醫(yī)學(xué)免疫學(xué)課件：CAR-T細(xì)胞在血液相關(guān)疾病中的應(yīng)用-20161223am3

1、The Applications of CAR-T Cells in Hematologic Malignancies and Related DiseasesOutlineIntroductionEvolutionProcedureFutureChimeric Antigen Receptor T cell therapyFirst paper in 1989Hibernated for a long timeFast-developing field with exponential growth in recent yearsModified immunocytesTargeting i

2、mmunotherapy for malignant tumorsPapers Related with CAR-T on PubMedData retrieved from PubMed on Dec. 19th, 2016. Search keyword: CAR-T, smart expanded. Part of the unrelated results are removed manually.Basic StructureGill, S., Maus, M. V., & Porter, D. L. (2016). Chimeric antigen receptor T cell

3、therapy: 25years in the making. Blood Rev, 30(3), 157-167. doi:10.1016/j.blre.2015.10.003The RETURNImmunologyBiochemistry and molecular biologySynthetic biologyPioneer1989Gideon Gross, Tova Waks, and Zelig EshharTcR C domains & Abs V domainsSV40Cytotoxic T-cell hybridomaTarget cell killing rateGross

4、, G., Waks, T., & Eshhar, Z. (1989). Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A, 86(24), 10024-10028. Gross, G., Waks, T., & Eshhar, Z. (1989). Expression of immunoglobulin-T-cell receptor chimeric

5、molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A, 86(24), 10024-10028. Evolution1st generation: ScFv+Hinge+TransMem+ITAM2nd generation: ScFv+Hinge+TransMem+Costimulatory+ITAM3rd generation: ScFv+Hinge+TransMem+Costimulatory*2+ITAM4th generation: (TRUCK, T ce

6、lls redirected for universal cytokine killing) ScFv+Hinge+TransMem+Costimulatory+ITAM+Engineered Cytokines Gross, G., & Eshhar, Z. (2016). Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy. Annu Rev P

7、harmacol Toxicol, 56, 59-83. doi:10.1146/annurev-pharmtox-010814-124844Urba, W. J., & Longo, D. L. (2011). Redirecting T cells. N Engl J Med, 365(8), 754-757. doi:10.1056/NEJMe1106965TRUCKsPegram, H. J., Lee, J. C., Hayman, E. G., Imperato, G. H., Tedder, T. F., Sadelain, M., & Brentjens, R. J. (201

8、2). Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood, 119(18), 4133-4141. doi:10.1182/blood-2011-12-400044ProcedureCollecting cells Genetically modified T cells expansionT cells traffickingCells expansion in vivoPersist long enough

9、Mato, A., & Porter, D. L. (2015). A drive through cellular therapy for CLL in 2015: allogeneic cell transplantation and CARs. Blood, 126(4), 478-485. doi:10.1182/blood-2015-03-585091Gill, S., Maus, M. V., & Porter, D. L. (2016). Chimeric antigen receptor T cell therapy: 25years in the making. Blood

10、Rev, 30(3), 157-167. doi:10.1016/j.blre.2015.10.003Clinical Applications117 clinical trials on ClinicalT (Dec. 19, 2016)65 are related with blood-related diseases, like leukemiaPhase 0 to IINCT00586391 NCT00924326 NCT01218867 NCT01355965 NCT01454596 NCT01475058 NCT01583686 NCT01735604 NCT01822652 NC

11、T01837602 NCT01853631 NCT01864889 NCT01864902 NCT01865617 NCT01886976 NCT01897415 NCT01953900 NCT02028455 NCT02030847 NCT02081937 NCT02107963 NCT02132624 NCT02134262 NCT02186860 NCT02194374 NCT02203825 NCT02208362 NCT02215967 NCT02247609 NCT02259556 NCT02274584 NCT02277522 NCT02311621 NCT02331693 NC

12、T02349698 NCT02349724 NCT02395250 NCT02414269 NCT02416466 NCT02442297 NCT02443831 NCT02445222 NCT02445248 NCT02529813 NCT02535364 NCT02537977 NCT02541370 NCT02546739 NCT02547948 NCT02547961 NCT02575261 NCT02580747 NCT02587689 NCT02617134 NCT02624258 NCT02631044 NCT02652910 NCT02659943 NCT02663297 NC

13、T02664363 NCT02672501 NCT02685670 NCT02690545 NCT02706392 NCT02706782 NCT02710149 NCT02713984 NCT02715362 NCT02721407 NCT02723942 NCT02725125 NCT02728882 NCT02729493 NCT02735291 NCT02737085 NCT02744287 NCT02761915 NCT02765243 NCT02772198 NCT02782351 NCT02792114 NCT02794961 NCT02819583 NCT02822326 NC

14、T02830724 NCT02842138 NCT02844062 NCT02846584 NCT02850536 NCT02851589 NCT02862028 NCT02873390 NCT02876978 NCT02903810 NCT02905188 NCT02915445 NCT02917083 NCT02919046 NCT02930993 NCT02932956 NCT02935153 NCT02935257 NCT02935543 NCT02937103 NCT02937844 NCT02954445 NCT02958384 NCT02958397 NCT02958410 NC

15、T02959151 NCT02963038 NCT02965092 NCT02965157 NCT02968472 NCT02975687 NCT02980315 NCT02992210Leukemia and Solid TumorsAcute lymphoblastic leukemiaChronic lymphocytic leukemiaAcute myeloid leukemiaB lymphomaHodgkin lymphomaMultiple myelomaMyeloid malignanciesBreast cancerHepatocellular carcinomaCervi

16、cal cancerGlioblastomaColorectal carcinomaGastric carcinomaMesotheliomaLung cancerNasopharyngeal neoplasmsNeuroblastomaPancreatic cancerClinical Trials WorldwideWorld117East Asia67Japan2Europe5Middle East1North America44Canada2United States44Pacifica2Retrieved from ClinicalT on Dec. 19th, 2016. Keyw

17、ord: CAR-TTarget Antigens of CAR-T Cells in Clinical and Preclinical StudiesAntigenKey structural and functional featuresMalignancyPotential off-tumor targetsCD19Pan-B cell marker involved in signal transduction by the BCRALL, CLL, NHL, HL, PLLNormal B cellsCD20Tetra-transmembrane; regulation of Ca

18、transport and B cell activationCLL, NHLNormal B cellsCD22B lineagespecic adhesion receptor; sialic acidbinding Ig-type lectin familyALL, NHLNormal B cellsIgIg light-chain isotype expressed by approximately 65% of normal human B cellsCLL, NHL, MMNormal B cellsROR1Type I orphan-receptor tyrosine-kinas

19、e-like; survival-signaling receptor in tumorsCLL, NHLPancreas, adipose cellsCD30TNFR member; pleiotropic effects on cell growth and survival involving NF-BNHL, TCL, HLResting CD8 T cells, activated B and Th2 cellsLewis YAlso called CD174; a membrane oligosaccharide harboring two fucose groupsAML, MM

20、Early myeloid progenitor cellsCD33Sialic acidbinding Ig-type lectin serving as adhesion molecule of the myelomonocytic lineageAMLHematopoietic progenitors, myelomonocytic precursors, monocytesCD123The chain of the IL-3 receptorAMLBM myeloid progenitors, DCs, B cells, mast cells, monocytes, macrophag

21、es, megakaryocytes, endothelial cellsNKG2D-LLigands for the NK and T cell activating receptor NKG2D; bear similarity to MHC class I molecules; upregulated during inammationAML, MMGastrointestinal epithelium, endothelial cells, broblastsCD138Syndecan-1; cell surface heparan sulfate proteoglycan; ECM

22、receptorMMPrecursor and plasma B cells, epitheliaBCMATNFR member; binds BAFF and APRIL; involved in proliferation signalingMMB cellsCD38A surface cyclic ADP ribose hydrolase involved in transmembrane signaling and cell adhesionCLL, NHL, MMPBMCs, BM, brain, eye, prostate, gut, pancreas, muscle, bone,

23、 kidneyCS1Cell surface signaling lymphocytic activation moleculeMMPC, NK, NK-like T cells, CD8 + T cells, activated monocytes, DCs Gross, G., & Eshhar, Z. (2016). Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T

24、Cell Therapy. Annu Rev Pharmacol Toxicol, 56, 59-83. doi:10.1146/annurev-pharmtox-010814-124844B Cell MalignanciesCLL: chronic lymphocytic leukemiaALL: acute lymphoblastic leukemiaAnti-CD20: first trial in 2008Anti-CD19: most usedOther: CD22, CD23, ROR1, or the kappa light chainGill, S., Maus, M. V.

25、, & Porter, D. L. (2016). Chimeric antigen receptor T cell therapy: 25years in the making. Blood Rev, 30(3), 157-167. doi:10.1016/j.blre.2015.10.003Brentjens, R. J., Davila, M. L., Riviere, I., Park, J., Wang, X., Cowell, L. G., . . . Sadelain, M. (2013). CD19-targeted T cells rapidly induce molecul

26、ar remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med, 5(177), 177ra138. doi:10.1126/scitranslmed.3005930Brentjens, R. J., Davila, M. L., Riviere, I., Park, J., Wang, X., Cowell, L. G., . . . Sadelain, M. (2013). CD19-targeted T cells rapidly induce molecu

27、lar remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med, 5(177), 177ra138. doi:10.1126/scitranslmed.3005930Gill, S., Maus, M. V., & Porter, D. L. (2016). Chimeric antigen receptor T cell therapy: 25years in the making. Blood Rev, 30(3), 157-167. doi:10.1016

28、/j.blre.2015.10.003Gill, S., Maus, M. V., & Porter, D. L. (2016). Chimeric antigen receptor T cell therapy: 25years in the making. Blood Rev, 30(3), 157-167. doi:10.1016/j.blre.2015.10.003Hodgkin LymphomaDo NOT express B cell-associated surface markersBright, uniform expression of CD30Antibody-drug

29、conjugate brentuximab vedotinCD30 expressed on anti-CD30 CAR-TChinese PLA General Hospital-CD30 phase IDec 1, 2014-Mar 1, 20151/11 maintained continuous complete remission5/11achieved partial response3/11 achieved stable disease1/11 self-limiting side effectsWang, C.-M., Wu, Z.-Q., Wang, Y., Guo, Y.

30、-L., Wang, X.-H., Li, X., . . . Han, W.-D. (2016). Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory Hodgkins lymphoma: an open-label phase 1 trial. The Lancet, 386, S12. doi:10.1016/S0140-6736(15)00590-5MyelomaIncurable diseaseKappa light chain: but most do no

31、t express CD138 (syndecan-1): also in various epithelia.Other: B cell maturation antigen (BCMA), CS-1, CD38, NKG2D ligands, and CD44v6. BCMA for Multiple MyelomaCarpenter, R. O., Evbuomwan, M. O., Pittaluga, S., Rose, J. J., Raffeld, M., Yang, S., . . . Kochenderfer, J. N. (2013). B-cell maturation

32、antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res, 19(8), 2048-2060. doi:10.1158/1078-0432.ccr-12-2422Acute Myeloid LeukemiaAML: a malignancy of the hematopoietic stem cellIdeal target: present on AML blasts & absent from normal hematopoietic cellsTargets

33、: Lewis Y, CD123, CD33, CD44, NKG2D ligandsT Cell MalignanciesThe most difcult application of CAR-TOn the malignant & Absent from the CAR-T & Absent from healthy T cellsSome cases, CD5: downregulating CAR-Ts CD5Some cases, CD30NK cellsHIVIn vivo in humanized miceProtective CAR in hematopoietic stem/

34、progenitor cell (HSPC)-based approach to engineer HIV immunityCAR-modified HSPC differentiate into functional T cells as well as NK cellsResistant to HIV infection and suppress HIV replicationStem cell-based gene therapy with a CAR may be feasible and effective in treating chronic HIV infectionZhen,

35、 A., Kamata, M., Rezek, V., Rick, J., Levin, B., Kasparian, S., . . . Kitchen, S. G. (2015). HIV-specific Immunity Derived From Chimeric Antigen Receptor-engineered Stem Cells. Mol Ther, 23(8), 1358-1367. doi:10.1038/mt.2015.102Restricted by HLA type and many identified highly effective HIV CTL util

36、ize uncommon HLA allelesThe vast majority of latent viruses carry CTL escape mutationsSide EffectsCytokine release syndrome (CRS): high persistent fevers, nausea, myalgias, athralgias, and can evolve to capillary leak, hypoxia, and hypotension that can be life threatening. Neurological toxicity: Con

37、fusion, word-nding difculty, or aphasia, and sometimes leads to seizures.On-target effect: Normal tissue with TAA will be assaulted.Tumor lysis syndrome (TLS): Related with cytokines releasing and cell proliferation.Brudno, J. N., & Kochenderfer, J. N. (2016). Toxicities of chimeric antigen receptor

38、 T cells: recognition and management. Blood, 127(26), 3321-3330. Davila, M. L., Riviere, I., Wang, X., Bartido, S., Park, J., Curran, K., . . . Brentjens, R. (2014). Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med, 6(224), 224ra225

39、. doi:10.1126/scitranslmed.3008226Brudno, J. N., & Kochenderfer, J. N. (2016). Toxicities of chimeric antigen receptor T cells: recognition and management. Blood, 127(26), 3321-3330. Brudno, J. N., & Kochenderfer, J. N. (2016). Toxicities of chimeric antigen receptor T cells: recognition and managem

40、ent. Blood, 127(26), 3321-3330. Brudno, J. N., & Kochenderfer, J. N. (2016). Toxicities of chimeric antigen receptor T cells: recognition and management. Blood, 127(26), 3321-3330. In B-ALL, CD19-negative relapses occur while CAR T cells are still detectable. A Recent EventJuno TherapeuticsNCT025353

41、64JCAR015Phase II (ROCKET)Relapsed or refractory B-ALL Nov. 23rd, 2016 CLINICAL HOLDRetrieved on /phoenix.zhtml?c=253828&p=irol-newsArticle_Print&ID=2225491/ on Dec. 19th,2016. Juno Therapeutics Inc.The Problem and Its Design”The clinical hold was initiated after two patients suffered cerebral edema

42、 earlier this week. One patient died and as of last night the other is not expected to recover.”scFv (Our most clinically-advanced CAR T cell: CD19)Spacer and Transmembrane DomainCostimulatory Domains (CD3-zeta, also include either a CD28 or 4-1BB to mimic a “second signal”)Retrieved on https:/our-s

43、cience/car-technology/ on Dec. 19th,2016. Juno Therapeutics Inc.Future OutlookSolutions for On-target Off-organ EffectsPossible targets on malignant cellsNew structures with synthetic biological technologiesLong period of follow-upManagement of toxicitiesRetrieved on https:/our-science/car-technolog

44、y/ on Dec. 19th,2016. Juno Therapeutics Inc.ReferenceGross, G., Waks, T., & Eshhar, Z. (1989). Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A, 86(24), 10024-10028. Urba, W. J., & Longo, D. L. (2011). Re

45、directing T cells. N Engl J Med, 365(8), 754-757. doi:10.1056/NEJMe1106965Gill, S., Maus, M. V., & Porter, D. L. (2016). Chimeric antigen receptor T cell therapy: 25years in the making. Blood Rev, 30(3), 157-167. doi:10.1016/j.blre.2015.10.003 Gross, G., & Eshhar, Z. (2016). Therapeutic Potential of

46、 T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy. Annu Rev Pharmacol Toxicol, 56, 59-83. doi:10.1146/annurev-pharmtox-010814-124844Zhen, A., Kamata, M., Rezek, V., Rick, J., Levin, B., Kasparian, S., . . . Kitchen, S. G. (2

47、015). HIV-specific Immunity Derived From Chimeric Antigen Receptor-engineered Stem Cells. Mol Ther, 23(8), 1358-1367. doi:10.1038/mt.2015.102趙玲娣, 高全立. (2015). CAR-T細(xì)胞在腫瘤治療中的研究進(jìn)展. 中國腫瘤臨床 , Chinese Journal of Clinical Oncology, 2015,3. doi:10.3969/j.issn.1000-8179.20141675Brudno, J. N., & Kochenderfer, J. N. (2016). Toxicities of chimeric antigen receptor T cells: recognition and management. Blood, 127(26), 3321-3330. Brentjens, R. J., Davila, M. L., Rivi