in 48-well plates for 2 hours at 37°C in the presence of CD49d (Becton Dickinson), anti-CD28, monensin (e-Bioscience) and CD107a-FITC antibody (eBiosciences) essentially as described (Berts et al., 2003, J Immunol Methods 281 :6578).
  • MDA-CAR a murine anti CD 19 CAR antibody conjugated to Aiexa647 was a generous gift of Drs. Bipulendu Jena and Laurence Cooper (MD Anderson Cancer Center).
  • TCM T cell medium
  • X-vivo 15 (Lonza, 04-418Q) supplemented with 5% human AB serum (GemCall, 100-5 12), 1 % Hepes (Gibco, 15630-080), 1 % Pen-Strep (Gibco, 15140- 122), 1% Glutamax (Gibco, 35050-061 ), and 0.2% N-Acetyl Cysteine
  • Multi-parametric immunophenotyping was performed on 4 x 10 6 total cells/condition, using FMO stains as described in the text.
  • Cells were stained at a density of 1 x 10 6 cel!s/100 ⁇ PBS for 30 minutes on ice using antibody and reagent concentrations recommended by the manufacturer, washed, re- suspended in 0.5% paraformaldehyde and acquired using a modified LSRII (BD Immunocytometry systems) equipped with Blue (488 nm) Violet (405 nm), Green (532), and Red (633 nm) lasers and appropriate filter sets for the detection and separation of the above antibody combinations. A minimum of 100,000 CD3+ cells were acquired) for each stain.
  • a minimum of 100,000 CD3+ cells were acquired) for each stain.
  • Patient UPN 01 was first diagnosed with stage II B cell CLL at age 55. The patient was asymptomatic and observed for approximately 1 - 1/2 years until requiring therapy for progressive lymphocytosis, thrombocytopenia, adenopathy, and splenomegaly. After 4 cycles of fludarabine the patient had complete normalization of blood counts and a complete response by CT scans, Progression was noted within 5 months with asymptomatic lymphocytosis, thrombocytopenia, and increasing adenopathy. The patient was observed without symptoms for approximately 3 years, and later required treatment with Rituxtmab and fludarabine for progressive leukocytosis, anemia, and thrombocytopenia.
  • the patient was treated with 4 cycles of ritiiximab with fludarabine with partial improvement in blood counts, The patient again had progression within one year requiring therapy manifested by leukocytosis (WBC 150,000/ ⁇ 1) and thrombocytopenia (platelets 30,000/ ⁇ 1) and was treated with alemtuzumab with normalization of blood counts. Progression was noted within 13 months.
  • the patient then received single agent rituximab without a significant response and followed by rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) for 2 cycles with minimal response and followed by lenalidomide.
  • Lenalidomide was discontinued because of toxicity.
  • the patient received 2 cycles of pentostatin, cyclophosphamide and rituximab with a minimal response.
  • the patient achieved a rapid and complete response as depicted in Figure 5.
  • a rapid and complete response between 1 and 6 months after infusion no circulating CLL cells have been detected in the blood by flow cytometry.
  • Bone marrow at 1, 3 and 6 months after CART- 19 cell infusions shows sustained absence of the lymphocytic infiltrate by morphology and flow cytometry testing.
  • the CT scans at 1 and 3 months after infusion show complete resolution of abnormal adenopathy.
  • the patient has had a persistent leukopenia (WBC 1000-3900/ul) and thrombocytopenia (platelets).
  • Patient UPN 02 was treated with CART 19 cells at age 77.
  • the patient had a relevant history of coronary artery disease and was first diagnosed with CLL in 2000 at age 68 when the patient presented with fatigue and leukocytosis.
  • the patient was relatively stable for 4 years when the patient developed progressive leukocytosis ( 195,000/ ⁇ 1), anemia and thrombocytopenia requiring therapy. Genetic testing at that time showed that the CLL cells had deletion of chromosome 17p. Because of progressive disease, the patient was treated with a 12 week course of alemtuzumab with a partial response and improvement in biood counts, Within one and a half years the patient had progressive leukocytosis, anemia, thrombocytopenia, and
  • Patient UPN 03 was diagnosed with asymptomatic stage 1 CLL at age 50 and was followed with observation for 6 years, Later, the patient had progressive leukocytosis (white blood count 92,000/ ⁇ ) and progressive adenopathy requiring therapy.
  • the patient received 2 cycles of rituximab with fludarabine that resulted in normalization of blood counts and significant improvement though not complete resolution in adenopathy.
  • the patient had approximately a 3 year progression free interval followed over the next 6 months by rapidly progressive leukocytosis (WBC 165,000/ ⁇ ) and progressive adenopathy requiring therapy.
  • the patient received one cycle of fludarabine and 3 cycles of rituximab with fludarabine with normalization of blood counts and resolution of palpable adenopathy.
  • the patient had an approximate 20 month progression free interval until the patient again developed rapidly progressing leukocytosis and adenopathy.
  • bone marrow was extensively infiltrated with CLL and karyotypic analysis showed cells to contain deletion of chromosome 17p with FISH demonstrating a TP53 deletion in 170/200 cells.
  • the patient received one cycle of rituximab with beiidamustine followed by 4 cycles of bendamustine only (due to a severe allergic reaction to rituximab).
  • the patient had initial normalization of blood counts but shortly after discontinuation of therapy had progressive leukocytosis and adenopathy.
  • cyclophosphamide as lymphodepleting chemotherapy prior to CART19 ceil infusion.
  • CART19 T cells were prepared as depicted in Figure IB and details of the cell manufacturing and product characterization for each patient are shown in Table 4, All patients were pretreated 1 -4 days before CART19 T cell infusions with
  • 1BB signaling domain is believed to be in improvement to CARs lacking 4-1 BB
  • a Q-PCR assay was developed to enable quantitative tracking of CARTI cells in blood and bone marrow. All patients had expansion and persistence of the CART19-cells in blood for at least 6 months as depicted in Figures 2A and 2C, Notably, patients UPN 01 and UPN 03 had a 1 ,000 to 10,000 fold expansion of CAR+ T cells in blood during the first month post infusion. The peak expansion levels coincided with onset of the post-infusion clinical symptoms in patient UPN 01 (day 15) and patient UPN 03 (day 23).
  • the CART19 T cell levels stabilized in all 3 patients from day 90 to 180 post infusion.
  • the CARTI 9 T ceils also trafficked to bone marrow in all patients, albeit at 5-to 10-fold lower levels than observed in blood as depicted in Figures 2D through 2F, Patients UPN 01 and 03 had a log linear decay in the marrow, with a disappearance T1 ⁇ 2 of -35 days.
  • 4 cytokines IL-6, 1NF- ⁇ , IL-8 and IL- i O
  • 5 chemokines ⁇ - ⁇ , ⁇ - ⁇ ⁇ , MCP- , CXCL9, CXCL10
  • soluble receptors for IL-lR and IL-2Ra Of thirty analytes tested, eleven had
  • CAR-negative CD8+ cells consisted of mixtures of effector and central memory cells, with CCR7 expression in a subset of cells, and substantial numbers in the CD27+/CD28-and CD27+/CD28+ fractions. While both CART19 and CAR-negative cell populations substantially expressed CD57, this molecule was uniformly co-expressed with PD- 1 in the CART19 cells, a possible reflection of the extensive implicative history of these cells, In contrast to the CAR-negative cell population, the entirety of the CART19 CD8+ population lacked expression of both CD25 and CD 127, By day 169, while the phenotype of the CAR-negative cell population remained similar to the day 56 sample, the CART19 population had evolved to contain a minority population with features of central memory ceils, notably expression of CCR7, higher levels of CD27 and CD28, as well as CAR+ cells that were PD- 1 -negative, CD57-negative and CD 127- positive.
  • CART 19 cells were characterized by uniform lack of CCR7 and a predominance of CD27+/CD28+/PD- 1+ cells distributed within both CD57+ and -compartments, and an essential absence of CD25 and CD127 expression as depicted in Figure 4B.
  • CAR-negative cells at this time-point were heterogeneous in CCR7, CD27 and PD- 1 expression, expressed CD 127 and also contained a substantial CD25+/CD127- (potential regulatory T cell) population.
  • CART 19 cells can retain effector function after 6 months in blood
  • patient UPN 01 developed a febrile syndrome, with rigors and transient hypotension beginning 10 days after infusion. The fevers persisted for approximately 2 weeks and resolved; the patient has had no further constitutional symptoms. The patient achieved a rapid and complete response as depicted in Figure 5. Between 1 and 6 months after infusion, no circulating CLL cells have been detected in the blood by flow cytometry. Bone marrow at 1, 3, and 6 months after CART19 cell infusions shows sustained absence of the lymphocytic infiltrate by morphology and flow cytometric analysis as depicted in Figure 5B. CT scans at 1 and 3 months after infusion show resolution of adenopathy as depicted in Figure 5C, Complete remission was sustained for 10+ months at the time of this report.
  • Patient UPN 02 was treated with 2 cycles of bendamustine with ritiiximab resulting in stable disease as depicted in Figure 5A.
  • the patient received a third dose of bendamustine as lymphodepleting chemotherapy prior to CART 19 T cell infusion.
  • the patient developed fevers to 40°C, rigors and dyspnea requiring a 24 hour hospitalization on day 1 1 after the first infusion and on the day of the second CART19 cell boost. Fevers and constitutional symptoms persisted and on day 15, the patient had transient cardiac dysfunction; all symptoms resolved after corticosteroid therapy was initiated on day 1 8.
  • Patient UPN 03 received pentostatin and cyclophosphamide as !ymphodepleting chemotherapy prior to CART19 cell infusion.
  • the patient received a low dose of CART 19 cells (1.5xl 0 5 CAR+ T cells/kg divided over 3 days). Again, there were no acute infusional toxicities. However, 14 days after the first infusion, the patient began having rigors, fevers, nausea and diarrhea. By day 22 after infusion, tumor lysis syndrome was diagnosed requiring hospitalization.
  • the patient had resolution of constitutional symptoms, and within 1 month of CART19 infusions, the patient had clearance of circulating CLL from the blood and bone marrow by morphology, flow cytometry, cytogenetic, and FISH analysis.
  • CT scans showed resolution of abnormal adenopathy as depicted in Figures 5B and 5C. Complete remission was sustained beyond 8 months from the initial CART 19 cell infusion,
  • CART 19 is the first CAR trial to incorporate a 4- I BB signaling domain and the first to use lentiviral vector technology.
  • the present results demonstrate efficient tracking of CARs to sites of tumor, with the de facto establishment of "tumor infiltrating lymphocytes" that exhibited CD 19 specificity.
  • CART19 is expressed in both central memory and effector T cells, and this likely contributes to their long term survival compared to previous reports.
  • CAR T cells may differentiate in vivo into a central memory-like state upon encounter and subsequent elimination of target cells (e.g. CLL tumor cells or normal B cells) expressing the surrogate antigen.
  • target cells e.g. CLL tumor cells or normal B cells
  • signaling of 4-lBB has been reported to promote the development of memory in the context of TCR signaling (Sabbagh et al., 2007, Trends Immunol 28:333-339).
  • CART19 has revealed aspects of the pharmacokinetics of CAR T cells that have not previously been reported. It was observed that the kinetics of cytokine release in serum and marrow correlated with peak CART 19 levels, so that it is possible that the decay is initiated when cellular targets expressing CD 19 become limiting.
  • the mechanism of the extended survival of CART19 may relate to the aforementioned incorporation of the 4-lBB domain or to signaling through the natural TCR and/or CAR, An interesting possibility is that the extended survival is related to the population of CART19 that has been identified in marrow specimens, raising the hypothesis that CD 19 CARs could be maintained by encounter with B ceil progenitors in the bone marrow.
  • CAR-modified T cells have the potential to replicate in vivo, and long-term persistence could lead to sustained tumor control.
  • the availability of an off the shelf therapy comprised of non-cross resistant kilie T cells has the potential to improve the outcome of patients with B ceil malignancies.
  • a limitation of antibody therapy, as for example, with agents such as rituximab and bevicizumab, is that the therapy requires repeated antibody infusions, that is inconvenient and costly.
  • a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimu!atory receptor in T cells [4- I BB]) and CD3-zeta (a signal-transduction component of the T- cell antigen receptor) signaling domains was designed, It was observed that a low dose (approximately 1.5x l 0 5 cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo. It was also observed that the patient exhibited delayed development of the tumor lysis syndrome and with complete remission.
  • CLL chronic lymphocytic leukemia
  • hypogammaglobulinemia was an expected chronic toxic effect.
  • a self-inactivating lentiviral vector (GeMCRTS 0607-793) was designed, which was subjected to preclinical safety testing, as reported previously (Milone et al., 2009, Mol Ther, 17: 1453-64). Methods of T-celi preparation have also been described previously (Porter et al, 2006, Blood, 107: 1325-31). Quantitative polymerase-chain-reaction (PCR) analysis was performed to detect chimeric antigen receptor T cells in blood and bone marrow. The lower limit of quantification was determined from the standard curve; average values below the lower limit of quantification (i.e., reportable but not quantifiable) are considered approximate. The lower limit of quantification of the assay was 25 copies per microgram of genomic DNA,
  • Soluble-factor analysis was performed with the use of serum from whole biood and bone marrow that was separated into aliquots for single use and stored at -80°C. Quantification of soluble cytokine factors was performed with the use of Luminex bead-array technology and reagents (Life Technologies).
  • PB C Peripheral blood mononuclear cells
  • Chemotherapy is started approximately 5- 10 days before infusion so that CART- 19 cells may be given 1 -2 days after completion of the chemotherapy.
  • the timing of chemotherapy initiation therefore depends on the length of the regimen,
  • the purpose of the chemotherapy is to induce lymphopenia in order to facilitate engraftment and homeostatic expansion of CART-19 cells.
  • the chemotherapy may be chosen also to reduce disease tumor burden.
  • the cytoreductive chemotherapy is chosen and administered by community oncologists. The choice of chemotherapy depends on the patients underlying disease and prior therapies. Fludarabine (30 mg/ni2/day x 3 days) and cyclophosphamide (300 mg/m2/day x 3 days) are the agents of choice, as there is the most experience with the use of these agents in facilitating adoptive immunotherapy.
  • Several other acceptable regimens using FDA-approved drugs are appropriate, including CHOP, HyperCVAD, EPOCH, DHAP, ICE or other regimens.
  • a limited restaging is performed at the completion of chemotherapy order to provide baseline tumor burden measurements. This includes imaging, physical examination, and minimal residual disease (MRD) assessments. Subjects undergo the following for pre-infusing testing: physical exam, documentation of adverse events and blood draws for hematology, chemistry and pregnancy testing (if applicable).
  • MRD minimal residual disease
  • Autologous T cells are engineered to express an extracellular single chain antibody (scFv) with specificity for CD 19.
  • the extracellular scFv can redirect specificity of the transduced T cells for cells that express CD 19, a molecule that is restricted in expression on the surface of the malignant cells and on normal B cells.
  • the cells are transduced to express an intracellular signaling molecule comprised of either the TCR ⁇ chain or a tandem signaling domain comprised of 4- I BB and TCRC, signaling modules.
  • the scFv is derived from a mouse monoclonal antibody, and thus contains mouse sequences, and the signaling domains are entirely of the native human sequences.
  • CART-19 T cells are manufactured by isolating the T cells by apheresis, and using ientiviral vector technology (Dropulic et a!., 2006, Human Gene Therapy, 17: 577-88; Naldini et al., 1996, Science, 272: 263- 7; Dull et al dislike 1998, J Virol, 72: 8463-71) to introduce the scFv:TCRC:4-l BB into CD4 and CD8 T cells.
  • a control is introduced into a portion of the cells for a competitive repopulation experiment.
  • These receptors are "universal" in that they bind antigen in an MHC-independent fashion, thus, one receptor construct can be used to treat a population of patients with CD19 antigen- positive tumors.
  • the CAR constructs were developed at the University of Pennsylvania, and the clinical grade vector was manufactured at Lentigen Corporation.
  • the CART- 19 cells are manufactured in the Clinical Cell and Vaccine Production Facility at the University of Pennsylvania according to the process shown in Figure 1 1. At the end of cell cultures, the cells are cryopreserved in infusible cryomedia. A single dose of CART- 19 transduced T cells comprising of the infusion of 2.5 x 10 9 to 5 x 10 9 total cells, are administered in either 1 or 2 bags.
  • Each bag contains an aliquot (volume dependent upon dose) of cryomedia containing the following infusible grade reagents (% v/v): 31 .25 plasmalyte-A, 31.25 dextrose (5%), 0.45 NaCl, up to 7.50 DMSO, 1.00 dextran 40, 5.00 human serum albumin with approximately 2.5-5 x 10 9 autologous T cells per bag.
  • the first dose is given as a split dose on days 0, 1 and 2, with -10% of the cells on day 0, 30% on day I , and 60% on day 2.
  • Bags (10 to 100 ml capacity) containing CART-19-transduced T cells are stored in blood bank conditions in a monitored - 135°C freezer. Infusion bags are stored in the freezer until needed.
  • frozen cells are transported in dry ice to the subject's bedside.
  • the ceils are thawed at the bedside one bag at a time using a water bath maintained at 36°C to 38°C.
  • the bag is gently massaged until the cells have just thawed, There should be no frozen clumps left in the container. If the CART- 19 cell product appears to have a damaged or leaking bag, or otherwise appears to be compromised, it should not be infused,
  • T cell infusions may include transient fever, chills, and/or nausea. It is recommended that the subject be pre-medicated with acetaminophen 650 mg by mo th and diphenhydramine hydrochloride 25-50 mg by mouth or IV, prior to the infusion of CART- 19 ceils. These medications may be repeated every six hours as needed. A course of non-steroidal anti-inflammatory medication may be prescribed if the patient continues to have fever not relieved by acetaminophen.
  • Infusions begin 1 to 2 days after completion of chemotherapy.
  • patients have a CBC with differential, and assessment of CD3, CD4 and CD8 counts since chemotherapy is given in part to induce lymphopenia.
  • an initial i.v, dose of 2.5-5x10 9 CART- 19 cells is optimal for this protocol, Because there are about 1 x 10 12 T cells in a healthy adult, the proposed total dose is equivalent to about 0,5% of the total body mass of T cells (Roederer, 1995, Nat Med, 1 : 621 -7; Macallan et al., 2003, Eur J Immunol, 33; 23 16-26).
  • the first dose is administered using a split dose on days 0 (10%), 1 (30%) and 2 (60%).
  • Subjects receive infusion in an isolated room.
  • the cells are thawed at the patient's bedside as described elsewhere herein.
  • the thawed cells are given at an infusion rate as quickly as tolerated so that the duration of the infusion is approximately 10-15 minutes.
  • the transduced T cells are administered by rapid intravenous infusion at a flow rate of approximately lOmL to 20mL per minute through an 1 8-gauge latex free Y-type blood set with a 3-way stopcock.
  • the duration of the infusion is approximately 15 minutes.
  • One or two bags of CART-19 modified cells are delivered on ice, and the cells are administered to the subject while cold.
  • the cells are administered simultaneously using a Y-adapter.
  • Subjects are infused and premedicated as described elsewhere herein, Subjects' vital signs are assessed and pulse oximetry is done prior to dosing, at the end of the infusion and every 15 minutes thereafter for 1 hour and until these are stable and satisfactory, A blood sample for determination of baseline CART- 19 level is obtained before infusion and 20 minutes post infusion. Patients experiencing toxicities from their preceding cytoreductive chemotherapy have their infusion schedule delayed until these toxicities have resolved.
  • T cell infusions include: 1) Pulmonary: Requirement for supplemental oxygen to keep saturation greater than 95% or presence of radiographic abnormalities on chest x-ray that are progressive; 2) Cardiac: New cardiac arrhythmia not controlled with medical management. 3) Hypotension requiring pressor support. 4) Active Infection: Positive blood cultures for bacteria, fungus, or virus within 48-hours of T cell infusion, A serum sample for potassium and uric acid is collected before the first infusion as well as two hours after each subsequent infusion.
  • Subjects return at day 4 and 10 after the initial CART- 19 cell infusion to have blood drawn for serum cytokine levels, and CART- 19 PCR in order to evaluate the presence of CART- 19 cells, Subjects return once a week for three weeks to undergo the following: physical exam, documentation of adverse events and blood draws for hematology, chemistry, engraftment and persistence of CART- 1 cells and research labs. Second infusion
  • a second dose of CART- 19 cells can be given on day 11 to patients, provided that they exhibit adequate tolerance to the first dose and sufficient CART- 19 ceils were manufactured.
  • the dose is 2-5 x 10 9 total cells.
  • a serum sample for potassium and uric acid can be collected two hours after the infusion.
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • Subjects undergo the following: physical exam, documentation of adverse events and blood draws for hematology, chemistry, engraftment and persistence of CART-19 cells and research labs, In addition restaging is done in order to provide tumor burden measurements. Restaging testing is determined by disease type and includes imaging, MRD assessments, bone marrow aspirate and biopsy and/or lymph node biopsy,
  • Subjects return on a monthly basis during months 2 to 6 post CART- 19 cell infusion. At these study visits, subjects undergo the following: concomitant medication, physical exam, documentation of adverse events and blood draws for hematology, chemistry, engraftment and persistence of CART- 1 9 cells and research labs.
  • the HTV DNA assay is performed at months 2-6 post CART-19 cell infusion to exclude the presence of detectable RCL. Quarterly evaluations up to 2 years post infusion
  • Subjects are evaluated on a quarterly basis until 2 years post infusion. At these study visits, subjects undergo the following: concomitant medication, physical exam, documentation of adverse events and blood draws for hematology, chemistry, engraftment and persistence of CART- 19 cells and research labs.
  • the HIV DNA assay is performed at months 3 and 6 post CART- 19 cell infusion to exclude the presence of detectable RCL.
  • Cytogenetic analysis showed that 3 of 15 cells contained a deletion of chromosome 17p, and fluorescence in situ hybridization (FISH) testing showed that 170 of 200 cells had a deletion involving TP 53 on chromosome 17p.
  • FISH fluorescence in situ hybridization
  • the uric acid level was 10.6 mg per deciliter (630.5 ⁇ per liter), the phosphorus level was 4.7 mg per deciliter (1.5 mmol per liter) (normal range, 2.4 to 4.7 mg per deciliter [0,8 to 1.5 mmol per liter]), and the lactate dehydrogenase level was 1 130 U per liter (normal range, 98 to 192).
  • the patient was hospitalized and treated with fluid resuscitation and rasburicase.
  • the uric acid level returned to the normal range within 24 hours, and the creatinine level within 3 days; he was discharged on hospital day 4.
  • the lactate dehydrogenase level decreased gradually, becoming normal over the following month,
  • the cell infusions had no acute toxic effects.
  • the only serious (grade 3 or 4) adverse event noted was the grade 3 tumor lysis syndrome described above.
  • the patient had grade 1 lymphopenia at baseline and grade 2 or 3 lymphopenia beginning on day 1 and continuing through at least 10 months after therapy.
  • Grade 4
  • lymphopenia with an absolute lymphocyte count of 140 cells per cubic millimeter, was recorded on day 19, but from day 22 through at least 10 months, the absolute lymphocyte count ranged between 390 and 780 cells per cubic millimeter (grade 2 or 3 iymphopenia),
  • the patient had transient grade 1 thrombocytopenia (platelet count, 98,000 to 131 ,000 per cubic millimeter) from day 19 through day 26 and grade 1 or 2 neutropenia (absolute neutrophil count, 1090 to 1630 per cubic millimeter) from day 17 through day 33.
  • grade 1 and 2 elevations in aminotransferase and alkaline phosphatase levels which developed 17 days after the first infusion and resolved by day 33
  • Grade 1 and 2 constitutional symptoms consisted of fevers, chills, diaphoresis, myalgias, headache, and fatigue.
  • Grade 2 hypogammaglobulinemia was corrected with infusions of intravenous immune globulin.
  • the patient's clinical response was accompanied by a delayed increase in levels of inflammatory cytokines (Figure I 3A through Figure 13D), with levels of interferon- ⁇ , the interferon-y-responsive chemokines CXCL9 and CXCL10, and interleukin-6 that were 160 times as high as baseline levels.
  • the temporal rise in cytokine levels paralleled the clinical symptoms, peaking 17 to 23 days after the first CART19-cell infusion.
  • CART 19 cells were identified in bone marrow specimens beginning 23 days after the first infusion ( Figure 14B) and persisted for at least 6 months, with a decay half-life of 34 days.
  • the highest levels of CART19 cells in the bone marrow were identified at the first assessment 23 days after the first infusion and coincided with induction of an immune response, as indicated by cytokine-secretion profiles ( Figure 13E).
  • Flow-cytometric analysis of bone marrow aspirates indicated a clonal expansion of CD5+CD19+ cells at baseline that was absent 1 month after infusion and in a sample obtained 3 months after infusion (data not shown). Normal B cells were not detected after treatment (Figure 14C).
  • Described herein is the delayed development of the tumor lysis syndrome and a complete response 3 weeks after treatment with autologous T cells genetically modified to target CD 19 through transduction with a lentivirus vector expressing anti-CD19 linked to CD3-zeta and CD 137 (4-1BB) signaling domains.
  • Genetically modified cells were present at high levels in bone marrow for at least 6 months after infusion.
  • the generation of a CD 19-specific immune response in bone marrow was demonstrated by temporal release of cytokines and ablation of leukemia ceils that coincided with peak infiltration of chimeric antigen receptor T cells.
  • CD19 is an attractive tumor target, with expression limited to normal and malignant B cells, there is concern that persistence of the chimeric antigen receptor T cells may mediate long-term B-cell deficiency.
  • Targeting B cells through CD20 with rituximab is an effective and relatively safe strategy for patients with B-cell neoplasms, and long-term B-cell lymphopenia is manageable (Molina, 2008, Ann Rev Med, 59: 237-50). Patients treated with rituximab have been reported to have a return of B ceils within months after discontinuation of therapy. It is not yet clear whether such recovery occurs in patients whose anti— B-cell T cells persist in vivo.

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PH1/2013/501201A PH12013501201A1 (en) 2010-12-09 2011-02-09 Use of chimeric antigen receptor-modified t cells to treat cancer
EP17153799.6A EP3214091B1 (en) 2010-12-09 2011-12-09 Use of chimeric antigen receptor-modified t cells to treat cancer
BR122021026173-3A BR122021026173B1 (pt) 2010-12-09 2011-12-09 Composição farmacêutica
ES11846757.0T ES2641870T3 (es) 2010-12-09 2011-12-09 Utilización de linfocitos T modificados con receptores de antígeno quiméricos para tratar el cáncer
BR112013014265A BR112013014265B8 (pt) 2010-12-09 2011-12-09 Molécula de ácido nucleico isolada, receptor antígeno quimérico isolado, e, vetor
JP2013543380A JP5947311B2 (ja) 2010-12-09 2011-12-09 癌を治療するためのキメラ抗原受容体改変ｔ細胞の使用
CA2820681A CA2820681C (en) 2010-12-09 2011-12-09 Use of chimeric antigen receptor-modified t cells to treat cancer
MA36089A MA34813B1 (fr) 2010-12-09 2011-12-09 Utilisation de lymphocytes t modifies par un recepteur chimerique d'antigenes chimerique pour traiter le cancer
BR122021026169-5A BR122021026169B1 (pt) 2010-12-09 2011-12-09 Uso de uma célula
TR2018/20015T TR201820015T4 (tr) 2010-12-09 2011-12-09 Kanser Tedavisi İçin Kimerik Antijen Reseptörü-Modifiye Edilmiş T Hücrelerinin Kullanılması
EP11846757.0A EP2649086B1 (en) 2010-12-09 2011-12-09 Use of chimeric antigen receptor-modified t cells to treat cancer
LTEP11846757.0T LT2649086T (lt) 2010-12-09 2011-12-09 Chimeriniu antigenų receptoriumi modifikuotų ląstelių naudojimas vėžio gydymui
EA201390847A EA027153B1 (ru) 2010-12-09 2011-12-09 Применение модифицированных t-клеток с химерными антигенными рецепторами для лечения злокачественных новообразований
SG2013043229A SG190997A1 (en) 2010-12-09 2011-12-09 Use of chimeric antigen receptor-modified t cells to treat cancer
AU2011338200A AU2011338200B2 (en) 2010-12-09 2011-12-09 Use of chimeric antigen receptor-modified T cells to treat cancer
KR1020237030855A KR20230133410A (ko) 2010-12-09 2011-12-09 암을 치료하기 위한 키메릭 항원 수용체 변형 t 세포의 용도
AP2013006918A AP2013006918A0 (en) 2010-12-09 2011-12-09 Use of chimeric antigen receptormodified T-cells to treat cancer
MX2013006570A MX347078B (es) 2010-12-09 2011-12-09 Uso de celulas t modificadas por receptor de antigeno quimerico para tratar cancer.
US13/992,622 US9499629B2 (en) 2010-12-09 2011-12-09 Use of chimeric antigen receptor-modified T-cells to treat cancer
CN201711345686.8A CN108103085B (zh) 2010-12-09 2011-12-09 嵌合抗原受体-修饰的t细胞治疗癌症的用途
KR1020217011458A KR102417796B1 (ko) 2010-12-09 2011-12-09 암을 치료하기 위한 키메릭 항원 수용체 변형 t 세포의 용도
PL11846757T PL2649086T3 (pl) 2010-12-09 2011-12-09 Zastosowanie komórek T modyfikowanych chimerycznymi receptorami antygenowymi do leczenia nowotworów
KR1020137017546A KR102062407B1 (ko) 2010-12-09 2011-12-09 암을 치료하기 위한 키메릭 항원 수용체 변형 t 세포의 용도
PL17153799T PL3214091T3 (pl) 2010-12-09 2011-12-09 Zastosowanie komórek T modyfikowanych chimerycznymi receptorami antygenowymi do leczenia nowotworów
SI201131301T SI2649086T1 (en) 2010-12-09 2011-12-09 Use of chimeric antigen receptor-modified t cells to treat cancer
CN201180067173.XA CN103492406B (zh) 2010-12-09 2011-12-09 嵌合抗原受体-修饰的t细胞治疗癌症的用途
HRP20171577TT HRP20171577T1 (hr) 2010-12-09 2011-12-09 Uporaba t stanica modificiranih himernim receptorom za antigen za liječenje karcinoma
MX2016013253A MX385933B (es) 2010-12-09 2011-12-09 Uso de celulas t modificadas por receptor de antigeno quimerico para tratar cancer.
RS20171041A RS56453B1 (sr) 2010-12-09 2011-12-09 Upotreba t ćelija modifikovanih himernim receptorom za antigen za lečenje kancera
DK11846757.0T DK2649086T3 (en) 2010-12-09 2011-12-09 USING CHEMICAL ANTIGEN RECEPTOR-MODIFIED T-CELLS TO TREAT CANCER
KR1020227022607A KR20220101745A (ko) 2010-12-09 2011-12-09 암을 치료하기 위한 키메릭 항원 수용체 변형 t 세포의 용도
NZ612512A NZ612512A (en) 2010-12-09 2011-12-09 Use of chimeric antigen receptor-modified t cells to treat cancer
EP19199404.5A EP3660029A1 (en) 2010-12-09 2011-12-09 Use of chimeric antigen receptor-modified t cells to treat cancer
IL226694A IL226694B (en) 2010-12-09 2013-06-02 Use of chimeric antigen receptor-modified t-cells to treat cancer
CL2013001645A CL2013001645A1 (es) 2010-12-09 2013-06-07 Secuencia de acido nucleico aislada que codifica un receptor de antigeno quimerico, el cual comprende un dominio de union a antigeno, un dominio transmembrana, una region de señalizacion coestimulatoria y un dominio de señalizacion cd3 zeta; dicho receptor; celula; vector; y su uso para tratar una enfermedad relacionada con la expresion elevada de un antigeno tumoral.
CR20130269A CR20130269A (es) 2010-12-09 2013-06-07 Uso de células t modificadas por receptor de antígeno quimérico para tratar cáncer
TNP2013000246A TN2013000246A1 (en) 2011-06-29 2013-06-07 Use of chimeric antigen receptor-modified t cells to treat cancer
CU2013000079A CU20130079A7 (es) 2011-06-29 2013-06-10 Uso de células t modificadas por receptor de antígeno quimérico para tratar cáncer
ZA2013/04470A ZA201304470B (en) 2010-12-09 2013-06-18 Use of chimeric antigen receptor-modified t cells to treat cancer
US13/938,923 US8911993B2 (en) 2010-12-09 2013-07-10 Compositions for treatment of cancer
US13/938,947 US8906682B2 (en) 2010-12-09 2013-07-10 Methods for treatment of cancer
EC2013012739A ECSP13012739A (es) 2010-12-09 2013-07-13 Uso de células t modificadas por receptor de antígeno quimérico para tratar cáncer
US14/107,302 US9328156B2 (en) 2010-12-09 2013-12-16 Use of chimeric antigen receptor-modified T cells to treat cancer
US14/465,952 US8975071B1 (en) 2010-12-09 2014-08-22 Compositions for treatment of cancer
US14/466,096 US8916381B1 (en) 2010-12-09 2014-08-22 Methods for treatment of cancer
US14/567,426 US9102760B2 (en) 2010-12-09 2014-12-11 Compositions for treatment of cancer
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US14/568,195 US9101584B2 (en) 2010-12-09 2014-12-12 Methods for treatment of cancer
US14/984,371 US9481728B2 (en) 2010-12-09 2015-12-30 Compositions and methods for treatment of cancer
US14/997,042 US9518123B2 (en) 2010-12-09 2016-01-15 Compositions and methods for treatment of cancer
US14/996,953 US9464140B2 (en) 2010-12-09 2016-01-15 Compositions and methods for treatment of cancer
US14/997,136 US9540445B2 (en) 2010-12-09 2016-01-15 Compositions and methods for treatment of cancer
US15/353,899 US20170283775A1 (en) 2010-12-09 2016-11-17 Compositions and Methods for Treatment of Cancer
AU2017203087A AU2017203087B2 (en) 2010-12-09 2017-05-09 Use of chimeric antigen receptor-modified t cells to treat cancer
US15/696,584 US20180258391A1 (en) 2010-12-09 2017-09-06 Compositions and Methods for Treatment of Cancer
AU2017225161A AU2017225161C1 (en) 2010-12-09 2017-09-10 Use of chimeric antigen receptor-modified t cells to treat cancer
CY20171101020T CY1119760T1 (el) 2010-12-09 2017-09-27 Χρηση τ κυτταρων τροποποιημενων απο χιμαιρικο υποδοχεα αντιγονου για τη θεραπευτικη αγωγη καρκινου
FR19C1006C FR19C1006I2 (fr) 2010-12-09 2019-02-15 Utilisation de lymphocytes t modifies par un recepteur d'antigenes chimerique pour traiter le cancer
NL300967C NL300967I2 (nl) 2010-12-09 2019-02-15 tisagenlecleucel
LTPA2019502C LTC2649086I2 (lt) 2010-12-09 2019-02-15 Chimeriniu antigenų receptoriumi modifikuotų ląstelių naudojimas vėžio gydymui
LTPA2019503C LTPA2019503I1 (lt) 2010-12-09 2019-02-15 Modifikuotų T ląstelių, turinčių chimerinų antigeno receptorių, panaudojimas vėžio gydymui
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