Chimeric antigen receptor therapy in combination with il-15r and il15
AssigneesNovartis AG, The Trustees of the University of Pennsylvania
InventorsJohn Scholler, Carl H. June
Life of this patent
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Abstract
The invention provides compositions and methods for treating diseases such as cancer. The invention also relates to a method of administering a therapy comprising a chimeric antigen receptor, an IL-15R molecule and an IL-15 molecule.
Claims60
A nucleic acid molecule, e.g., an isolated nucleic acid molecule, comprising
- (i) a first nucleic acid sequence encoding a chimeric antigen receptor (CAR) molecule that binds to an antigen (e.g., CD19, Mesothelin or BCMA);
- (ii) a second nucleic acid sequence comprising an IL-15 receptor (IL-15R) molecule;
- and
- (iii) a third nucleic acid sequence comprising an IL-15 molecule,
- wherein the first nucleic acid sequence, second nucleic acid sequence and third nucleic acid sequence are disposed on a single nucleic acid molecule, e.g., a viral vector, e.g., a lentivirus vector.
The nucleic acid molecule of any of the preceding claims, wherein the CAR molecule comprises, in an N- to C-terminal orientation, an antigen binding domain that binds to the antigen, a transmembrane domain, and an intracellular signaling domain, optionally wherein the antigen binding domain is connected to the transmembrane domain by a hinge domain.
The nucleic acid molecule of any of the preceding claims, wherein the third nucleic acid sequence encodes an amino acid comprising the sequence of SEQ ID NO:
- 1002, a sequence at least about 85%, 90%, 95%, 99% or more identical to SEQ ID NO:1002, or a sequence having one, two, three or more substitutions, insertions, deletions, or modifications compared to SEQ ID NO:
- 1002.
The nucleic acid molecule of any of the preceding claims, wherein the second nucleic acid sequence encodes an amino acid comprising the sequence of SEQ ID NO:
- 1001, a sequence at least about 85%, 90%, 95%, 99% or more identical to SEQ ID NO:1001, or a sequence having one, two, three or more substitutions, insertions, deletions, or modifications compared to SEQ ID NO:
- 1001.
The nucleic acid molecule of any of the preceding claims, wherein the antigen is selected from:
- CD19;
- CD123;
- CD22;
- CD30;
- CD171;
- CS-1;
- C-type lectin-like molecule-1, CD33;
- epidermal growth factor receptor variant III (EGFRvIII);
- ganglioside G2 (GD2);
- ganglioside GD3;
- TNF receptor family member;
- B-cell maturation antigen;
- Tn antigen ((Tn Ag) or (GalNAcα-Ser/Thr));
- prostate-specific membrane antigen (PSMA);
- Receptor tyrosine kinase-like orphan receptor 1 (ROR1);
- Fms-Like Tyrosine Kinase 3 (FLT3);
- Tumor-associated glycoprotein 72 (TAG72);
- CD38;
- CD44v6;
- Carcinoembryonic antigen (CEA);
- Epithelial cell adhesion molecule (EPCAM);
- B7H3 (CD276);
- KIT (CD117);
- Interleukin-13 receptor subunit alpha-2;
- Mesothelin;
- Interleukin 11 receptor alpha (IL-11Ra);
- prostate stem cell antigen (PSCA);
- Protease Serine 21;
- vascular endothelial growth factor receptor 2 (VEGFR2);
- Lewis (Y) antigen;
- CD24;
- Platelet-derived growth factor receptor beta (PDGFR-beta);
- Stage-specific embryonic antigen-4 (SSEA-4);
- CD20;
- Folate receptor alpha;
- Receptor tyrosine-protein kinase ERBB2 (Her2/neu);
- Mucin 1, cell surface associated (MUC1);
- epidermal growth factor receptor (EGFR);
- neural cell adhesion molecule (NCAM);
- Prostase;
- prostatic acid phosphatase (PAP);
- elongation factor 2 mutated (ELF2M);
- Ephrin B2;
- fibroblast activation protein alpha (FAP);
- insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase IX (CAIX);
- Proteasome (Prosome, Macropain) Subunit, Beta Type, 9 (LMP2);
- glycoprotein 100 (gp100);
- oncogene polypeptide consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (Abl) (bcr-abl);
- tyrosinase;
- ephrin type-A receptor 2 (EphA2);
- Fucosyl GM1;
- sialyl Lewis adhesion molecule (sLe);
- ganglioside GM3;
- transglutaminase 5 (TGS5);
- high molecular weight-melanoma-associated antigen (HMWMAA);
- o-acetyl-GD2 ganglioside (OAcGD2);
- Folate receptor beta;
- tumor endothelial marker 1 (TEM1/CD248);
- tumor endothelial marker 7-related (TEM7R);
- claudin 6 (CLDN6);
- thyroid stimulating hormone receptor (TSHR);
- G protein-coupled receptor class C group 5, member D (GPRC5D);
- chromosome X open reading frame 61 (CXORF61);
- CD97;
- CD179a;
- anaplastic lymphoma kinase (ALK);
- Polysialic acid;
- placenta-specific 1 (PLAC1);
- hexasaccharide portion of globoH glycoceramide (GloboH);
- mammary gland differentiation antigen (NY-BR-1);
- uroplakin 2 (UPK2);
- Hepatitis A virus cellular receptor 1 (HAVCR1);
- adrenoceptor beta 3 (ADRB3);
- pannexin 3 (PANX3);
- G protein-coupled receptor 20 (GPR20);
- lymphocyte antigen 6 complex, locus K 9 (LY6K);
- Olfactory receptor 51E2 (OR51E2);
- TCR Gamma Alternate Reading Frame Protein (TARP);
- Wilms tumor protein (WT1);
- Cancer/testis antigen 1 (NY-ESO-1);
- Cancer/testis antigen 2 (LAGE-1a);
- Melanoma-associated antigen 1 (MAGE-A1);
- ETS translocation-variant gene 6, located on chromosome 12p (ETV6-AML);
- sperm protein 17 (SPA17);
- X Antigen Family, Member 1A (XAGE1);
- angiopoietin-binding cell surface receptor 2 (Tie 2);
- melanoma cancer testis antigen-1 (MAD-CT-1);
- melanoma cancer testis antigen-2 (MAD-CT-2);
- Fos-related antigen 1;
- tumor protein p53 (p53);
- p53 mutant;
- prostein;
- surviving;
- telomerase;
- prostate carcinoma tumor antigen-1, melanoma antigen recognized by T cells 1;
- Rat sarcoma (Ras) mutant;
- human Telomerase reverse transcriptase (hTERT);
- sarcoma translocation breakpoints;
- melanoma inhibitor of apoptosis (ML-IAP);
- ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene);
- N-Acetyl glucosaminyl-transferase V (NA17);
- paired box protein Pax-3 (PAX3);
- Androgen receptor;
- Cyclin B1;
- v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN);
- Ras Homolog Family Member C (RhoC);
- Tyrosinase-related protein 2 (TRP-2);
- Cytochrome P450 1B1 (CYP1B1);
- CCCTC-Binding Factor (Zinc Finger Protein)-Like, Squamous Cell Carcinoma Antigen Recognized By T Cells 3 (SART3);
- Paired box protein Pax-5 (PAX5);
- proacrosin binding protein sp32 (OY-TES1);
- lymphocyte-specific protein tyrosine kinase (LCK);
- A kinase anchor protein 4 (AKAP-4);
- synovial sarcoma, X breakpoint 2 (SSX2);
- Receptor for Advanced Glycation Endproducts (RAGE-1);
- renal ubiquitous 1 (RU1);
- renal ubiquitous 2 (RU2);
- legumain;
- human papilloma virus E6 (HPV E6);
- human papilloma virus E7 (HPV E7);
- intestinal carboxyl esterase;
- heat shock protein 70-2 mutated (mut hsp70-2);
- CD79a;
- CD79b;
- CD72;
- Leukocyte-associated immunoglobulin-like receptor 1 (LAIR1);
- Fc fragment of IgA receptor (FCAR or CD89);
- Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2);
- CD300 molecule-like family member f (CD300LF);
- C-type lectin domain family 12 member A (CLEC12A);
- bone marrow stromal cell antigen 2 (BST2);
- EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2);
- lymphocyte antigen 75 (LY75);
- Glypican-3 (GPC3);
- Fc receptor-like 5 (FCRL5);
- or immunoglobulin lambda-like polypeptide 1 (IGLL1).
The nucleic acid molecule of any of the preceding claims, wherein the antigen is chosen from CD19, CD22, BCMA, CD20, CD123, EGFRvIII, or mesothelin.
The nucleic acid molecule of any of the preceding claims, wherein the antigen is a solid tumor antigen.
The nucleic acid molecule of any of the preceding claims, wherein the antigen is selected from mesothelin, EGFRvIII, GD2, Tn antigen, sTn antigen, Tn-O-Glycopeptides, sTn-O-Glycopeptides, PSMA, CD97, TAG72, CD44v6, CEA, EPCAM, KIT, IL-13Ra2, leguman, GD3, CD171, IL-11Ra, PSCA, MAD-CT-1, MAD-CT-2, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, folate receptor alpha, ERBBs (e.g., ERBB2), Her2/neu, MUC1, EGFR, NCAM, Ephrin B2, CAIX, LMP2, sLe, HMWMAA, o-acetyl-GD2, folate receptor beta, TEM1/CD248, TEM7R, FAP, Legumain, HPV E6 or E7, ML-IAP, CLDN6, TSHR, GPRC5D, ALK, polysialic acid, Fos-related antigen, neutrophil elastase, TRP-2, CYP1B1, sperm protein 17, beta human chorionic gonadotropin, AFP, thyroglobulin, PLAC1, globoH, RAGE1, MN-CA IX, human telomerase reverse transcriptase, intestinal carboxyl esterase, mut hsp 70-2, NA-17, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, NY-ESO-1, GPR20, Ly6k, OR51E2, TARP, or GFRα4.
The nucleic acid molecule of any of the preceding claims, wherein the transmembrane domain comprises a transmembrane domain of a protein chosen from the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD123, CD134, CD137 or CD154,
- optionally wherein the transmembrane domain comprises:
- (i) a transmembrane domain of CD8;
- or
- (ii) the amino acid sequence of SEQ ID NO:
- 1026 (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions).
The nucleic acid molecule of any of the preceding claims, wherein the intracellular signaling domain comprises a primary signaling domain, optionally wherein the primary signaling domain comprises:
- (i) a functional signaling domain derived from CD3 zeta, TCR zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD79a, CD79b, CD278 (ICOS), FcεRI, DAP10, DAP12, or CD66d;
- or
- (ii) the amino acid sequence of SEQ ID NO:
- 1034 or 1037 (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions).
The nucleic acid molecule of any of the preceding claims, wherein the intracellular signaling domain comprises a costimulatory domain, optionally wherein:
- (i) the costimulatory domain comprises a functional signaling domain derived from MHC class I molecule, TNF receptor protein, Immunoglobulin-like protein, cytokine receptor, integrin, signalling lymphocytic activation molecule (SLAM), activating NK cell receptor, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CD5, ICAM-1, 4-1BB (CD137), B7-H3, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, CD28-OX40, CD28-4-1BB, or a ligand that specifically binds with CD83;
- (ii) the costimulatory domain comprises a functional signaling domain derived from 4-1BB;
- or
- (iii) the costimulatory domain comprises the amino acid sequence of SEQ ID NO:
- 1029 (or a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and/or having one, two, three or more substitutions, insertions or deletions, e.g., conserved substitutions).
A CAR IL-15/IL15R polypeptide comprising:
- (i) a chimeric antigen receptor (CAR) molecule that binds to an antigen (e.g., an antigen described herein, e.g., CD19 or Mesothelin);
- (ii) an IL-15 receptor (IL-15R) molecule;
- and
- (iii) an IL-15 molecule,
- wherein (i)-(iii) are expressed in the same frame on a single polypeptide chain.
A method of evaluating a population of CAR IL-15/IL-15R expressing cells, comprising measuring the level, e.g., activity or expression level, of CD45RO and CCR7 in the population of cells, wherein:
- a low level of CD45RO expression (e.g., CD45RO−) and a high level of CCR7 expression (e.g., CCR7+) is indicative that the sample is suitable for treatment;
- and
- a high level of CD45RO expression (e.g., CD45RO+) and a low level of CCR7 expression (e.g., CCR7−) is indicative that the sample is not suitable for treatment
- thereby evaluating the CAR-IL-15 complex expressing cell.
A cell, e.g., an immune effector cell, e.g., a T cell or NK cell, comprising:
- (i) a first nucleic acid sequence encoding a chimeric antigen receptor (CAR) molecule that binds to an antigen (e.g., an antigen described herein);
- (ii) a second nucleic acid sequence encoding an IL-15 receptor (IL-15R) molecule;
- and
- (iii) a third nucleic acid sequence encoding an IL-15 molecule,
- wherein the first nucleic acid sequence, the second nucleic acid sequence, and the third nucleic acid sequence are disposed on a single nucleic acid molecule.
A method of providing an anti-cancer immune response in a subject having a disease associated with expression of an antigen, e.g., a tumor antigen described herein, e.g., CD19, Mesothelin or BCMA, comprising administering to the subject an effective number of a population of cells of any one of claims 45-51, or a population of cells comprising the nucleic acid molecule of any of claims 1-17, or a population of cells comprising the polypeptide of any of claims 18-25, thereby providing the anti-cancer immune response.
A method of evaluating or predicting a subject's responsiveness to a CAR-expressing cell therapy, comprising acquiring a value for the level, e.g., activity or expression level, of CD45RO and CCR7 in the population of cells, wherein:
- a low level of CD45RO expression (e.g., CD45RO−) and a high level of CCR7 expression (e.g., CCR7+) is indicative or predictive of increased responsiveness of the subject to the CAR IL-15/IL-15R-expressing cell therapy;
- and
- a high level of CD45RO expression (e.g., CD45RO+) and a low level of CCR7 expression (e.g., CCR7−) is indicative or predictive of decreased responsiveness of the subject to the CAR IL-15/IL-15R-expressing cell therapy,
- thereby evaluating or predicting the subject's responsiveness to the CAR IL-15/IL-15R expressing cell therapy.
Dependencies are inferred from the claim text.