醫(yī)學免疫學課件：CAR-T治療實體瘤

1、CAR-T Cell Therapy for Solid TumorsCONTENTS01 INTRODUCTION02 ANTIGEN CHOICE IN SOLID TUMORS03 TRAFFICKING04 TUMOR MICROENVIRONMENT05 INTRINSIC REGULATION OF T CELLS06 FUTURE PERSPECTIVESCARChimeric antigen receptorTCRT cell receptorscFvSingle chain variable fragment TAATumor-associated antigenFAPFib

2、roblast activation proteinTMETumor microenvironmentMDSCMyeloid-derived suppressor cellTAMTumor associated macrophageTANTumor associated neutrophilNOTESINTRODUCTION01Fesnak, A.D., C.H. June and B.L. Levine, Engineered T cells: the promise and challenges of cancer immunotherapy. Nature Reviews Cancer,

3、 2016. 16(9): p. 566-581.INTRODUCTION01Fesnak, A.D., C.H. June and B.L. Levine, Engineered T cells: the promise and challenges of cancer immunotherapy. Nature Reviews Cancer, 2016. 16(9): p. 566-581.INTRODUCTION01INTRODUCTION01Antigen choice in solid tumors TraffickingTumor microenvironment(TME)Intr

4、insic regulation of T cellsNewick, K., et al., CAR T Cell Therapy for Solid Tumors. Annual Review of Medicine, 2017. 68(1)ANTIGEN CHOICE IN SOLID TUMORS02Di, S. and Z. Li, Treatment of solid tumors with chimeric antigen receptor-engineered T cells: current status and future prospects. Science China

5、Life Sciences, 2016. 59(4): p. 360-369.ANTIGEN CHOICE IN SOLID TUMORS02Criteria for ideal target: On tumor cells: Expressed at high levels;Expressed on 100% of the tumor cellsOn the surface of important normal tissues:Not expressed(If expressed, it should be at a very low level)ANTIGEN CHOICE IN SOL

6、ID TUMORS02Tumor specific antigen (TSA) Tumor associated antigen (TAA) Oncofetal antigensEGFRvIIIHer-2CEADifferentiation antigenMUC1; MUC16Tumor-selective antigensMesothelinMorello, A., M. Sadelain and P.S. Adusumilli, Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors. Cancer Discovery, 2016

7、. 6(2): p. 133-146.ANTIGEN CHOICE IN SOLID TUMORS02Epidermal growth factor receptor variant III (EGFRvIII) - specific CAR-T cellsTreat: GlioblastomaState: PhaseI and phase I/II trials NCT02209376, NCT02664363, NCT01454596ANTIGEN CHOICE IN SOLID TUMORS02HER-2-specific CAR-T cells Treat: Medulloblasto

8、ma, osteosarcoma, glioblastomaState: Phase I studies NCT00924287, NCT00902044, NCT02442297, NCT01109095IL-13R2 - specific CAR T cell Treat: GlioblastomaState: PhaseI studies NCT00730613, NCT02208362Fesnak, A.D., C.H. June and B.L. Levine, Engineered T cells: the promise and challenges of cancer immu

9、notherapy. Nature Reviews Cancer, 2016. 16(9): p. 566-581.ANTIGEN CHOICE IN SOLID TUMORS02Hegde, M., et al., Tandem CAR T cells targeting HER2 and IL13R2 mitigate tumor antigen escape. Journal of Clinical Investigation, 2016. 126(8): p. 3036-3052ANTIGEN CHOICE IN SOLID TUMORS02HER-2-specific CAR-T c

10、ells Treat: Medulloblastoma, osteosarcoma, glioblastomaState: Phase I studies NCT00924287, NCT00902044, NCT02442297, NCT01109095IL-13R2 - specific CAR T cell Treat: GlioblastomaState: PhaseI studies NCT00730613, NCT02208362Hegde, M., et al., Tandem CAR T cells targeting HER2 and IL13R2 mitigate tumo

11、r antigen escape. Journal of Clinical Investigation, 2016. 126(8): p. 3036-3052ANTIGEN CHOICE IN SOLID TUMORS02Hegde, M., et al., Tandem CAR T cells targeting HER2 and IL13R2 mitigate tumor antigen escape. Journal of Clinical Investigation, 2016. 126(8): p. 3036-3052ANTIGEN CHOICE IN SOLID TUMORS02I

12、L-13R2 - specific CAR T cell Treat: GlioblastomaState: PhaseI studies NCT00730613, NCT02208362Christine E. Brown, Ph.D., Darya Alizadeh, Ph.D., et all. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N Engl J Med 2016; 375:2561-2569ANTIGEN CHOICE IN SOLID TUMORS02Christine

13、 E. Brown, Ph.D., Darya Alizadeh, Ph.D., et all. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N Engl J Med 2016; 375:2561-2569ANTIGEN CHOICE IN SOLID TUMORS02Tn-MUC1-specific CAR-T cells Treat: Pancreatic cancerState: Preclinical studiesBlidner, A.G., K.V. Marino and G.

14、A. Rabinovich, Driving CARs into Sweet Roads: Targeting Glycosylated Antigens in Cancer. Immunity, 2016. 44(6): p. 1248-50.ANTIGEN CHOICE IN SOLID TUMORS02Posey, A.D., et al., Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma. Immun

15、ity, 2016. 44(6): p. 1444-1454.ANTIGEN CHOICE IN SOLID TUMORS02Mesothelin(MSLN)-specific CAR-T cells Treat: Ovarian cancer, mesothelioma and pancreatic cancer State: Phase I studiesMorello, A., M. Sadelain and P.S. Adusumilli, Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors. Cancer Discove

16、ry, 2016. 6(2): p. 133-146.ANTIGEN CHOICE IN SOLID TUMORS02Mesothelin(MSLN)-specific CAR-T cells Treat: Ovarian cancer, mesothelioma and pancreatic cancer State: Phase I studiesJackson, H.J., S. Rafiq and R.J. Brentjens, Driving CAR T-cells forward. Nature Reviews Clinical Oncology, 2016. 13(6): p.

17、370-383ANTIGEN CHOICE IN SOLID TUMORS02Strategies to overcome obstacles:HeterogeneitySpecificityScreen patients for expression of TAATarget multiple antigensRequire two antigens to promote activityUse “self limited CARs”Fesnak, A.D., C.H. June and B.L. Levine, Engineered T cells: the promise and cha

18、llenges of cancer immunotherapy. Nature Reviews Cancer, 2016. 16(9): p. 566-581.TRAFFICKING03Intravenous injectionVSLocal instillationNCT02498912，NCT02414269，NCT01818323 TRAFFICKING03Appropriate expression and pairing of:Adhesion receptorsChemokine receptors CAR-T cells expressed CCR2 (the receptor

19、for CCL2) Oncolytic viruses armed with chemotactic chemokinesFesnak, A.D., C.H. June and B.L. Levine, Engineered T cells: the promise and challenges of cancer immunotherapy. Nature Reviews Cancer, 2016. 16(9): p. 566-581.TUMOR MICROENVIRONMENT04TUMOR MICROENVIRONMENT04Obstacles:Physical and metaboli

20、c barriersTumor derived soluble factors and cytokinesImmunosuppressive immune cellsTUMOR MICROENVIRONMENT04Physical and metabolic barriersCancer-associated fibroblasts (CAFs)Fibroblast activation protein (FAP)-specific CAR T-cells State: Clinical trial for malignant pleural mesothelioma NCT01722149

21、CARs secrete enzyme that degrades matrix State: Pre-clinical studiesBlood vesselsVEGFR-2-specific CAR T-cells State: Phase I/II studies NCT01218867TUMOR MICROENVIRONMENT04Physical and metabolic barriersReactive oxygen species (ROS)CAR T-cells with co-expression of catalase (CAR-CAT) State: Pre-clini

22、cal studiesHypoxia; Nutrient starvationCAR T-cells with co-expression of IL-12 State: Pre-clinical studiesTUMOR MICROENVIRONMENT04Tumor derived soluble factors and cytokinesTUMOR MICROENVIRONMENT04Tumor derived soluble factors and cytokinesProstaglandin E2 (PGE2); AdenosineGenetic inhibition of PKA

23、activation in CAR-T cells State: Pre-clinical studiesTransforming growth factor (TGF)Systemic blockade of TGF using soluble receptors to antibodies; Express dominant negative TGF receptor State: Pre-clinical studiesTUMOR MICROENVIRONMENT04Immunosuppressive immune cellsTregsMDSCsM2 TAMs, N2 TANsDeple

24、tion of immunosuppressive cells INTRINSIC REGULATION OF T CELLS05Obstacles: Surface inhibitory receptorsIntracellular negative feedback loopActivation induced cell deathINTRINSIC REGULATION OF T CELLS05Surface inhibitory receptors PD1 CTLA4 PD1 blockade; CTLA4 blockade PD1 dominant negative receptor

25、INTRINSIC REGULATION OF T CELLS05Intracellular negative feedback loopEnzymes, such as diacylglycerol kinase; Phosphatases, such as SHP1; Ubiquitin ligases, such as CblB;Transcription factors, such as Ikaros Reducing the expression or function of these inhibitors INTRINSIC REGULATION OF T CELLS05Acti

26、vation induced cell deathFas (CD95) on the T cells Fas ligand in most tumor cells, in tumor vasculature, and on activated T cells Engineering T cells to express higher levels of antiapoptotic proteins FUTURE PERSPECTIVES06Jin, C., D. Yu and M. Essand, Prospects to improve chimeric antigen receptor T

27、-cell therapy for solid tumors. Immunotherapy, 2016. 8(12): p. 1355-1361.FUTURE PERSPECTIVES06Fesnak, A.D., C.H. June and B.L. Levine, Engineered T cells: the promise and challenges of cancer immunotherapy. Nature Reviews Cancer, 2016. 16(9): p. 566-581.FUTURE PERSPECTIVES06Newick, K., et al., CAR T

28、 Cell Therapy for Solid Tumors. Annual Review of Medicine, 2017. 68(1).FUTURE PERSPECTIVES06Newick, K., et al., CAR T Cell Therapy for Solid Tumors. Annual Review of Medicine, 2017. 68(1).參考文獻REFERENCE07 1.Fesnak, A.D., C.H. June and B.L. Levine, Engineered T cells: the promise and challenges of can

29、cer immunotherapy. Nature Reviews Cancer, 2016. 16(9): p. 566-581. 2.Posey, A.D., et al., Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma. Immunity, 2016. 44(6): p. 1444-1454. 3.Blidner, A.G., K.V. Marino and G.A. Rabinovich, Driv

30、ing CARs into Sweet Roads: Targeting Glycosylated Antigens in Cancer. Immunity, 2016. 44(6): p. 1248-50. 4.Morello, A., M. Sadelain and P.S. Adusumilli, Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors. Cancer Discovery, 2016. 6(2): p. 133-146. 5.Jackson, H.J., S. Rafiq and R.J. Brentjens,

31、Driving CAR T-cells forward. Nature Reviews Clinical Oncology, 2016. 13(6): p. 370-383. 6.Hegde, M., et al., Tandem CAR T cells targeting HER2 and IL13R2 mitigate tumor antigen escape. Journal of Clinical Investigation, 2016. 126(8): p. 3036-3052. 7.Beatty, G.L. and M. OHara, Chimeric antigen recept

32、or-modified T cells for the treatment of solid tumors: Defining the challenges and next steps. Pharmacology & Therapeutics, 2016. 166: p. 30-39. 8.Newick, K., et al., CAR T Cell Therapy for Solid Tumors. Annual Review of Medicine, 2017. 68(1). 9.Gilham, D.E., et al., CART cells and solid tumors: tun

33、ing T cells to challenge an inveterate foe. Trends in Molecular Medicine, 2012. 18(7): p. 377-384.10.Long, A.H., et al., Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas. Cancer Immunology Research, 2016. 4(10): p. 869-880.11.Gad, A.Z., S. El-Naggar and N. Ahmed, Realism and pragmatism in developing an effectiv