WO2023238103A1 - Thérapie car-t pour le traitement du cancer - Google Patents

Thérapie car-t pour le traitement du cancer Download PDF

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Publication number
WO2023238103A1
WO2023238103A1 PCT/IB2023/055982 IB2023055982W WO2023238103A1 WO 2023238103 A1 WO2023238103 A1 WO 2023238103A1 IB 2023055982 W IB2023055982 W IB 2023055982W WO 2023238103 A1 WO2023238103 A1 WO 2023238103A1
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cells
cell
crc01
immune
car
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PCT/IB2023/055982
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English (en)
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Young-Ho Lee
Sang Hoon Lee
Youngsam Park
Hyung Cheol Kim
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Curocell Inc.
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Publication of WO2023238103A1 publication Critical patent/WO2023238103A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • A61K39/464411—Immunoglobulin superfamily
    • A61K39/464412—CD19 or B4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule

Definitions

  • the present disclosure is broadly concerned with the field of cancer immunotherapy using CAR-T that specifically binds to a target antigen and downregulates or silences the expression of immune checkpoint receptors.
  • CAR-T specifically binds to a target antigen and downregulates or silences the expression of immune checkpoint receptors.
  • the subject matter described herein generally relates to products and methods for treating patients with relapsed and refractory B cell malignancies.
  • CAR-T Chimeric Antigen Receptor (CAR) - T cells
  • CAR-T Chimeric Antigen Receptor
  • ICRs inhibitory immune checkpoint receptors
  • U.S. Patent Application Publication No. US20210060067A1 (which is incorporated herein by reference) discloses a lentiviral two-in-one CAR-T approach in which two checkpoint receptors are downregulated simultaneously by a dual shorthairpin RNA (shRNA) cassette integrated into a CAR vector.
  • the vector comprised of (i) a first nucleotide sequence encoding a first shRNA that inhibits expression of Programmed Cell Death 1 (PD-1 ) and a second shRNA that inhibits expression of T cell immunoreceptor with Ig and ITIM domains (TIGIT), and (ii) a second nucleotide sequence encoding a CAR.
  • PD-1 Programmed Cell Death 1
  • TAGIT T cell immunoreceptor with Ig and ITIM domains
  • CD19 Cluster of Differentiation 19-targeting CAR-T cells have become an important therapeutic option for patients with relapsed and refractory (R/R) B cell malignancies such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphomas (NHLs).
  • ALL acute lymphoblastic leukemia
  • NHLs non-Hodgkin lymphomas
  • CLL chronic lymphoblastic leukemia
  • Figure 3 shows CRS incident data comparing CRC01 with commercially available CD19 CAR-T products.
  • Figure 4 shows ICANS incident data comparing CRC01 with commercially available CD19 CAR-T products.
  • Figure 5 illustrates the cellular kinetics by qPCR method.
  • US20210060067A1 are vectors comprising: a base sequence encoding two types of short hairpin RNA (shRNA) which inhibit the expression of one or more genes that weaken the function of immune cells, including immune checkpoint receptors and ligands, and a base sequence encoding an antigen receptor such as a chimeric antigen receptor (CAR) or a T cell receptor (TCR), for example, a monoclonal T cell receptor (mTCR); an immune cell comprising a genetically engineered antigen receptor that specifically binds to a target antigen and one or more genetic disruption agents that reduce or are capable of reducing the expression in the immune cell of a gene or genes that weakens the function of the immune cell; methods of producing the immune cell; a composition or pharmaceutical composition comprising the immune cell, e.g., for immune therapy of human patients; and a method of treatment comprising administering the immune cell to a subject having a disease or a condition.
  • shRNA short hairpin RNA
  • an antigen receptor such as
  • composition, or pharmaceutical composition comprises one or more genetic disruption agents, e.g., encodes two shRNAs that reduce the expression of two immune checkpoint molecule genes which may be activated by cancer cells to weaken the function of immune cells, it is possible to eliminate severe and systemic adverse reactions such as cytokine release syndrome or autoimmune symptoms which can result from use of a separate inhibitor for these genes, as well as reducing the burden due to the increased cost of treatment resulting from expensive concurrent therapies, while providing cell therapy more effective than cases where only one shRNA is expressed.
  • genetic disruption agents e.g., encodes two shRNAs that reduce the expression of two immune checkpoint molecule genes which may be activated by cancer cells to weaken the function of immune cells
  • the phrases “at least one of A, B, and C;” “one or more of A, B, and C;” and “A, B, and/or C” are each intended to mean “A alone, B alone, C alone, A and B together, A and C together, B and C together, or A and B and C together.”
  • use of the term “based on,” above and in the claims is intended to mean, “based at least in part on,” such that an unrecited feature or element is also permissible.
  • a “construct” refers to a macromolecule or complex of molecules comprising a polynucleotide to be delivered to a target cell, either in vitro or in vivo.
  • a “vector,” as used herein refers to any nucleic acid construct capable of directing the delivery or transfer of a foreign genetic material to target cells, where it can be replicated and/or expressed.
  • the term “vector” as used herein comprises the construct to be delivered.
  • a vector can be a linear or a circular molecule.
  • a vector can be integrating or nonintegrating.
  • the major types of vectors include, but are not limited to, plasmids, episomal vector, viral vectors, cosmids, and artificial chromosomes.
  • Viral vectors include, but are not limited to, adenovirus vector, adeno-associated virus vector, retrovirus vector, lentivirus vector, Sendai virus vector, and the like.
  • a “two-in-one vector,” as described herein is a vector that comprises a base sequence encoding one or more short hairpin RNAs (shRNAs) which inhibit the expression of a gene or genes that weaken the function of immune cells, and a base sequence encoding a chimeric antigen receptor (CAR) or a T cell receptor, e.g., a monoclonal T cell receptor (mTCR).
  • shRNAs short hairpin RNAs
  • CAR chimeric antigen receptor
  • T cell receptor e.g., a monoclonal T cell receptor (mTCR).
  • a “dual two-in-one vector” as described herein is a vector that comprises a base sequence encoding two types of short hairpin RNA (shRNA) which inhibit the expression of genes that weaken the function of immune cells, and a base sequence encoding any one of a chimeric antigen receptor (CAR) and T cell receptor, e.g., monoclonal T cell receptor (mTCR).
  • dual two-in-one vectors described herein are a form of two-in-one vector.
  • RNAi also known as post-transcriptional gene silencing (PTGS), quelling, or co-suppression
  • PTGS post-transcriptional gene silencing
  • RNAi is a post-transcriptional gene silencing process in which RNA molecules, in a sequence specific manner, inhibit gene expression, typically by causing the destruction of specific mRNA molecules.
  • the active components of RNAi are short/small double stranded RNAs (dsRNAs), called small interfering RNAs (siRNAs), that typically contain 15-30 nucleotides (e.g., 19 to 25, 19 to 24 or 19-21 nucleotides) and 2 nucleotide 3' overhangs and that match the nucleic acid sequence of the target gene.
  • dsRNAs short/small double stranded RNAs
  • siRNAs small interfering RNAs
  • the antisense strand of siRNA acts as a guide for the RISC complex to attach to the mRNA of the target gene, and gene silencing occurs when the RISC complex, which has attached in this manner, cuts the mRNA.
  • shRNA in a target gene allows for gene silencing which is lasting and specific to a certain gene, it is included in the vector for the purpose of inhibiting the target gene.
  • CAR is generally a set of polypeptides which, when existing on an immune cell, causes the immune cell to have specificity to a target cell (normally a cancer cell) while causing signal transduction in the cell.
  • CAR at minimum comprises an extracellular antigen recognition domain which recognizes the target antigen to be described below, a transmembrane domain, and an intracellular signal transduction domain, wherein the intracellular signal transduction domain is derived from the promoting molecules or costimulatory molecules to be described below.
  • the set comprising polypeptides may be attached, or may be in a form where they attach through a switch which is dimerized through stimulation.
  • the promoting molecule may be the zeta chain of the TCR described in the above.
  • CD19 CAR is a CAR which targets the CD19 cancer antigen.
  • T-cell receptor refers to a protein receptor on T cells that is composed of a heterodimer of an alpha (a) and beta (P) chain, although in some cells the TCR consists of gamma and delta (y/5) chains.
  • the TCR may be modified on any cell comprising a TCR, including a helper T cell, a cytotoxic T cell, a memory T cell, regulatory T cell, natural killer T cell, and gamma delta T cell, for example.
  • the CD3 zeta domain has been combined with the signaling domains of co-stimulatory molecules such as CD28, 4-1 BB or 0X40.
  • co-stimulatory molecules such as CD28, 4-1 BB or 0X40.
  • mTCRs Monoclonal T cell receptors
  • mTCRs Monoclonal T cell receptors
  • their applications in cancer therapy are described in Stauss et aL, 2007, Molecular Therapy, 15(10):1744-50, Zhang and Morgan, 2012, Advanced Drug Delivery Reviews, 64(8): 756-762, and Liddy et aL, 2012, Nature Medicine, 18(6):980-7, the content of each of which is herein incorporated by reference in its entirety.
  • T lymphocyte and “T cell” are used interchangeably and refer to a principal type of white blood cell that completes maturation in the thymus and that has various roles in the immune system, including the identification of specific foreign antigens in the body and the activation and deactivation of other immune cells.
  • a T cell can be any T cell, such as a cultured T cell, e.g., a primary T cell, or a T cell from a cultured T cell line, e.g., Jurkat, SupT1 , etc., or a T cell obtained from a mammal.
  • the T cell can be CD3+ cells.
  • the T cell can be any type of T cell and can be of any developmental stage, including but not limited to, CD4+/CD8+ double positive T cells, CD4+ helper T cells (e.g., Th1 and Th2 cells), CD8+ T cells (e.g., cytotoxic T cells), peripheral blood mononuclear cells (PBMCs), peripheral blood leukocytes (PBLs), tumor infiltrating lymphocytes (TILs), memory T cells, naive T cells, regulator T cells, gamma delta T cells (y6 T cells), and the like.
  • helper T cells include cells such as Th3 (Treg), Th 17, Th9, or Tfh cells.
  • T cells such as central memory T cells (Tern cells), effector memory T cells (Tern cells and TEMRA cells).
  • the T cell can also refer to a genetically engineered T cell, such as a T cell modified to express a T cell receptor (TCR) or a chimeric antigen receptor (CAR).
  • TCR T cell receptor
  • CAR chimeric antigen receptor
  • the T cell can also be differentiated from a stem cell or progenitor cell.
  • immune checkpoints refer to molecules that exist in the immune system and are able to turn immune response on or off. Originally, they are safety devices to regulate excessive activation of immune cells, which causes cell death or autoimmune response. These immune checkpoint molecules can be broadly categorized into stimulatory immune checkpoint molecules which increase immune response, and inhibitory immune checkpoint molecules which inhibit immune response.
  • the immune checkpoint receptor and ligands may be selected from a group consisting of PD1 (Programmed cell death protein 1 ), PD-L1 (Programmed death-ligand 1 ), CTLA4 (Cytotoxic T-lymphocyte associated protein 4), TIM-3 (T-cell immunoglobulin and mucin-domain containing-3), CEACAM (Carcinoembryonic antigen-related cell adhesion molecule, including the three subtypes CEACAM-1 , CEACAM-3 or CEACAM- 5), LAG3 (Lymphocyte-activation gene 3), VISTA (V- domain Ig suppressor of T cell activation), BTLA (B- and T-lymphocyte attenuator), TIGIT (T cell immunoreceptor with Ig and ITIM domains), LAIR1 (Leukocyte- associated immunoglobulin-like receptor 1 ), CD160 (Cluster of differentiation 160), CD96 (Cluster of differentiation 96), MerTK (Protooncogene tyrosine-protein
  • a “pharmaceutical composition” for immune therapy in human patients described herein comprises the immune cells.
  • other pharmaceutically acceptable salts, carriers, excipients, vehicles and other additives, etc. which may further improve immune response may be added to the pharmaceutical composition, a detailed explanation thereof shall be omitted.
  • subject refers to any animal (e.g., a mammal), including, but not limited to, humans, non-human primates, canines, felines, rodents, and the like, which is to be the recipient of a particular treatment.
  • subject and patient are used interchangeably herein in reference to a human subject.
  • Effective amount or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, such as T cells, as described herein effective to achieve a particular biological result. Such results may include, but are not limited to, the inhibition of cancer as determined by any means suitable in the art.
  • administer or “administration” refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body into a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery, and/or any other method of physical delivery described herein or known in the art.
  • Tumor cells express various immune checkpoints, e.g., checkpoint ligands. Therefore, even if one immune checkpoint is inhibited, it might be difficult to expect sustained effect of CAR-T through activation of other immune checkpoints.
  • Combination of monoclonal antibodies has been mainly used to inhibit multiple immune checkpoints and its antitumor effect has been reported (J Clin Invest., 2015, Chauvin J M; PNAS, 2010, Curran M A; Blood, 2018, Wierz M; Cancer cell. 2014, Johnston R J). However, it was known that therapeutic antibodies could induce systemically excessive immune response.
  • CAR-T cell therapy is also associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity (Nat Rev Clin Oncol, 2017, Neelapu S S), suggesting that the combination of CAR-T and antibody therapy could maximize the potential of side effects.
  • CRS life-threatening cytokine-release syndrome
  • neurotoxicity Neelapu S S
  • the conventional concurrent immune cell therapies place an even greater economic burden on patients due to their high cost and that they also act on T cells other than CAR-T and pose a risk of autoimmune symptoms and cytokine release syndrome.
  • the present invention has been devised to address the above problems.
  • the expression of the two types of shRNA is characterized in that they are respectively regulated by two different promoters.
  • the two promoters are RNA polymerase III promoters.
  • the two promoters are U6 promoters derived from different species.
  • the two promoters are oriented in different directions from each other on the vector. For example, in a certain embodiment, the promoters are oriented in a head-to-head orientation. In another embodiment, the promoters are oriented in a tail- to- tail orientation.
  • the gene weakening the function of immune cells is an immune checkpoint receptor or ligand.
  • the immune checkpoint receptor or ligand is selected from a group consisting of PD1 , PD-L1 , CTLA4, TIM3, CEACAM (CEACAM- 1 , CEACAM-3 or CEACAM-5), LAG 3, VISTA, BTLA, TIGIT, LAIR1 , CD160, CD96, MerTK and 2B4.
  • the target of the CAR or TCR is a human tumor antigen selected from among increased cancer antigens in cancer or from mutated forms of cancer antigen found in cancer.
  • RNA species may be naturally produced in vivo by Dicer- mediated cleavage of larger dsRNAs and they are functional in mammalian cells.
  • DNA expression plasmids can be used to stably express the siRNA duplexes or dsRNA described herein in cells and achieve long-term inhibition of the target gene expression.
  • the sense and antisense strands of a siRNA duplex are typically linked by a short spacer sequence leading to the expression of a stem-loop structure termed short hairpin RNA (shRNA). The hairpin is recognized and cleaved by Dicer, thus generating mature siRNA molecules.
  • shRNA short hairpin RNA
  • Short hairpin RNA as used herein is an RNA molecule wherein some self-complementary sequences create a tight hairpin structure with its stem.
  • the shRNA molecules described herein may be about 40 to 120 nucleotides long, e.g.i, about 70 to 90 nucleotides long. In an exemplary embodiment, the shRNA can be 80 nucleotides long.
  • the shRNA is modeled on micro interfering RNA (miRNA), an endogenous trigger of the RNAi pathway (Lu et aL, 2005, Advances in Genetics 54: 117- 142, Fewell et aL, 2006, Drug Discovery Today 1 1 : 975-982).
  • RNAi molecules which were designed to target against a nucleic acid sequence that encodes poly-glutamine repeat proteins which cause poly-glutamine expansion diseases such as Huntington's Disease, are described in U.S. Pat. Nos. 9,169,483 and 9,181 ,544 and International Patent Publication No. WO2015179525, the content of each of which is herein incorporated by reference in their entirety. U.S. Pat. Nos. 9,169,483 and 9,181 ,544 and International Patent Publication No.
  • WO2015179525 each provide isolated RNA duplexes comprising a first strand of RNA (e.g., 15 contiguous nucleotides) and second strand of RNA (e.g., complementary to at least 12 contiguous nucleotides of the first strand) where the RNA duplex is about 15 to 30 base pairs in length.
  • the first strand of RNA and second strand of RNA may be operably linked by an RNA loop ("4 to 50 nucleotides) to form a hairpin structure which may be inserted into an expression cassette.
  • Non-limiting examples of loop portions include SEQ ID NOs: 9-14 of U.S. Pat. No. 9,169,483, the content of which is herein incorporated by reference in its entirety.
  • Non-limiting examples of strands of RNA which may be used, either full sequence or part of the sequence, to form RNA duplexes include SEQ ID NOs: 1 -8 of U.S. Pat. No. 9,169,483 and SEQ ID NOs: 1 -1 1 , 33-59, 208-210, 213-215 and 218-221 of U.S. Pat. No. 9,181 ,544, the contents of each of which is herein incorporated by reference in its entirety.
  • Non-limiting examples of RNAi molecules include SEQ ID NOs: 1 -8 of U.S. Pat. No. 9,169,483, SEQ ID NOs: 1 -1 1 , 33-59, 208-210, 213-215 and 218- 221 of U.S. Pat. No. 9,181 ,544 and SEQ ID NOs: 1 , 6, 7, and 35-38 of International Patent Publication No. WQ2015179525, the contents of each of which is herein incorporated by reference in their entirety.
  • siRNA sequence preference include, but are not limited to, (i) A/U at the 5' end of the antisense strand; (ii) G/C at the 5' end of the sense strand; (iii) at least five A/U residues in the 5' terminal one-third of the antisense strand; and (iv) the absence of any GC stretch of more than 9 nucleotides in length.
  • highly effective siRNA molecules essential for suppressing mammalian target gene expression may be readily designed.
  • a Two-in-One vector includes a base sequence encoding one or more types of short hairpin RNA (shRNA) which inhibit the expression of one or more genes that weaken the function of immune cells, and a base sequence encoding any one of a chimeric antigen receptor (CAR) or a T cell receptor, for example, a monoclonal T cell receptor (mTCR).
  • shRNA short hairpin RNA
  • CAR chimeric antigen receptor
  • T cell receptor for example, a monoclonal T cell receptor (mTCR).
  • the base sequence encodes one type of shRNA, which inhibits the expression of a gene that weaken the function of immune cells.
  • the base sequence encodes two types of shRNA, which inhibits the expression of two genes that weaken the function of immune cells, wherein the vector can be referred to as a “dual Two-in-One vector.”
  • the base sequence encodes more than two types of shRNA, which inhibit the expression of more than two genes that weaken the function of immune cells.
  • the two or more types of shRNA may be characterized in that they target a single gene, for example different parts of a single gene, which weakens the function of immune cells.
  • the two or more types of shRNA can target PD-1 , for example, different parts of PD-1.
  • the two or more types of shRNA may be characterized in that they target different genes which weaken the function of immune cells, for example targeting PD-1 and TIM-3.
  • CAR is generally a set of polypeptides which, when existing on an immune cell, causes the immune cell to have specificity to a target cell (normally a cancer cell) while causing signal transduction in the cell.
  • CAR at minimum comprises an extracellular antigen recognition domain which recognizes the target antigen to be described below, a transmembrane domain, and an intracellular signal transduction domain, wherein the intracellular signal transduction domain is derived from the promoting molecules or costimulatory molecules.
  • T- cells modified to express CAR that have been prepared in this manner can be activated by recognizing cancer cells which express the target antigen with high specificity, effectively induce the death of such cancer cells, simultaneously proliferate exponentially in the body, and remain alive for a long time.
  • CAR-T cells CART- 19
  • B cell-specific antigen a B cell-specific antigen
  • immune checkpoint receptors such as CTLA-4 (cytotoxic T-lymphocyte associated protein-4) or PD-1 (programmed cell death protein-1 ). These receptors are originally safety devices to regulate excessive activation and cell death of T cells, or the triggering of autoimmune responses.
  • cancer cells especially solid cancers, are reported to use this to avoid immunosurveillance by T cells. For example, if a cancer cell expresses PD-L1 (programmed death-ligand 1 ) on the surface, a T cell which expresses PD-1 , the receptor therefor, recognizes the cancer cell and is activated, but will soon become exhausted by an activation inhibition signal from the PD-1.
  • PD-L1 programmed death-ligand 1
  • CAR-T cells are also ultimately a therapy that relies on the cytotoxicity of activated T cells, the existence of an immunosuppressive environment around CAR-T cells acts as a major hindrance to their therapeutic effect.
  • CAR-Ts prepared to target solid tumors have rarely exhibited hopeful therapeutic effects. This is thought to be because solid tumors, unlike blood cancers, create immune-suppressive tumor microenvironments to suppress the activity and proliferation of CAR-T cells.
  • the genetically engineered antigen receptor is a chimeric antigen receptor (CAR) or a T cell receptor (TCR).
  • the genetically engineered antigen receptor is a CAR.
  • the CAR comprises an extracellular antigen recognition domain, a transmembrane domain, and an intracellular signal transduction domain.
  • the gene that weakens the function of the immune cell is selected from the group consisting of: PD1 , PD-L1 , CTLA4, TIM3, CEACAM (CEACAM-1 , CEACAM-3 or CEACAM-5), LAG 3, VISTA, BTLA, TIGIT, LAIR1 , CD160, CD96, MerTK, 2B4, FAS, CD45, PP2A, SHP1 , SHP2, DGK alpha, DGK zeta, Cbl-b, Cbl- c, CD148, LRR1 , TGFBR1 , IL10RA, KLGR1 , DNMT3A, and A2aR.
  • the gene that weakens the function of the immune cell increases reactions of the immune cell with a molecule which suppresses immune response of the immune cell. In some embodiments, the gene that increases reactions of the immune cell with a molecule which suppresses immune response of the immune cell encodes an immune checkpoint receptor or ligand.
  • the immune checkpoint receptor or ligand is selected from the group consisting of: PD1 , PD-L1 , CTLA4, TIM3, CEACAM (CEACAM-1 , CEACAM-3 or CEACAM-5), LAG 3, VISTA, BTLA, TIGIT, LAIR1 , CD160, CD96, MerTK, and 2B4.
  • the genetic disruption agent reduces the expression of a gene in the immune cell that weakens the function of the immune cell by at least 30, 40, 50, 60, 70, 80, 90, or 95% as compared to the immune cell in the absence of the genetic disruption agent. In some embodiments, the genetic disruption agent reduces the expression of a gene that increases reactions of the immune cell with a molecule which suppresses immune response of the immune cell. In some embodiments, the genetic disruption agent reduces the expression of a gene that encodes an immune checkpoint receptor or ligand.
  • the genetic disruption agent reduces the expression of a gene selected from the group consisting of: PD1 , PD-L1 , CTLA4, TIM3, CEACAM (CEACAM-1 , CEACAM-3 or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1 , CD160, CD96, MerTK, and 2B4.
  • a gene selected from the group consisting of: PD1 , PD-L1 , CTLA4, TIM3, CEACAM (CEACAM-1 , CEACAM-3 or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1 , CD160, CD96, MerTK, and 2B4.
  • the RNAi is mediated by two shRNAs.
  • two shRNAs target different parts of PD-1.
  • two shRNAs target PD-1 and TIM-3, respectively.
  • two shRNAs target PD-1 and CTLA-4, respectively.
  • two shRNAs target PD-1 and LAG-3, respectively.
  • two shRNAs target PD-1 and TIGIT, respectively.
  • a variety of diseases may be ameliorated by introducing immune cells as described herein to a subject suitable for adoptive immune therapy.
  • the produced CAR-T cells as provided is for allogeneic adoptive cell therapies.
  • therapeutic use of the compositions described herein comprising introducing the composition to a subject suitable for adoptive cell therapy, wherein the subject has an autoimmune disorder; a hematological malignancy; a solid tumor; or an infection associated with HIV, RSV, EBV, CMV, adenovirus, or BK polyomavirus.
  • Examples of hematological malignancies include, but are not limited to, acute and chronic leukemias (acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), lymphomas, non-Hodgkin lymphoma (NHL), Hodgkin's disease, multiple myeloma, and myelodysplastic syndromes.
  • AML acute myelogenous leukemia
  • ALL acute lymphoblastic leukemia
  • CML chronic myelogenous leukemia
  • NHL non-Hodgkin lymphoma
  • Hodgkin's disease multiple myeloma
  • myelodysplastic syndromes examples include, but are not limited to, cancer of the brain, prostate, breast, lung, colon, uterus, skin, liver, bone, pancreas, ovary, testes, bladder, kidney, head, neck, stomach, cervix, rectum, larynx, and
  • autoimmune disorders include, but are not limited to, alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, diabetes (type 1 ), some forms of juvenile idiopathic arthritis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, some forms of myocarditis, multiple sclerosis, pemphigus/pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma/systemic sclerosis, Sjogren's syndrome, systemic lupus, erythematosus, some forms of thyroiditis, some forms of uveitis, vitiligo, granulomato
  • viral infections include, but are not limited to, HIV - (human immunodeficiency virus), HSV- (herpes simplex virus), KSHV - (Kaposi's sarcoma-associated herpesvirus), RSV- (Respiratory Syncytial Virus), EBV- (Epstein- Barr virus), CMV- (cytomegalovirus), VZV - (Varicella zoster virus), adenovirus-, a lentivirus- , a BK polyomavirus-associated disorders.
  • HIV - human immunodeficiency virus
  • HSV- herpes simplex virus
  • KSHV - Kaposi's sarcoma-associated herpesvirus
  • RSV- Respiratory Syncytial Virus
  • EBV- Epstein- Barr virus
  • CMV- cytomegalovirus
  • VZV - Varicella zoster virus
  • Acute leukemia is characterized by the rapid proliferation of immature blood
  • Acute forms of leukemia can occur in children and young adults. In fact, it is a more common cause of death for children in the U.S. than any other type of malignant disease. Immediate treatment is required in acute leukemia due to the rapid progression and accumulation of the malignant cells, which then spill over into the bloodstream and spread to other organs of the body. Central nervous system (CNS) involvement is uncommon, although the disease can occasionally cause cranial nerve palsies.
  • Chronic leukemia is distinguished by the excessive build-up of relatively mature, but still abnormal, blood cells. Typically taking months to years to progress, the cells are produced at a much higher rate than normal cells, resulting in many abnormal white blood cells in the blood. Chronic leukemia mostly occurs in older people but can theoretically occur in any age group.
  • Acute lymphocytic leukemia also known as acute lymphoblastic leukemia, or ALL
  • ALL acute lymphoblastic leukemia
  • CLL Chronic lymphocytic leukemia
  • AML acute myelogenous leukemia
  • Lymphoma is a type of cancer that originates in lymphocytes (a type of white blood cell in the vertebrate immune system). There are many types of lymphoma. According to the U.S. National Institutes of Health, lymphomas account for about five percent of all cases of cancer in the United States, and Hodgkin's lymphoma in particular accounts for less than one percent of all cases of cancer in the United States. Because the lymphatic system is part of the body's immune system, patients with a weakened immune system, such as from HIV infection or from certain drugs or medication, also have a higher incidence of lymphoma.
  • the pharmaceutical composition When a pharmaceutical composition is administered to a patient having a cancer wherein the target molecule of the CAR or TCR, for example, mTCR, is expressed, the pharmaceutical composition can recognize the cancer and have immune activity without the activation of genes which weaken the function of immune cells with regard to cancer cells, and without problems such as exhaustion due to activationinhibiting signaling caused thereby.
  • the target molecule of the CAR or TCR for example, mTCR
  • dual immune checkpoints can be selected from a group consisting of PD1 (Programmed cell death protein 1 ), PD-L1 (Programmed death-ligand 1 ), CTLA4 (Cytotoxic T-lymphocyte associated protein 4), TIM-3 (T-cell immunoglobulin and mucin-domain containing-3), CEACAM (Carcinoembryonic antigen-related cell adhesion molecule, including the three subtypes CEACAM-1 , CEACAM-3 or CEACAM-5), LAG3 (Lymphocyte-activation gene 3), VISTA (V-domain Ig suppressor of T cell activation), BTLA (B- and T- lymphocyte attenuator), TIGIT (T-cell immunoreceptor with Ig and ITIM domains), LAIR1 (Leukocyte- associated immunoglobulin-like receptor 1 ), CD160 (Cluster of differentiation 160), CD96 (Cluster of differentiation 96), MerTK (Proto-oncogene tyrosine-protein kinase
  • the types of targeted immune checks affect the antitumor effect of the pharmaceutical composition.
  • a pharmaceutical composition targeting PD-1 and TIM3 can show different level of anti-tumor effect from that of a pharmaceutical composition targeting PD-1 and TIGIT.
  • said difference in the anti-tumor effect is unpredictable from known knowledge on antitumor effects of other drugs targeting the same immune checkpoint, for example the other drugs can include an antibody targeting the immune checkpoint.
  • targeting certain two immune checkpoints can produce surprisingly high anti-tumor effect.
  • a composition described herein can be provided in unit dosage form wherein each dosage unit, e.g., an injection, contains a predetermined amount of the composition, alone or in appropriate combination with other active agents.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of a composition described herein, alone or in combination with other active agents, calculated in an amount sufficient to produce the desired effect, in association with a pharmaceutically acceptable diluent, carrier, or vehicle, where appropriate.
  • the specifications for the novel unit dosage forms of cells or compositions described herein depend on the particular pharmacodynamics associated with the pharmaceutical composition in the particular subject.
  • the antibodies suitable for combinational treatment as an additional therapeutic agent to the administered genomically engineered immune cells include, but are not limited to, anti-CD20 (rituximab, veltuzumab, ofatumumab, ublituximab, ocaratuzumab, obinutuzumab), anti-HER2 (trastuzumab, pertuzumab), anti- CD52 (alemtuzumab), anti-EGFR (certuximab), anti-GD2 (dinutuximab), anti-PDL1 (avelumab), anti-CD38 (daratumumab, isatuximab, MOR202), anti-CD123 (7G3, CSL362), anti-SLAMF7 (elotuzumab); and their humanized or Fc modified variants or fragments, or their functional equivalents and biosimilars.
  • anti-CD20 rituximab, veltuzumab, ofatumumab,
  • an effective amount or sufficient number of the isolated transduced T cells is present in the composition and introduced into the subject such that long-term, specific, anti-tumor responses are established to reduce the size of a tumor or eliminate tumor growth or regrowth than would otherwise result in the absence of such treatment.
  • the amount of transduced T cells reintroduced into the subject causes a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 100% decrease in tumor size when compared to otherwise same conditions wherein the transduced T cells are not present.
  • compositions described herein may be comprised in a kit.
  • the CAR T-cells are provided in the kit, which also may include reagents suitable for expanding the cells, such as media, aAPCs, growth factors, antibodies (e.g., for sorting or characterizing CAR T-cells) and/or plasmids encoding CARs or transposase.
  • immune cells and compositions are provided herein.
  • provided herein is use of the immune cells or compositions.
  • provided is use of the immune cells or compositions described above in the manufacture of a medicament for use in a method for treating a disease or a condition.
  • the genetically engineered antigen receptor specifically binds to an antigen associated with the disease or the condition.
  • the disease or the condition is a cancer or a tumor.
  • PD-1/TIGIT-silenced CAR-T cells generated from diffuse large B-cell lymphoma patient-derived T cells using a clinically applicable manufacturing process, which demonstrated a robust antitumor activity and significantly improved persistence in vivo compared with conventional CD19-targeting CAR-T cells.
  • the PD-1/TIGIT-silenced CAR-T cells demonstrated that the cell-intrinsic PD-1/TIGIT dual downregulation strategy is effective in overcoming immune checkpoint- mediated resistance in CAR-T therapy.
  • Aims A multi-center, single-arm Phase 1 clinical trials with 91 participants to determine the tolerability, safety and efficacy of CRC01 (PD-1/TIGIT- downregulated CD19-targeting CAR-T cells generated from diffuse large B cell lymphoma patient- derived T cells) in adult patients with relapsed or refractory large B- cell lymphoma. Participants’ inclusion and exclusion criteria are as described in ClinicalTrials.gov Identifier NCT04836507.
  • a conditioning chemotherapy regimen of fludarabine and cyclophosphamide are be administered followed by investigational treatment of CRC01.
  • Fludarabine and Cyclophosphamide are administered in accordance with instructions in the corresponding package inserts.
  • Phase 1 trial consisted of 3 cohorts, differing in the dose administered:
  • Figure 2 illustrates treatment duration and efficacy of different Cohorts. Out of the seven subjects who achieved CR, four were still maintaining CR. (S01003: death from stomach cancer, S01006: relapse, S01008: death from an infectious disease). In the case of S01002 subject in Cohort 1 , CR was maintained for more than 11 months.
  • CRS is one of the adverse reactions. CRS grading and treatment were conducted per ‘CRS adverse reaction management protocol’ as described in the CRC01 clinical trial protocol.
  • Safety evaluation criteria include adverse events such as treatment- emergent adverse event (TEAE), Adverse drug reaction (ADR), Severe AE (SAE), and Severe ADR (SADR).
  • TEAE treatment- emergent adverse event
  • ADR Adverse drug reaction
  • SAE Severe AE
  • SADR Severe ADR
  • Figure 3 shows safety CRS data comparing with the results of other clinical trials of commercially available CD19 CAR-T products.
  • Table 5 provides data on CRS: Incidents and Treatments.
  • ICANS is one of the adverse reactions. ICANS grading and treatment were conducted per ‘CRS adverse reaction management protocol’ as described in the CRC01 clinical trial protocol.
  • Figure 4 shows safety ICANS data comparing with the results of other clinical trials of commercially available CD19 CAR-T products. Only one subject showed low grade ICANS (grade 2), indicating that CRC01 does not cause a severe ICANS. CRC01 was well tolerated up to 2x106 cells/kg dose level.
  • Table 6 provides data on Neurological Events (NEs): Incidents and Treatments.
  • CRS and NEs occurred at median 7 days after CRC01 (Anbal-cel)’s infusion.
  • DNA samples extracted from the subject’ s whole blood collected at different time points (Days and Months) D1 , D4, D7, D11 , D14, D17, D21 , D28, M2, M3 and M6.
  • DNAs were extracted from the subject's whole blood using a commercially available genomic DNA extraction kit (MagMAX DNA multi-sample ultra 2.0 kit, Thermofisher).
  • MagMAX DNA multi-sample ultra 2.0 kit, Thermofisher the copy numbers of the CAR gene present in 1 pg DNA were measured.
  • Figure 5 illustrates the cellular kinetics by quantitative polymerase chain reaction (qPCR).
  • Cmax and AUC of CRC01 transduced cells into target tissues increased in a dose-dependent manner.
  • Table 7 also shows that the Cmax and AUC of CRC01 (Anbal-cel) transduced cells into target tissues increased in a dose-dependent manner.
  • Cmax, AUC0-28d & AUC0-2M were proportionally increased to Anbal-cel’s dose & Tmax was reached at around 14 days after infusion.
  • a method of treating a cancer comprising: administering CRC01 (Anbal-cel) to a cancer patient.
  • parenteral introduction is selected from the group consisting of intramuscular, intravenous, intraportal, intrahepatic, intraperitoneal, subcutaneous, and intradermal administration.
  • cancer patient is treated for conditions selected from the groups consisting of Relapsed and Refractory B cell Malignancy, Relapsed Large B-cell Lymphoma; Refractory Large B-cell Lymphoma; Diffuse Large B-cell Lymphoma (DLBCL); Primary Mediastinal Large B-Cell Lymphoma (PMBCL); High-grade B-cell Lymphoma; and Transformed Follicular Lymphoma (TFL).
  • a method of treating a cancer patient comprising: administering to the patient a pharmaceutical composition comprising CRC01 (Anbal-cel) cells.
  • parenteral introduction is selected from the group consisting of intramuscular, intravenous, intraportal, intrahepatic, intraperitoneal, subcutaneous, and intradermal administration.
  • composition comprises CRC01 at a dose level selected from the group consisting of about 2x105 cells/kg, about 7x105 cells/kg, and about 2x106 cells/kg.

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Abstract

La présente divulgation concerne d'une manière générale le domaine de l'immunothérapie anticancéreuse utilisant une thérapie par cellules T porteuses d'un récepteur antigénique chimérique (CAR). La présente invention concerne d'une manière générale une méthode de traitement de patients atteints de malignités récidivantes et réfractaires à cellules B, à l'aide d'une cellule immunitaire comprenant un récepteur d'antigène génétiquement modifié qui se lie spécifiquement à un antigène cible (CD-19) et un agent de disruption génétique qui inactive, régule à la baisse ou réduit au silence deux récepteurs de point de contrôle simultanément par une cassette d'ARN court en épingle à cheveux (shRNA) intégrée dans un vecteur CAR. Un exemple décrit une étude de phase I, multicentre, pour déterminer la tolérabilité, l'efficacité et la sécurité de la thérapie CAR-T ciblant CD-19 chez des patients atteints d'un lymphome à grandes cellules B, récidivant ou réfractaire.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210260119A1 (en) * 2018-01-12 2021-08-26 Curocell Inc. Enhanced immune cells using dual shrna and composition including the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210260119A1 (en) * 2018-01-12 2021-08-26 Curocell Inc. Enhanced immune cells using dual shrna and composition including the same

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
‘Curocell announces Korean FDA clearance of the IND for CRC01, a first in kind immune checkpoint receptors downregulated CD19 CAR-T therapy’, CISION PR Newswire, 2021, pp. 1-2 *
KIM W. S., KIM S. J., YOON S. E., KIM J. R.: "S214: PHASE 1/2 STUDY OF ANBAL-CEL, NOVEL ANTI-CD19 CAR-T THERAPY WITH DUAL SILENCING OF PD-1 AND TIGIT IN RELAPSED OR REFRACTORY LARGE B CELL LYMPHOMA", HEMASPHERE, WOLTERS KLUWER HEALTH, US, vol. 6, 23 June 2022 (2022-06-23), US , pages 115 - 116, XP093113608, ISSN: 2572-9241, DOI: 10.1097/01.HS9.0000843748.64635.ac *
KIM W.S., S.J. KIM, S.E. YOON, J. KIM: "208MO Immune related adverse events and biomarkers after Anbalcel, novel anti-CD19 CAR-T therapy with dual silencing of PD-1 and TIGIT: Updates from phase I study", ANNALS OF ONCOLOGY, vol. 33, no. 59, 1 November 2022 (2022-11-01), pages S1516, XP093113605, ISSN: 0923-7534, DOI: 10.1016/j.annonc.2022.10.242 *
KIM, WON SEOG ET AL: "‘Phase 1/2 study of anbalcabtagene autoleucel", NOVEL ANTI-CD19 CAR-T CELL THERAPY WITH DUAL SILENCING OF PD-1 AND TIGIT IN RELAPSED OR REFRACTORY LARGE B-CELL LYMPHOMA.’, vol. 02, no. 7522, Journal of Clinical Oncology, pages 10, XP093113588 *
LEE YOUNG-HO, LEE HYEONG JI, KIM HYUNG CHEOL, LEE YUJEAN, NAM SU KYUNG, HUPPERETZ CEDRIC, MA JENNIFER S.Y., WANG XINXIN, SINGER OD: "PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells", MOLECULAR THERAPY, ELSEVIER INC., US, vol. 30, no. 2, 1 February 2022 (2022-02-01), US , pages 579 - 592, XP093113601, ISSN: 1525-0016, DOI: 10.1016/j.ymthe.2021.10.004 *
PARK YONG-SAM, DONG-HYUK JEON, HYUNHWAN YI, SANG-HOON LEE, HYUNG CHEOL KIM; CUROCELL, DAEJEON, SOUTH KOREA: "Characteristics of CRC01, an investigational CD19 CAR-T product with PD-1 and TIGIT genes silenced by shRNAs", JOURNAL OF CLINICAL ONCOLOGY, vol. 40, no. suppl. 16, 1 June 2022 (2022-06-01), pages e14514, XP093113596 *
PLIETH JACOB: "EHA 2022 preview - some good news at last", EVALUATE VANTAGE, 13 May 2022 (2022-05-13), pages 1 - 8, XP093113599, Retrieved from the Internet <URL:https://www.evaluate.com/vantage/articles/events/conferences-trial-results/eha-2022-preview-some-good-news-last> [retrieved on 20231219] *

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