Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges

Journal of Hematology & Oncology

Shuang-yin Han³  Tian-fang Li²  Chun-rong Wang³  Xiu-ling Li³  Ethan Q Han¹ 

[1] Drexel University College of Medicine, Philadelphia, PA 19129, USA;Rush University Medical Center, Chicago, IL 60612, USA;Translational Research Center, Zhengzhou University People’s Hospital, Zhengzhou, Henan 450003, China

关键词: T cell receptor;    Single chain variable fragment;    Adoptive immunotherapy;    Chimeric antigen receptor;   

Others  :  804628
DOI  :  10.1186/1756-8722-6-47

 received in 2013-07-03, accepted in 2013-07-03,  发布年份 2013

【 摘 要 】

Recent years have witnessed much progress in both basic research and clinical trials regarding cancer immunotherapy with chimeric antigen receptor (CAR)-engineered T cells. The unique structure of CAR endows T cell tumor specific cytotoxicity and resistance to immunosuppressive microenvironment in cancers, which helps patients to better tackle the issue of immunological tolerance. Adoptive immunotherapy (AIT) using this supernatural T cell have gained momentum after decades of intense debates because of the promising results obtained from preclinical models and clinical trials. However, it is very important for us to evaluate thoroughly the challenges/obstacles before widespread clinical application, which clearly warrants more studies to improve our understanding of the mechanism underlying AIT. In this review, we focus on the critical issues related to the clinical outcomes of CAR-based adoptive immunotherapy and discuss the rationales to refine this new cancer therapeutic modality.

【 授权许可】

   
2013 Han et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Eshhar Z, Waks T, Gross G, Schindler DG: Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA 1993, 90(2):720-724.
• [2]Cheadle EJ, Sheard V, Hombach AA, Chmielewski M, Riet T, Berrevoets C, Schooten E, Lamers C, Abken H, Debets R, et al.: Chimeric antigen receptors for T-cell based therapy. Methods Mol Biol 2012, 907:645-666.
• [3]Kochenderfer JN, Rosenberg SA: Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol 2013, 10(5):267-276.
• [4]Porter DL, Levine BL, Kalos M, Bagg A, June CH: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011, 365(8):725-733.
• [5]Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, et al.: CD19-Targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013, 5(177):177ra38.
• [6]Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, et al.: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013, 368(16):1509-1518.
• [7]Xu XJ, Zhao HZ, Tang YM: Efficacy and safety of adoptive immunotherapy using anti-CD19 chimeric antigen receptor transduced T-cells: a systematic review of phase I clinical trials. Leuk Lymphoma 2013, 54(2):255-260.
• [8]Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM, Pastan IH, Dimitrov DS, Morgan RA, FitzGerald DJ, Barrett DM, et al.: Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 2013, 121(7):1165-1174.
• [9]Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang WC, Ostberg JR, et al.: Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther 2007, 15(4):825-833.
• [10]Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, Rossig C, Russell HV, Diouf O, Liu E, et al.: Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 2011, 118(23):6050-6056.
• [11]Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, Vulto A, den Bakker M, Oosterwijk E, Debets R, et al.: Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther 2013, 21(4):904-912.
• [12]Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA: Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010, 18(4):843-851.
• [13]Kandalaft LE, Powell DJ Jr, Coukos G: A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer. J Transl Med 2012, 10:157. BioMed Central Full Text
• [14]Schlimper C, Hombach AA, Abken H, Schmidt-Wolf IG: Improved activation toward primary colorectal cancer cells by antigen-specific targeting autologous cytokine-induced killer cells. Clin Dev Immunol 2012, 201(2):238924.
• [15]Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD, Reap EA, Feldman SA, Chinnasamy N, Kuan CT, Song H, et al.: Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther 2012, 23(10):1043-1053.
• [16]Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M: Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol 2013, 31(1):71-75.
• [17]Shirasu N, Kuroki M: Functional design of chimeric T-cell antigen receptors for adoptive immunotherapy of cancer: architecture and outcomes. Anticancer Res 2012, 32(6):2377-2383.
• [18]Hudecek M, Lupo-Stanghellini MT, Kosasih PL, Sommermeyer D, Jensen MC, Rader C, Riddell SR: Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin Cancer Res 2013, 19(12):3153-3164.
• [19]Chinnasamy D, Tran E, Yu Z, Morgan RA, Restifo NP, Rosenberg SA: Simultaneous targeting of tumor antigens and the tumor vasculature using T lymphocyte transfer synergize to induce regression of established tumors in mice. Cancer Res 2013, 73(11):3371-3380.
• [20]Zhang T, Barber A, Sentman CL: Chimeric NKG2D modified T cells inhibit systemic T-cell lymphoma growth in a manner involving multiple cytokines and cytotoxic pathways. Cancer Res 2007, 67(22):11029-11036.
• [21]Hombach A, Hombach AA, Abken H: Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc spacer domain in the extracellular moiety of chimeric antigen receptors avoids off-target activation and unintended initiation of an innate immune response. Gene Ther 2010, 17(10):1206-1213.
• [22]Guest RD, Hawkins RE, Kirillova N, Cheadle EJ, Arnold J, O’Neill A, Irlam J, Chester KA, Kemshead JT, Shaw DM, et al.: The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens. J Immunother 2005, 28(3):203-211.
• [23]Bridgeman JS, Hawkins RE, Bagley S, Blaylock M, Holland M, Gilham DE: The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J Immunol 2010, 184(12):6938-6949.
• [24]Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, Kamble RT, Bollard CM, Gee AP, Mei Z, et al.: CD28 Costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest 2011, 121(5):1822-1826.
• [25]Tammana S, Huang X, Wong M, Milone MC, Ma L, Levine BL, June CH, Wagner JE, Blazar BR, Zhou X: 4-1BB And CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies. Hum Gene Ther 2010, 21(1):75-86.
• [26]Finney HM, Akbar AN, Lawson AD: Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol 2004, 172(1):104-113.
• [27]Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, Samanta M, Lakhal M, Gloss B, Danet-Desnoyers G, et al.: Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 2009, 17(8):1453-1464.
• [28]Shen CJ, Yang YX, Han EQ, Cao N, Wang YF, Wang Y, Zhao YY, Zhao LM, Cui J, Gupta P, et al.: Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma. J Hematol Oncol 2013, 6:33. BioMed Central Full Text
• [29]Klebanoff CA, Gattinoni L, Restifo NP: Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? J Immunother 2012, 35(9):651-660.
• [30]Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR: Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 2008, 118(1):294-305.
• [31]Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, et al.: A human memory T cell subset with stem cell-like properties. Nat Med 2011, 17(10):1290-1297.
• [32]Wang X, Naranjo A, Brown CE, Bautista C, Wong CW, Chang WC, Aguilar B, Ostberg JR, Riddell SR, Forman SJ, et al.: Phenotypic and functional attributes of lentivirus-modified CD19-specific human CD8+ central memory T cells manufactured at clinical scale. J Immunother 2012, 35(9):689-701.
• [33]Turtle CJ, Riddell SR: Artificial antigen-presenting cells for use in adoptive immunotherapy. Cancer J 2010, 16(4):374-381.
• [34]Antony PA, Paulos CM, Ahmadzadeh M, Akpinarli A, Palmer DC, Sato N, Kaiser A, Hinrichs CS, Klebanoff CA, Tagaya Y, et al.: Interleukin-2-dependent mechanisms of tolerance and immunity in vivo. J Immunol 2006, 176(9):5255-5266.
• [35]Mueller YM, Makar V, Bojczuk PM, Witek J, Katsikis PD: IL-15 enhances the function and inhibits CD95/Fas-induced apoptosis of human CD4+ and CD8+ effector-memory T cells. Int Immunol 2003, 15(1):49-58.
• [36]Rao RR, Li Q, Odunsi K, Shrikant PA: The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and eomesodermin. Immunity 2010, 32(1):67-78.
• [37]Colovos C, Villena-Vargas J, Adusumilli PS: Safety and stability of retrovirally transduced chimeric antigen receptor T cells. Immunotherapy 2012, 4(9):899-902.
• [38]Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, Vogel AN, Kalos M, Riley JL, Deeks SG, et al.: Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med 2012, 4(132):132ra53.
• [39]McGarrity GJ, Hoyah G, Winemiller A, Andre K, Stein D, Blick G, Greenberg RN, Kinder C, Zolopa A, Binder-Scholl G, et al.: Patient monitoring and follow-up in lentiviral clinical trials. J Gene Med 2013, 15(2):78-82.
• [40]Schroers R, Hildebrandt Y, Hasenkamp J, Glass B, Lieber A, Wulf G, Piesche M: Gene transfer into human T lymphocytes and natural killer cells by Ad5/F35 chimeric adenoviral vectors. Exp Hematol 2004, 32(6):536-546.
• [41]Maiti SN, Huls H, Singh H, Dawson M, Figliola M, Olivares S, Rao P, Zhao YJ, Multani A, Yang G, et al.: Sleeping beauty system to redirect T-cell specificity for human applications. J Immunother 2013, 36(2):112-123.
• [42]Nakazawa Y, Huye LE, Salsman VS, Leen AM, Ahmed N, Rollins L, Dotti G, Gottschalk SM, Wilson MH, Rooney CM: PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T-cells expressing HER2-specific chimeric antigen receptor. Mol Ther 2011, 19(12):2133-2143.
• [43]Barrett DM, Zhao Y, Liu X, Jiang S, Carpenito C, Kalos M, Carroll RG, June CH, Grupp SA: Treatment of advanced leukemia in mice with mRNA engineered T cells. Hum Gene Ther 2011, 22(12):1575-1586.
• [44]Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, et al.: Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 2008, 26(32):5233-5239.
• [45]Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, et al.: Durable complete responses in heavily pretreted patients with metastatic melanoma using T cell transfer immunotherapy. Clin Cancer Res 2011, 17(13):4550-4557.
• [46]Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011, 3(95):95ra73.
• [47]Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, et al.: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med 2004, 10(9):942-949.
• [48]Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, et al.: Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumour-specific CD8+ T cells. J Exp Med 2005, 202(7):907-912.
• [49]Russo V, Tanzarella S, Dalerba P, Rigatti D, Rovere P, Villa A, Bordignon C, Traversari C: Dendritic cells acquire the MAGE-3 human tumour antigen from apoptotic cells and induce a class I-restricted T cell response. Proc Natl Acad Sci USA 2000, 97(5):2185-2190.
• [50]Brentjens R, Yeh R, Bernal Y, Riviere I, Sadelain M: Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther 2010, 18(4):666-668.
• [51]Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, et al.: B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric- antigen -receptor-transduced T cells. Blood 2012, 119(12):2709-2720.
• [52]Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, et al.: Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 2011, 365(18):1673-1683.