WO2011084479A1 - Substance p et analogues de celle-ci utiles en tant que traitement adjuvant pour l'immunothérapie cellulaire adoptive - Google Patents

Substance p et analogues de celle-ci utiles en tant que traitement adjuvant pour l'immunothérapie cellulaire adoptive Download PDF

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WO2011084479A1
WO2011084479A1 PCT/US2010/060505 US2010060505W WO2011084479A1 WO 2011084479 A1 WO2011084479 A1 WO 2011084479A1 US 2010060505 W US2010060505 W US 2010060505W WO 2011084479 A1 WO2011084479 A1 WO 2011084479A1
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xaa
substance
analog
seq
cells
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PCT/US2010/060505
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Hal Siegel
Daniel A. Holterman
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Immuneregen Biosciences, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/046—Tachykinins, e.g. eledoisins, substance P; Related peptides

Definitions

  • the present invention relates to use of a Substance P and analogs thereof to increase the effectiveness of immunotherapies for diseases such as cancer, allergies, autoimmune -related diseases, fibrotic diseases and other diseases where a dysregulation of the immune system mediates the symptoms of disease in patients.
  • Immunotherapies can include ex vivo immunizations, adoptive cellular immunotherapies (AO) and autologous or allogeneic transplantation of genetically or functionally modified cells with immune regulating properties 1 ' 2 ' 3 .
  • Increasingly immunotherapy in humans is being expanded to include the use of extraction, genetic or functional modification and re-implantation of selective and/or modified cells from the patient himself or another donor to treat an ever increasing number of immune-related conditions 4 .
  • These cells can target the immune system to recognize and mount an effective immune response against a previously hidden antigen (augmented immunity) or can suppress specific or general immunity that causes a disease, syndrome or condition. Therefore, currently envisioned immunotherapies can increase, decrease or rebalance the immune system for therapeutic benefit to the patient.
  • Conditions for which the immune system might be augmented include ex vivo generation of unique cellular or molecular components of the immune system.
  • Cellular components might include generation of adaptive or innate immunity through adoptive transfer of specific cell types.
  • Adoptive immune cells can include T cells and/or specific functional subsets of T cells such as cancer-specific cytotoxic T cells (CTLs) or B cells producing disease-specific antibodies as well as innate immune cells.
  • CTLs cancer-specific cytotoxic T cells
  • B cells producing disease-specific antibodies as well as innate immune cells.
  • cellular components that can be transferred include
  • suppressor cells examples include; regulatory T cells (Tregs), immature dendritic cells (iDCs), myeloid-derived suppressor cells (MDSCs), alternatively activated macrophages (M2 macrophages) or alternatively activated natural killer cells (NK2 cells) 5 ' 6 ' 7 ' 8 ' 9 .
  • Tregs regulatory T cells
  • iDCs immature dendritic cells
  • MDSCs myeloid-derived suppressor cells
  • M2 macrophages alternatively activated macrophages
  • NK2 cells alternatively activated natural killer cells
  • Molecular components of the immune system used for therapeutic intervention include; whole or fragments of immunoglobulin molecules, cytokines or chemokines 10 .
  • exosomes produced by certain immune cells in both in vivo and ex vivo circumstances have immunomodulating properties; capable of suppressing or stimulating an immune response 11 .
  • exosome -based therapies can be combined with conventional therapy such as chemotherapies in certain instances of envisioned usage of this invention 12 .
  • DCs dendritic cells
  • T cells are removed from patient blood and an in vitro activation procedure is performed to generate tumor specific CTLs.
  • the DCs are loaded with melanoma- specific peptides and subsequently Ag-specific T cells recognize the presented MHC/peptide complexes and become activated.
  • T cells for specificity and perhaps function, such as target cell killing or cytokine production, before selecting specific cells for expansion 13 .
  • These single cells (clones) are expanded to > lxlO 10 cells and reinjected back into the patient at several different time intervals to try to generate CTLs that will seek out and kill melanoma cells.
  • the current application of this technology in
  • a method of treating a subject suffering from a disease selected from the group consisting of cancer, an autoimmune disease, an allergic disease, a fibrotic disease, an infectious disease, and a genetic disease with adoptive cellular immunotherapy comprising administering to the subject immune cells that have been contacted with a first substance P analog wherein said first substance P analog is according to Formula (I):
  • Xaa 1 is Arg, Lys, 6-N methyllysine, or (6-N, 6-N) dimethyllysine
  • Xaa 2 is Pro or Ala
  • Xaa 3 is Lys, Arg, 6-N-methyllysine, or (6-N, 6-N) dimethyllysine;
  • Xaa 4 is Pro or Ala;
  • Xaa 5 is Gin or Asn;
  • Xaa 6 is Gin or Asn;
  • Xaa 7 is Phe or Phe substituted with chlorine at position 2, 3 or 4;
  • Xaa 8 is Tyr, Phe, or Phe substituted with chlorine at position 2, 3 or 4;
  • Xaa 9 is Gly, Pro, Ala or N-methylglycine;
  • Xaa 10 is Leu, Val, He, Norleucine, Met, Met sulfoxide, Met sulfone, N- methylleucine, or N-methylvaline;
  • Xaa 11 is Met, Met sulfoxide, Met sulfone or Norleucine; Zi is R 2 N- or RC(0)NR-;
  • Z 2 is -C(0)NR 2 or -C(0)OR or a salt thereof; each R is independently R is H, (Ci -C 6 ) alkyl, (Ci -C 6 ) alkenyl, (Ci -C 6 ) alkynyl, (C 5 -C 2 o) aryl, (C 6 -C 26 ) alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl; and each "— " between residues Xaa 1 through Xaa 11 independently designates an amide linkage, a substitute amide linkage or an isostere of an amide.
  • Xaa 1 is Arg
  • Xaa 2 is Pro
  • Xaa 3 is Lys
  • Xaa 4 is Pro
  • Xaa 5 is Gin
  • Xaa 6 is Gin
  • Xaa 7 is Phe or Phe substituted with chlorine at position 4;
  • Xaa 8 is Tyr, Phe, or Phe substituted with chlorine at position 4;
  • Xaa 9 is Gly, Pro or N-methylglycine;
  • Xaa 10 is Leu;
  • Xaa 11 is Met, Met sulfoxide, Met sulfone or Norleucine.
  • the "— " in said first Substance P analog between residues Xaa 1 through Xaa 11 designates -C(0)NH-;Zi is H 2 N-; and Z 2 is -C(0)NH 2 .
  • the first substance P analog is selected from the group consisting of:
  • RPKPQQFFGLM (SEQ ID NO. : 1);
  • RPKPQQFFGLNle (SEQ ID NO. : 2);
  • RPKPQQFFPLM (SEQ ID NO. : 3);
  • RPKPQQFFMeGlyLM SEQ ID NO. : 4
  • RPKPQQFTGLM SEQ ID NO.: 5
  • RPKPQQF(4-C1)F(4-C1)GLM (SEQ ID NO. : 6);
  • RPKPQQFFMeGlyLM(0 2 ) (SEQ ID NO.: 10).
  • the first substance P analog is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
  • Zi-RPKPQQFFMeGlyLM(0 2 )-Z 2 wherein Zi is NH 2 and Z 2 is C(0)NH 2 .
  • the disease is cancer.
  • the disease is an autoimmune disease.
  • the autoimmune disease is multiple sclerosis, lupus erythematosus, rheumatoid arthritis, or glomerulonephritis.
  • the disease is an allergic disease.
  • the disease is a fibrotic disease.
  • the fibrotic disease is sarcoidosis or pulmonary, hepatic or renal fibrosis.
  • the disease is an infectious disease.
  • the infectious disease is an infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) .
  • the disease is a genetic disease.
  • the genetic disease is X-linked hemophilia or neonatal severe combined immune deficiency syndrome.
  • the method further comprises administering to the subject a second substance P analog wherein said second substance P analog is according to Formula (I):
  • Xaa 1 is Arg, Lys, 6-N methyllysine, or (6-N, 6-N) dimethyllysine
  • Xaa 2 is Pro or Ala
  • Xaa 3 is Lys, Arg, 6-N-methyllysine, or (6-N, 6-N) dimethyllysine;
  • Xaa 4 is Pro or Ala;
  • Xaa 5 is Gin or Asn;
  • Xaa 6 is Gin or Asn;
  • Xaa 7 is Phe or Phe substituted with chlorine at position 2, 3 or 4;
  • Xaa 8 is Tyr, Phe, or Phe substituted with chlorine at position 2, 3 or 4;
  • Xaa 9 is Gly, Pro, Ala or N-methylglycine
  • Xaa 10 is Leu, Val, He, Norleucine, Met, Met sulfoxide, Met sulfone, N- methylleucine, or N-methylvaline;
  • Xaa 11 is Met, Met sulfoxide, Met sulfone or Norleucine;
  • Zi is R 2 N- or RC(0)NR-;
  • Z 2 is -C(0)NR 2 or -C(0)OR or a salt thereof;
  • each R is independently R is H, (Ci -C 6 ) alkyl, (Ci -C 6 ) alkenyl, (Ci -C 6 ) alkynyl, (C 5 -C 2 o) aryl, (C 6 -C 26 ) alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl; and
  • each "— " between residues Xaa 1 through Xaa 11 independently designates an amide linkage, a substitute amide linkage or an isostere of an amide.
  • Xaa 1 is Arg
  • Xaa 2 is Pro
  • Xaa 3 is Lys
  • Xaa 4 is Pro
  • Xaa 5 is Gin
  • Xaa 6 is Gin
  • Xaa 7 is Phe or Phe substituted with chlorine at position 4;
  • Xaa 8 is Tyr, Phe, or Phe substituted with chlorine at position 4;
  • Xaa 9 is Gly, Pro or N-methylglycine
  • Xaa 10 is Leu
  • Xaa 11 is Met, Met sulfoxide, Met sulfone or Norleucine.
  • the "— " in said second Substance P analog between residues Xaa 1 through Xaa 11 designates -C(0)NH-; Z 1 is H 2 N-; and Z 2 is -C(0)NH 2 .
  • the second substance P analog is selected from the group consisting of:
  • RPKPQQFFGLM (SEQ ID NO.: i);
  • RPKPQQFFGLNle (SEQ ID NO.: 2);
  • RPKPQQFFPLM (SEQ ID NO.: 3);
  • RPKPQQFFMeGlyLM SEQ ID NO.: 4
  • RPKPQQFTGLM (SEQ ID NO.: 5);
  • RPKPQQF(4-C1)F(4-C1)GLM (SEQ ID NO. : 6);
  • RPKPQQFFMeGlyLM(0 2 ) (SEQ ID NO.: 10).
  • the second substance P analog is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
  • the second substance P analog is administered to the subject prior to administration of said immune cells.
  • administration of the second Substance P analog is intradermal, intravenous, transdermal, oral, by inhalation, or subcutaneous.
  • said first Substance P analog is contacted to said immune cells while said immune cells are being activated and induced. In certain embodiments, said first Substance P analog is contacted to said immune cells while said immune cells are being expanded. In certain embodiments, said first Substance P analog is contacted to said immune cells while said immune cells are being activated and induced and being expanded. In certain embodiments, said first Substance P analog is contacted to said immune cells after said immune cells are activated and induced and expanded but prior to administration to the subject.
  • the concentration of the first Substance P analog is about lng/ml to about lOOmg/ml. In certain embodiments, the concentration of the first Substance P analog is about lng/ml to about lOOmg/ml. In certain embodiments, the concentration of the first Substance P analog is about lng/ml to about lOOmg/ml. In certain embodiments, the concentration of the first Substance P analog is about lng/ml to about lOOmg/ml.
  • transplanted CTLs often do not survive long in the patient so their immunological impact is limited 14 , 15 , 16 .
  • Attempts to extend the survival of transplanted effector cells in contemporary immunotherapies have involved either the use of co-stimulatory molecules or genetic manipulations. These results have not been shown to be effective in clinical management of diseases like cancer so there is a real need for compounds that can extend the survival and function of these ex vivo expanded CTLs, DCs and other immune effector cells 17 .
  • Whether Sar9, Met(02)l 1 - Substance P is able to augment or suppress the immune response in specific patients after ACI may be determined by the type of cell targeted and expanded, the immunomicroenvironment and additional immune modulating signals from cytokines and/or co-stimulatory/suppressive molecules.
  • Diseases where immunity is weakened by the disease such as cancer or viral infections may be effectively treated using ACI protocols that transfer immune stimulating cells.
  • Diseases where excess immunity causes the disease may be effectively treated using protocols that transfer immune suppressing cells. In both cases it is advantageous for the patient that the immune modifications mediated by the specific ACI protocol last as long as possible for the maximum clinical benefit.
  • alkyl refers to a saturated branched, straight chain or cyclic hydrocarbon radical.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, and the like.
  • the alkyl groups are (Ci -C 6 ) alkyl.
  • alkenyl refers to an unsaturated branched, straight chain or cyclic hydrocarbon radical having at least one carbon-carbon double bond.
  • the radical may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, tert-butenyl, pentenyl, hexenyl and the like.
  • the alkenyl group is (Ci -C 6 ) alkenyl.
  • alkynyl refers to an unsaturated branched, straight chain or cyclic hydrocarbon radical having at least one carbon-carbon triple bond.
  • Typical alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl and the like.
  • the alkynyl group is (Ci -C 6 ) alkynyl.
  • aryl refers to an unsaturated cyclic hydrocarbon radical having a conjugated ⁇ electron system.
  • Typical aryl groups include, but are not limited to, penta-2,4- diene, phenyl, naphthyl, anthracyl, azulenyl, chrysenyl, coronenyl, fluoranthenyl, indacenyl, idenyl, ovalenyl, perylenyl, phenalenyl, phenanthrenyl, picenyl, pleiadenyl, pyrenyl, pyranthrenyl, rubicenyl, and the like.
  • the aryl group is (C 5 -C 2 o) aryl, with (C 5 -Cio) being particularly preferred.
  • alkaryl refers to a straight-chain alkyl, alkenyl or alkynyl group wherein one of the hydrogen atoms bonded to a terminal carbon is replaced with an aryl moiety.
  • Typical alkaryl groups include, but are not limited to, benzyl, benzylidene, benzylidyne, benzenobenzyl, naphthenobenzyl and the like.
  • the alkaryl group is (C 6 -C 26 ) alkaryl, i.e., the alkyl, alkenyl or alkynyl moiety of the alkaryl group is (Ci -C 6 ) and the aryl moiety is (C 5 -C 2 o).
  • the alkaryl group is (C 6 -C 13 ) alkaryl, i.e., the alkyl, alkenyl or alkynyl moiety of the alkaryl group is (Ci -C3) and the aryl moiety is (C5-C10).
  • heteroaryl refers to an aryl moiety wherein one or more carbon atoms is replaced with another atom, such as N, P, O, S, As, Se, Si, Te, etc.
  • Typical heteroaryl groups include, but are not limited to, acridarsine, acridine, arsanthridine, arsindole, arsindoline, carbazole, ⁇ -carboline, chromene, cinnoline, furan, imidazole, indazole, indole, indolizine, isoarsindole, isoarsinoline, isobenzofuran, isochromene, isoindole,
  • the heteroaryl group is a 5- 20 membered heteroaryl, with 5-10 membered aryl being particularly preferred.
  • alkheteroaryl refers to a straight-chain alkyl, alkenyl or alkynyl group where one of the hydrogen atoms bonded to a terminal carbon atom is replaced with a heteroaryl moiety.
  • the alkheteroaryl group is 6-26 membered alkheteroaryl, i.e., the alkyl, alkenyl or alkynyl moiety of the alkheteroaryl is (Ci -C 6 ) and the heteroaryl is a 5-20-membered heteroaryl.
  • the alkheteroaryl is 6-13 membered alkheteroaryl, i.e., the alkyl, alkenyl or alkynyl moiety is a 5- 10 membered heteroaryl.
  • substituted alkyl, alkenyl, alkynyl, aryl alkaryl, heteroaryl or alkheteroaryl refers to an alkyl, alkenyl, alkynyl, aryl, alkaryl, heteroaryl or alkheteroaryl group in which one or more hydrogen atoms is replaced with another substituent.
  • Preferred substituents include -OR, -SR,— NRR, -N0 2 , -CN, halogen, -C(0)R, -C(0)OR and — C(0)NR, wherein each R is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl, heteroaryl or alkheteroaryl.
  • the term "antigen presenting cell” refers to an immune accessory cell that participates in antigen-inductive events, and includes mononuclear phagocytes, dendritic cells, and B cells, which express high levels of class I MHC.
  • the B cell antigen presenting cell is a lymphoblastoid cell or lymphoblastoid cell line (LCL), i.e., a B cell transformed by infection with Epstein-Barr virus (EBV).
  • the antigen presenting cell is a dendritic cell.
  • Autologous antigen presenting cells i.e., antigen presenting cells obtained from the same donor as the effector cells, are preferred.
  • class I MHC-matched antigen presenting cells from a different donor can be used with autologous T cells.
  • modified antigen presenting cell refers to an antigen presenting cell treated to process via the class I MHC molecule viral particles that are not actively infectious in the cells via the class I MHC molecule.
  • antigen presenting cells are treated to induce maturation or activation, e.g. , by culturing, preferably in the presence of a specific growth or stimulatory factor or factors.
  • dendritic cells are modified by culturing with GM-CSF to process and present whole viral particles.
  • B cells transformed with EBV are considered modified antigen presenting cells.
  • transduced antigen presenting cells refer to antigen presenting cells that have been effectively transfected or transformed with a vector that expresses an antigen, such as a latent virus antigen or a tumor antigen, such that the antigen is expressed and presented via class I MHC by the antigen presenting cell.
  • an antigen such as a latent virus antigen or a tumor antigen, such that the antigen is expressed and presented via class I MHC by the antigen presenting cell.
  • more than about 30% of the antigen presenting cells are transduced; more preferably, more than about 50% of the antigen presenting cells are transduced; still more preferably, more than about 60% of the antigen presenting cells are transduced. In a specific embodiment, 60%> of dendritic cells are successfully transduced.
  • effector cell refers to the cells of the immune system that mount responses to protect individuals from pathogens, preferably viruses, tumor viruses, and tumors (including viral and non-viral tumors) [see Fundamental Immunology, Third Edition, p. 18].
  • One effector cell is a population of cytotoxic T cells and T helper cells that host cellular immunity. The presence of both cell types enhances cellular immunity, both in terms of vigor and length.
  • Cytotoxic T cells generally are CD8-positive (CD8 + , or simply CD8), and class I MHC-restricted, although CD4-positive (CD4 + , or simply CD4) cytotoxic T cells and class II MHC-restricted CD8 cells have also been identified (Fitch et ah, Fundamental Immunology, Third Edition, pp. 748-750). Most such cells express an ⁇ , ⁇ - T cell antigen receptor-CD3 complex, which is antigen specific. Some CD8-positive cells may express a ⁇ , ⁇ - ⁇ cell antigen receptor-CD3 complex, which does not seem to be antigen specific.
  • virus- or antigen-specific effector cells include CD4-positive (class II MHC restricted) cells, also termed helper T cells.
  • helper T cells T cells
  • Thl cells T cells
  • Th2 cells T cell receptor-positive cells
  • the effector cell populations may include CD56-positive natural killer (NK) cells and lymphokine- activate killer (LAK) cells, and B cells.
  • B-cell and "B-lymphocyte” are used interchangeably and
  • T-cell and T-lymphocyte are used
  • a molecule is "antigenic” when it is capable of specifically interacting with an antigen recognition molecule of the immune system, such as an immunoglobulin (antibody) or T cell antigen receptor.
  • An "immunogenic" molecule is an antigen capable of eliciting an immune response, e.g. , a whole protein or organism.
  • An antigenic polypeptide contains at least about 5, and preferably at least about 10, amino acids.
  • the term "antigen” refers to a protein from a pathogen that is targeted by effector cells of the cellular immune system.
  • pathogen is used to refer to pathogenic viruses, latent viruses
  • tumor viruses are those viruses in which the active virus particle replication is the cause of morbidity.
  • a “latent virus” is a virus that exhibits pathogenic effects in its latent phase, and includes hepatitis viruses and tumor viruses, such as EBV and HPV.
  • a tumor is a transformed cell, such as a cancer cell, which may express tumor-specific antigens that can serve as targets for stimulating effector cell responses according to the invention.
  • the term "about” means within about 20%, preferably within about 10 %, and more preferably within about 5%.
  • Dendritic cell is used herein to refer to the active antigen presenting cells found in epithelia and thymus-dependent areas of lymphoid tissues [see Unanue, Fundamental Immunology, Third Edition, Paul (ed.), Raven Press, Ltd.: New York. pp. 119- 121 (1993)]. They are characterized by their peculiar dendritic morphology and multiple thin- membrane projections, and by a high density of class II MHC molecules. Dendritic cells include Langerhans cells of the skin, "veiled cells” of afferent lymphatics, follicular dendritic cells, dendritic cells of the spleen, and interdigitating cells of lymphoid organs. Dendritic cells can be obtained from the skin, spleen, bone marrow, or other lymphoid organs, lymph nodes, or blood.
  • CTL immunotherapy has great promise for treating Epstein-Barr virus (EBV) lymphoproliferative disease and EBV-associated Hodgkin disease following bone marrow transplant (BMT).
  • EBV lymphoproliferative disease occurs in about 3-30% of BMT recipients who receive marrow from unrelated donors.
  • Adenovirus infections are common in patients receiving chemotherapy, organ transplantation rejection therapy, and in 10-30% of BMT patients.
  • CTL immunotherapy has significant potential for treating these infections and for treating other viruses associated with malignancies such as adult nasopharyngeal carcinoma (NPC), and for recipients of organ transplants (who are also at risk for
  • NPC adult nasopharyngeal carcinoma
  • cytomegalovirus CMV
  • infection papillomavirus-induced laryngeal papillomatosis and certain cancers
  • immunocompromised patients such as acquired immunodeficiency syndrome (AIDS) or severe combined immunodeficiency disease (SCID) patients.
  • AIDS acquired immunodeficiency syndrome
  • SCID severe combined immunodeficiency disease
  • Virus-specific CTLs can be generated using antigen presenting cells actively infected with virus as stimulators.
  • Riddell et al. [Science 257:238 (1992)] described generating human CMV-specific CTL clones in vitro with CMV-infected fibroblasts as the stimulating cells.
  • Riddel used CD8 + clones (no CD4 cells were present), which persist only for 6-12 weeks [as described in Walter et al., NEJM 333: 1038 (1995)].
  • CD8 + and CD4 + cells (which maintain survival of CD8 + cells) can also be used, thereby permitting CTLs to persist for many months.
  • Rooney et al. [Lancet 345:9-13 (1995); see also Heslop et al., Nature Med. 2:551 (1996)] describe stimulating EBV-specific CTLs with EBV- transformed B cell lymphoblastoid lines.
  • Class I MHC -restricted antigen presentation can be achieved with whole virions, in the absence of productive viral infection of the antigen presenting cells by the virus.
  • whole virus can be processed and presented in the context of class I MHC, without requiring cellular expression of viral antigens and subsequent fragmentation of viral antigens into peptides.
  • the primary or secondary immune responses can be induced against viruses that do not actively infect the antigen presenting cell, thereby eliminating contamination of cell populations with infectious virus.
  • Antigen presenting cells can be transduced with nucleic acid encoding viral or tumor antigens to generate potent primary or secondary immune responses against these antigens. More importantly, the transduced antigen presenting cells can generate strong responses to relatively weak immunogenic or non- immunogenic antigens.
  • CTLs are generated against the weak EBV antigen LMP-2a. These CTLs are excellent candidates for immunotherapy for Hodgkin's disease and NPC, in which the tumors only express such weak EBV antigens.
  • B cells are well known antigen presenting cells [Unanue, supra, pp. 123-124]. Antigen-specific B cells present their cognate antigen very efficiently, demonstrating as much as 100- to 10,000-fold greater efficiency compared to non-specific antigen presentation. Generally, B cells require initial activation to become competent for antigen presentation, e.g., by treatment with polyclonal activators or cytokines, including but not limited to anti-Ig and IFN- ⁇ , by increasing expression of the B7 molecule on the B cells with T cell lymphokines such as IL-2 and IL-4, or by infection with EBV.
  • polyclonal activators or cytokines including but not limited to anti-Ig and IFN- ⁇
  • T cell lymphokines such as IL-2 and IL-4
  • EBV -transformed B cell lines are used as antigen presenting cells, either for whole virions or transduced with viral or tumor antigen expression vectors, or for endogenously expressed EBV latency-associated protein.
  • LCLs lymphoblastoid cell lines
  • a second virus e.g., adenovirus or CMV
  • a population of effector cells specific for both EBV and another pathogen can be generated using LCLs as antigen presenting cells.
  • LCLs Preparation of LCLs is well known in the art [Smith et al, J. Hematother. 4:73-79 (1995); Rooney et al, supra; Heslop et al, supra].
  • PBMCs peripheral blood mononuclear cells
  • the cells are treated with cyclosporin A alone for spontaneous transformation, or with concentrated supernatant derived from cultures of cells transformed with EBV.
  • marmoset B cells transformed with human type 1 EBV are marmoset B cells transformed with human type 1 EBV [Miller and Lipman, Proc. Natl. Acad. Sci. USA 84: 190 (1973); Rickinson et al, Cell. Immunol. 87:646 (1984)].
  • LCLs can be maintained in culture, e.g., in an RPMI-based culture medium, or frozen.
  • Antigen presenting cells also include "mononuclear phagocyte lineage" cells, e.g., macrophages [see Unanue, supra, pp. 112-115].
  • Macrophages for use as antigen presenting cell in accordance with the present invention include, but are not limited to, splenic macrophages, blood-borne macrophages, bone marrow macrophages, Kupfer cells, peritoneal macrophages ⁇ e.g., elicited with peptone or thioglycollate), alveolar macrophages, microglia, and macrophages of endocrine organs.
  • Macrophages can be activated to present antigen, e.g, by contacting them with GM-CSF, macrophage CSF (M-CSF), granulocyte CSF (G-CSF), tumor necrosis factor (TNF)-a, TNF- ⁇ , IL-1, IL-6, IL-8, IL-12, macrophage inflammatory protein ( ⁇ )- ⁇ , MIP- 1 ⁇ , MIP-2, and interferon- ⁇ (IFN- ⁇ ).
  • IFN- ⁇ is a preferred stimulatory agent to modify macrophages for stimulation of effector cells in accordance with the present invention.
  • Modified antigen presenting cells can be pulsed with viral particles which are not capable of productive infection in the antigen presenting cells.
  • Antigen presenting cells can be pulsed with virus at a multiplicity of at least 10, and preferably of at least 100; in a specific embodiment the cells are treated at a multiplicity of infection (MOI) of 100.
  • Multiplicity varies amongst viruses. For adenovirus the range should be between 50-1000. The MOI may range up to 10,000: 1.
  • the time of treatment should be sufficient to allow uptake of the virus by the cell; preferably, the cells are exposed to viral particles for at least 30 min to one hour.
  • the antigen presenting cells may then be irradiated, e.g., at from 1000 to 3000 cGy.
  • Dendritic cells and LCLs are preferably irradiated at 3000 cGy.
  • the viral-pulsed antigen presenting cells are particularly useful for generating effector cells against immunodominant viral antigens. Accordingly, these effector cells may be useful for treating viral infections characterized by morbidity to active infectious virus or viral tumors or transformed cells in which immunodominant viral antigens are present.
  • the former viruses include, but are by no means limited to, herpes virus, parainfluenza virus, adenovirus, cytomegalovirus, HIV-1, HIV-2, influenza virus, rabies virus, and rhino virus.
  • An examples of the latter include EBV in EBV
  • antigen presenting cells can be transduced to express specific antigens for generating antigen-specific immune responses.
  • a specific primary or secondary immune response against the weak EBV antigen LMP2a can be generated with LP2a-transduced dendritic cells.
  • Similar specific responses can be generated to tumor specific antigens, including but by no means limited to prostate-specific antigen (PSA), human leukemia-associated antigen, carcinoembryonic antigen (CEA), and the melanoma-specific antigens MAGE-1 and MART-1.
  • PSA prostate-specific antigen
  • CEA carcinoembryonic antigen
  • MAGE-1 and MART-1 melanoma-specific antigens
  • immunotherapy requires, effector cell population against a selected antigen, including a weakly immunogenic antigen, can be developed.
  • the adoptive immunotherapy is directed to the immunotherapeutic treatment of tumors, particularly solid tumors.
  • solid tumors that can be treated include sarcomas and carcinomas that are known or found to express a tumor specific antigen, such as, but not limited to: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary
  • hemangioblastoma acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, and retinoblastoma.
  • Identification of a tumor-specific antigen for such tumors such as a papillomavirus antigen of a cervical cancer tumor, an EBV antigen of a nasopharyngeal carcinoma, HTLV-1 antigen of a T cell lymphoma, or a MAGE-1 or MART- 1 antigen of a melanoma, provides a target antigen for transducing an antigen presenting cell and generating effector cells for immunotherapy.
  • latent viral infections which can erupt in active disease, particularly latent tumor viruses
  • latent viral infections in which a specific viral antigen can be targeted include, but are by no means limited to, Epstein-Barr virus, papillomavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, papovavirus, HIV-1, HIV-2, human T-lymphotrophic virus (HTLV)-l, and HTLV-2.
  • a vector can be prepared to express LMP2a or papillomavirus antigen to generate a latent virus-specific cellular immune response.
  • Effective transduction of the antigen presenting cells is preferred.
  • Effective transduction means high level transduction with sufficient antigen expression to generate an antigen-specific immune response.
  • effective transduction is achieved when 30% of antigen presenting cells are transduced.
  • Most preferably, 100% of the cells are transduced, and express, process, and present the transduced antigen in the context of the class I MHC molecule. Necessarily, any immune response must be against the specific antigen, i.e., a tumor specific antigen or latent virus antigen.
  • Viral vectors are commonly used for ex vivo targeting and therapy procedures; these include DNA-based vectors and retroviral vectors. Methods for constructing and using viral vectors are known in the art [see, e.g., Miller and Rosman, BioTechniques 7:980-990 (1992)].
  • DNA viral vectors include an attenuated or defective DNA virus, such as but not limited to herpes simplex virus (HSV), papillomavirus, Epstein Barr virus (EBV), adenovirus, adeno-associated virus (AAV), and the like.
  • HSV herpes simplex virus
  • EBV Epstein Barr virus
  • AAV adeno-associated virus
  • Defective viruses which entirely or almost entirely lack viral genes, are preferred. Defective virus is not infective after introduction into a cell.
  • different viral vectors may exhibit specificity for one or another cell type.
  • particular vectors include, but are not limited to, a defective herpes virus 1 (HSV1) vector [Kaplitt et al, Molec. Cell. Neurosci. 2:320-330 (1991)], defective herpes virus vector lacking a gly co-protein L gene [Patent Publication RD 371005 A], or other defective herpes virus vectors [International Patent Publication No. WO
  • Herpes virus vectors are preferred for dendritic cells.
  • the gene can be introduced in a retroviral vector, e.g., as described in Anderson et al, U.S. Pat. No. 5,399,346; Mann et al, 1983, Cell 33: 153; Temin et al, U.S. Pat. No. 4,650,764; Temin et al, U.S. Pat. No. 4,980,289; Markowitz et al, 1988, J. Virol. 62: 1120; Temin et al, U.S. Pat. No. 5,124,263; International Patent Publication No. WO 95/07358, published Mar.
  • infra a Harvey murine retroviral vector is used to transduce dendritic cells. Retroviral vectors can be constructed to function as infectious particles or to undergo a single round of transfection. In the former case, the virus is modified to retain only those genes responsible for packaging and replication and to express the heterologous gene. In a specific embodiment, infra, an infectious viral vector is used. Non-infectious viral vectors are prepared to destroy the viral packaging signal, but retain the structural genes required to package the co-introduced virus engineered to contain the heterologous gene and the packaging signals. Thus, the viral particles that are produced are not capable of producing additional virus.
  • the vector can be introduced in vivo by lipofection.
  • liposomes for encapsulation and transfection of nucleic acids in vitro.
  • Synthetic cationic lipids designed to limit the difficulties and dangers encountered with liposome mediated transfection can be used to prepare liposomes for in vivo transfection of a gene encoding a marker [Feigner, et. al, Proc. Natl. Acad. Sci. U.S.A.
  • cationic lipids may promote encapsulation of negatively charged nucleic acids, and also promote fusion with negatively charged cell membranes [Feigner and Ringold, Science 337:387-388 (1989)].
  • DNA vectors for gene therapy can be introduced into the desired host cells by methods known in the art, e.g., transfection, electroporation, microinjection, transduction, cell fusion, DEAE dextran, calcium phosphate precipitation, use of a gene gun, or use of a DNA vector transporter [see, e.g., Wu et al, J. Biol. Chem. 267:963-967 (1992); Wu and Wu, J. Biol. Chem. 263: 14621-14624 (1988); Hartmut et al, Canadian Patent Application No. 2,012,311, filed Mar. 15, 1990; Williams et al, Proc. Natl. Acad. Sci. USA 88:2726-2730 (1991)].
  • a DNA vector transporter see, e.g., Wu et al, J. Biol. Chem. 267:963-967 (1992); Wu and Wu, J. Biol. Chem. 263: 14621-14624 (1988); Hartmut e
  • LCLs population, such as LCLs.
  • a variety of antigen presenting cells can be used as targets including dendritic cells, B lymphoblastoid cell lines, primary B cells, macrophages, and leukemic blasts.
  • LNL6 or GINa vectors which encode the neomycin resistance gene
  • a NGFR vector which encodes a truncated nerve growth factor receptor
  • the neo transgene is detected by PCR or clonogenic assays in the presence of G418 [Brenner et al, Lancet 342: 1134, (1993); Heslop et al, Nature
  • the NGFR product is detected by flow cytometry.
  • BLCL are efficient antigen presenting cells and transduction may allow their use to stimulate CTL specific for an antigen encoded by the transferred gene.
  • a potential example would be adenovirus or CMV antigens.
  • Dendritic cells are the most potent antigen presenting cell and efficient retroviral transduction allows their use as stimulator cells to generate CTL specific for antigens encoded by the transferred gene. As these cells can also induce primary immune responses, this strategy may be particularly useful for adoptive immunotherapy approaches.
  • a source of functional effector cells comprising CTLs, provided to an
  • immunocompromised patient may overcome vulnerability to infection.
  • Great successes have been achieved using CTLs generated against EBV-transformed LCLs [Rooney et ah, supra; Heslop et al., supra].
  • Effector cells can be obtained from MHC-matched donors (or from a patient prior to immunosuppression) and co-cultured with the antigen presenting cells to generate an antigen- or virus-specific effector cell population.
  • the subject to receive treatment is undergoing bone marrow transplantation, preferably the bone marrow donor also provides the effector cells. Since the cells are obtained from donor (or the subject), and treated outside the body prior to administration for immunotherapy, the term "ex vivo" is employed to describe the selection process.
  • effector cells are cultured with irradiated antigen presenting cells that have been pulsed with viral particles or transduced with a vector for expression of a specific antigen.
  • Peripheral blood mononuclear cells (PBMCs) or peripheral blood lymphocytes (PBLs) from the donor are added to the antigen presenting cells, e.g., at a ratio of from 1 :5 to 100: 1, preferably 40: 1.
  • the PBMCs are added to dendritic cells at a ratio of 2: 1.
  • PBMCs are added to LCLs at a ratio of 40: 1.
  • the antigen presenting cells stimulate proliferation of antigen- or virus-specific effector cells; non-specific effector cells (CD4 and CD8 T cells) do not proliferate, and abate. Thus, for a population of effector cells consisting of virus- or antigen-specific cells are enriched.
  • PBMCs or PBLs are readily obtained and very easy to use as the source of effector cells, selection or isolation techniques can be used to enrich the effector population further.
  • the cells can be depleted of CD56-positive lymphocytes.
  • CD3 -positive cells, . ⁇ ,. ⁇ - ⁇ cell receptor-positive cells, or even ⁇ , ⁇ - ⁇ cell receptor positive cells can be selected (or the latter depleted), e.g., by FACS or panning.
  • B cells present in PBMCs or PBLs can be depleted, e.g., by panning or anti-Ig plus
  • T lymphocytes can be selected by nylon wool passage as well.
  • the effector cells are generally co-cultured with the irradiated APCs for about 7 to 14 days, and preferably about 10 days.
  • the effector cells are harvested and restimulated with fresh antigen presenting cells.
  • At least two cycles of stimulation are necessary to get a highly enriched population of virus- or antigen-specific effector cells. Additional stimulation cycles will result in maintenance of a highly specific population of effector cells, but will not provide significantly greater specificity.
  • Cellular immunotherapy with EBV-specific effector cells obtained after two cycles of stimulation on irradiated LCLs showed no evidence of GVH disease.
  • the effector cells g are useful for immunotherapy for active and latent viral infections, including but by no means limited to EBV, adenovirus, CMV, etc.
  • CTL immunotherapy may also prove useful for the treatment of adult nasopharyngeal carcinoma (an EBV associated malignancy); for recipients of heart, heart-lung or bowel transplant (10% of whom develop EBV lymphoma); and for other transplant recipients (1-2% of whom develop EBV lymphoma).
  • Transplant patients are also at risk for cytomegalovirus infection, a non-fatal but highly prevalent disease which should also be amenable to CTL immunotherapy.
  • Papilloma virus which causes laryngeal papillomatosis in infants, as well as certain head, neck and cervical cancers in adults, may also be treatable with CTL
  • AIDS patients who are severely immunocompromised and susceptible to opportunistic infections including herpesvirus and CMV, represent another group who may be treated with CTL immunotherapy.
  • either the transduced or viral particle-pulsed APCs of the invention can be used to generate a population of effector cells specific for more than one pathogen.
  • multi-pathogen effector cells are given prophylactically, after bone marrow transplantation, immunosuppressive therapy for organ transplantation, or chemotherapy.
  • the substance P analog can be of Formula (I):
  • Xaa 1 is Arg, Lys, 6-N methyllysine, or (6-N, 6-N) dimethyllysine;
  • Xaa 2 is Pro or Ala
  • Xaa 3 is Lys, Arg, 6-N-methyllysine, or (6-N, 6-N) dimethyllysine;
  • Xaa 4 is Pro or Ala;
  • Xaa 5 is Gin or Asn;
  • Xaa 6 is Gin or Asn;
  • Xaa 7 is Phe or Phe substituted with chlorine at position 2, 3 or 4;
  • Xaa 8 is Tyr, Phe, or Phe substituted with chlorine at position 2, 3 or 4;
  • Xaa 9 is Gly, Pro, Ala, or N-methylglycine;
  • Xaa is Leu, Val, He, Norleucine, Met, Met sulfoxide, Met sulfone, N- methylleucine, or N-methylvaline;
  • Xaa 11 is Met, Met sulfoxide, Met sulfone, or Norleucine;
  • Zi is R 2 N- or RC(0)NR-;
  • Z 2 is -C(0)NR 2 or -C(0)OR or a salt thereof; each R is independently R is H, (Ci -C 6 ) alkyl, (Ci -C 6 ) alkenyl, (Ci -C 6 ) alkynyl, (C 5 -C 2 o) aryl, (C 6 -C 26 ) alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl; and each "— " between residues Xaa 1 through Xaa 11 independently designates an amide linkage, a substitute amide linkage or an isostere of an amide.
  • the substance P analogs can be of Formula (I) wherein Xaa is Arg; Xaa is Pro; Xaa is Lys; Xaa is Pro; Xaa is Gin; Xaa is Gin; Xaa is Phe or
  • Xaa 8 is Tyr, Phe, or Phe substituted with chlorine at position 4;
  • Xaa 9 is Gly, Pro or N-methylglycine;
  • Xaa 10 is Leu;
  • Xaa 11 is Met, Met sulfoxide, Met sulfone, or Norleucine.
  • the "— " between residues Xaa 1 through Xaa 11 of the substance P analogs can be -C(0)NH-; and Zi is H 2 N-; and Z 2 is -C(0)NH 2 .
  • substance P analogs can be selected from the group consisting of:
  • RPKPQQFFGLM (SEQ ID NO. : 1);
  • RPKPQQFFGLNle (SEQ ID NO. : 2);
  • RPKPQQFFPLM (SEQ ID NO. : 3);
  • RPKPQQFFMeGlyLM (SEQ ID NO. : 4);
  • RPKPQQFTGLM (SEQ ID NO. : 5);
  • RPKPQQF(4-C1)F(4-C1)GLM (SEQ ID NO.: 6);
  • RPKPQQFFGLM(O) (SEQ ID NO. : 7); RPKPQQFFMeGlyLM(O) (SEQ ID NO. : 8);
  • RPKPQQFFMeGlyLM(0 2 ) (SEQ ID NO.: 10).
  • the substance P analog can be any substance P analog.
  • the amino (designated herein as Zi) or carboxy terminus (designated herein as Z 2 ) of the substance P analogs can be modified. Included are "blocked" forms of the substance P analogs, i.e., forms of the substance P analogs in which the N- and/or C-terminus is blocked with a moiety capable of reacting with the N-terminal— NH 2 or C-terminal— C(0)OH.
  • the N- and/or C- terminal charges of the substance P analogs can be an N-acylated peptide amide, ester, hydrazide, alcohol and substitutions thereof.
  • N- and/or C-terminus preferably both termini of the substance P analogs are blocked.
  • Typical N- terminal blocking groups include RC(O)— , where R is— H, (Ci -C 6 ) alkyl, (Ci -C 6 ) alkenyl, (Ci -C 6 ) alkynyl, (C 5 -C 20 ) aryl, (C 6 -C 26 ) alkaryl, 5-20 membered heteroaryl or 6-26 membered alkheteroaryl.
  • Preferred N-terminal blocking groups include acetyl, formyl and dansyl.
  • Typical C-terminal blocking groups include— C(0)NRR and— C(0)OR, where each R is independently defined as above. Preferred C-terminal blocking groups include those where each R is independently methyl. In another preferred embodiment the C-terminal group is amidated.
  • Substituted amides generally include, but are not limited to, groups of the formula -C(0)NR- where R is (Ci -C 6 ) alkyl, substituted (Ci -C 6 ) alkyl, (Ci -C 6 ) alkenyl, substituted (Ci -C 6 ) alkenyl, (Ci -C 6 ) alkynyl, substituted (Ci -C 6 ) alkynyl, (C 5 -C 20 ) aryl, substituted (C 5 -C 20 ) aryl, (C 6 -C 26 ) alkaryl, substituted (C 6 -C 26 ) alkaryl, 5-20 membered heteroaryl, substituted 5-20 membered heteroaryl, 6-26 membered alkheteroaryl and substituted 6-26 membered alkheteroaryl.
  • R is (Ci -C 6 ) alkyl, substituted (Ci -C 6 ) alky
  • Compounds having such non-amide linkages and methods for preparing such compounds are well-known in the art (see, e.g., Spatola, March 1983, Vega Data Vol. 1, Issue 3; Spatola, 1983, "Peptide Backbone Modifications" In: Chemistry and Biochemistry of Amino Acids Peptides and Proteins, Weinstein, ed., Marcel Dekker, New York, p.
  • one or more amide linkages can be replaced with peptidomimetic or amide mimetic moieties which do not significantly interfere with the structure or activity of the peptides.
  • Suitable amide mimetic moieties are described, for example, in Olson et al, 1993, J. Med. Chem. 36:3039-3049.
  • the substance P analogs can have a modified methionine residue.
  • the methionine residue side chain S can be oxidated.
  • the methionine is methionine sulfoxide (-NH-CHa(CO)-CH 2 -CH 2 - S(0)CH3).
  • the methionine is methionine sulfone or methionine S, S, dioxide, (-NH-CHa (CO)-CH 2 -CHa 2 -S(0 2 )CH 3 ) , also referred to herein as Met(0) 2 .
  • NK1R relevant human immune cells are assessed to determine expression of NK1R. These immune cells will include CD4 + helper T cells, CD8+ CTLs, B cells, NK cells, Tregs, DCs among others. a. If no expression of NK1R is detected then the likelihood that an analog of substance P would be beneficial is reduced so a series of studies areperformed incorporating in vitro pre -incubation steps (that may more closely approximate in situ microenvironmental conditions) with co-factors known to increase NK1R including cytokines, chemokines, co-stimulatory molecules and immune modulators like toll-like receptors (TLRs).
  • TLRs toll-like receptors
  • naive cellular subsets express the receptor for the peptide is whether the target cells used in commonly accepted ACI protocols express the receptor at specific stages of cell processing. These stages typically include extraction, enrichment, activation, selection, expansion, possibly cryopreservation and reinfusion.
  • leukopheresis leukopheresis, T cell and DC isolation, separation and enrichment of subpopulations of immune cells, in vitro immune activation procedures, selection of individual cells based on function and expansion of the clone to therapeutic numbers of cells.
  • 10 10 10 billion cells are used for a series of ACI regiments.
  • Cells from each step of either animal or human studies will be quantified for expression of the NK1R.
  • Penultimate confirmation can be determined by a Phase I/II clinical trial using the most promising ACI from the preliminary in vitro and ex vivo studies to determine whether the addition of Sar9, Met(02)l 1 - Substance P results in an improved clinical outcome for commonly accepted ACI protocols compared with patients receiving the ACI without Sar9, Met(02)l l - Substance P.

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Abstract

La présente invention concerne l'utilisation d'analogues de substance P (le peptide) pour accroître, par exemple, l'efficacité médicale d'immunothérapies pour des maladies telles que le cancer, une infection virale, une infection bactérienne, des maladies génétiques, des maladies auto-immunes et d'autres maladies et syndromes de type immunitaire. Les analogues sont appropriés à l'utilisation in vivo, ex vivo, ou in vitro du peptide en tant qu'adjuvant d'immunothérapies cellulaires adoptives (ICA) couramment utilisées ou de nouvelles combinaisons d'ICA et d'autres thérapies compatibles pour ces maladies. La présente invention concerne en outre des procédés associés à l'utilisation du peptide à différents stades de protocoles ICA suivant la maladie cible et le protocole ICA envisagé.
PCT/US2010/060505 2009-12-15 2010-12-15 Substance p et analogues de celle-ci utiles en tant que traitement adjuvant pour l'immunothérapie cellulaire adoptive WO2011084479A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030134341A1 (en) * 2001-09-19 2003-07-17 Medcell Biologics, Llc. Th1 cell adoptive immunotherapy
US20030175247A1 (en) * 2000-05-12 2003-09-18 Michael Salgaller Method to increase class I presentation of exogenous antigens by human dendritic cells
US20060121005A1 (en) * 2000-02-24 2006-06-08 Xcyte Therapies, Inc. Activation and expansion of cells
US20090028834A1 (en) * 2007-07-27 2009-01-29 Hal Siegel Methods and compositions for stimulating the proliferation or differentiation of stem cells with substance P or an analog thereof

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
US20060121005A1 (en) * 2000-02-24 2006-06-08 Xcyte Therapies, Inc. Activation and expansion of cells
US20030175247A1 (en) * 2000-05-12 2003-09-18 Michael Salgaller Method to increase class I presentation of exogenous antigens by human dendritic cells
US20030134341A1 (en) * 2001-09-19 2003-07-17 Medcell Biologics, Llc. Th1 cell adoptive immunotherapy
US20090028834A1 (en) * 2007-07-27 2009-01-29 Hal Siegel Methods and compositions for stimulating the proliferation or differentiation of stem cells with substance P or an analog thereof

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JANELSINS ET AL.: "Proinflammatory Tachykinins that Signal through the Neurokinin 1 Receptor Promote Survival of Dendritic Cells and Potent Cellular Immunity.", BLOOD, vol. 113, 2008, pages 3017 - 3026 *

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