The progress of CAR-T therapy in cancer and beyond

  • Yehong Huang Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
  • Lulu Li Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
  • Wenzhou Liu Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
  • Tao Tang Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
  • Liming Chen Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
Keywords: Chimeric antigen receptor, Cancer, Cell therapy, Immunology


Chimeric antigen receptor T (CAR-T) technology is the pinnacle of modern immunology, system biology, synthetic biology and cellular engineering. It is the powerful new player of cancer therapy since the concept of adoptive cell therapy. Clinical success of CAR-T cells targeting antigen unique to B cell leukemia has made it the focus of new development in cancer therapy. The latest success is reported in a clinical case of using CAR-T cells to treat pediatric acute lymphoblastic leukemia. However, the major challenges are to make CAR-T cells a reliable, controllable, safe and effective platform that could apply to diverse cancer types including solid tumors. In this review we summarize the recent research progress to tackle the challenges and discuss the broader application of CAR-T cells beyond cancer in the context of genome editing era.


Download data is not yet available.


Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.

Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science 2013;342:1432-3.

M Y. No cancer cells detected: first major step to recovery for British boy in Singapore for experimental treatment. Channel News Asia 2020 Jan 16.

Maldini CR, Ellis GI, Riley JL. CAR T cells for infection, autoimmunity and allotransplantation. Nat Rev Immunol 2018;18:605-16.

Seimetz D, Heller K, Richter J. Approval of first CAR-Ts: have we solved all hurdles for ATMPs? Cell Med 2019;11:2155179018822781.

Fischbach MA, Bluestone JA, Lim WA. Cell-based therapeutics: the next pillar of medicine. Sci Transl Med 2013;5:179ps7.

Brubaker SW, Bonham KS, Zanoni I, Kagan JC. Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 2015;33:257-90.

Cooper MD, Alder MN. The evolution of adaptive immune systems. Cell 2006;124:815-22.

Germain RN, Stefanova I. The dynamics of T cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu Rev Immunol 1999;17:467-522.

Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 2013;13:227-42.

van der Stegen SJ, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov 2015;14:499-509.

Burugu S, Dancsok AR, Nielsen TO. Emerging targets in cancer immunotherapy. Semin Cancer Biol 2018;52:39-52.

Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986;136:2348-57.

Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 2007;13:139-45.

Chatila TA. Role of regulatory T cells in human diseases. J Allergy Clin Immunol 2005;116:949-59; quiz 60.

Dustin ML. The cellular context of T cell signaling. Immunity 2009;30:482-92.

Valent P, Groner B, Schumacher U, Superti-Furga G, Busslinger M, Kralovics R, et al. Paul Ehrlich (1854-1915) and his contributions to the foundation and birth of translational medicine. J Innate Immun 2016;8:111-20.

Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 1988;319:1676-80.

Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008;8:299-308.

Levine BL, Bernstein WB, Aronson NE, Schlienger K, Cotte J, Perfetto S, et al. Adoptive transfer of costimulated CD4+ T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection. Nat Med 2002;8:47-53.

Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 1992;257:238-41.

Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A 1989;86:10024-8.

Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y, Itoh S, et al. Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem Biophys Res Commun 1987;149:960-8.

Irving BA, Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 1991;64:891-901.

Drent E, Poels R, Ruiter R, van de Donk N, Zweegman S, Yuan H, et al. Combined CD28 and 4-1BB costimulation potentiates affinity-tuned chimeric antigen receptor-engineered T cells. Clin Cancer Res 2019;25:4014-25.

Quintarelli C, Orlando D, Boffa I, Guercio M, Polito VA, Petretto A, et al. Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma. Oncoimmunology 2018;7:e1433518.

Adachi K, Kano Y, Nagai T, Okuyama N, Sakoda Y, Tamada K. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol 2018;36:346-51.

Gardner RA, Finney O, Smithers H, Leger K, Annesley CE, Summers C, et al. Prolonged functional persistence of CD19 CAR t cell products of defined CD4:CD8 composition and transgene expression determines durability of MRD-negative ALL remission. J Clin Oncol 2016;34:3048.

Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 2014;6:224ra25.

Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013;5:177ra38.

Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014;124:188-95.

Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 2015;385:517-28.

Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 2016;127:3321-30.

Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC, Fowler DH, et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol 2016;34:1112-21.

Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014;371:1507-17.

Cruz CR, Micklethwaite KP, Savoldo B, Ramos CA, Lam S, Ku S, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 2013;122:2965-73.

Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 2016;126:2123-38.

Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 2018;24:20-8.

Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015;7:303ra139.

Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 2009;17:1453-64.

Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378:158-68.

Sommermeyer D, Hill T, Shamah SM, Salter AI, Chen Y, Mohler KM, et al. Fully human CD19-specific chimeric antigen receptors for T-cell therapy. Leukemia 2017;31:2191-9.

Li J, Li W, Huang K, Zhang Y, Kupfer G, Zhao Q. Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward. J Hematol Oncol 2018;11:22.

Martinez M, Moon EK. CAR T cells for solid tumors: new strategies for finding, infiltrating, and surviving in the tumor microenvironment. Front Immunol 2019;10:128.

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;18:843-51.

Richman SA, Nunez-Cruz S, Moghimi B, Li LZ, Gershenson ZT, Mourelatos Z, et al. High-affinity GD2-specific CAR T cells induce fatal encephalitis in a preclinical neuroblastoma model. Cancer Immunol Res 2018;6:36-46.

Chinnasamy N, Wargo JA, Yu Z, Rao M, Frankel TL, Riley JP, et al. A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer. J Immunol 2011;186:685-96.

Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 2013;36:133-51.

Min IM, Shevlin E, Vedvyas Y, Zaman M, Wyrwas B, Scognamiglio T, et al. CAR T therapy targeting ICAM-1 eliminates advanced human thyroid tumors. Clin Cancer Res 2017;23:7569-83.

Park S, Shevlin E, Vedvyas Y, Zaman M, Park S, Hsu YS, et al. Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity. Sci Rep 2017;7:14366.

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;31:71-5.

Lanitis E, Poussin M, Klattenhoff AW, Song D, Sandaltzopoulos R, June CH, et al. Chimeric antigen receptor T Cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo. Cancer Immunol Res 2013;1:43-53.

Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM, Thomson M, et al. Engineering customized cell sensing and response behaviors using synthetic Notch receptors. Cell 2016;164:780-91.

Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS, et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 2016;164:770-9.

Fedorov VD, Themeli M, Sadelain M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med 2013;5:215ra172.

Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, et al. TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol Ther Nucleic Acids 2013;2:e105.

Zah E, Lin MY, Silva-Benedict A, Jensen MC, Chen YY. T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol Res 2016;4:498-508.

Patel K, Olivares S, Singh H, Hurton LV, Huls MH, Qazilbash MH, et al. Combination immunotherapy with NY-ESO-1-specific CAR+ T cells with T-cell vaccine improves anti-myeloma effect. Blood 2016;128:3366.

Jones BS, Lamb LS, Goldman F, Di Stasi A. Improving the safety of cell therapy products by suicide gene transfer. Front Pharmacol 2014;5:254.

Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, et al. An inducible caspase 9 safety switch for T-cell therapy. Blood 2005;105:4247-54.

Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 2011;365:1673-83.

Wang X, Chang WC, Wong CW, Colcher D, Sherman M, Ostberg JR, et al. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood 2011;118:1255-63.

Craddock JA, Lu A, Bear A, Pule M, Brenner MK, Rooney CM, et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother 2010;33:780-8.

Moon EK, Carpenito C, Sun J, Wang LC, Kapoor V, Predina J, et al. Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin Cancer Res 2011;17:4719-30.

Priceman SJ, Tilakawardane D, Jeang B, Aguilar B, Murad JP, Park AK, et al. Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2(+) breast cancer metastasis to the brain. Clin Cancer Res 2018;24:95-105.

Nellan A, Rota C, Majzner R, Lester-McCully CM, Griesinger AM, Mulcahy Levy JM, et al. Durable regression of Medulloblastoma after regional and intravenous delivery of anti-HER2 chimeric antigen receptor T cells. J Immunother Cancer 2018;6:30.

Suarez ER, Chang de K, Sun J, Sui J, Freeman GJ, Signoretti S, et al. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 2016;7:34341-55.

Li S, Siriwon N, Zhang X, Yang S, Jin T, He F, et al. Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors. Clin Cancer Res 2017;23:6982-92.

Morrot A, da Fonseca LM, Salustiano EJ, Gentile LB, Conde L, Filardy AA, et al. Metabolic symbiosis and immunomodulation: how tumor cell-derived lactate may disturb innate and adaptive immune responses. Front Oncol 2018;8:81.

Ohta A. A Metabolic Immune checkpoint: adenosine in tumor microenvironment. Front Immunol 2016;7:109.

Poggi A, Varesano S, Zocchi MR. How to hit mesenchymal stromal cells and make the tumor microenvironment immunostimulant rather than immunosuppressive. Front Immunol 2018;9:262.

Ligtenberg MA, Mougiakakos D, Mukhopadhyay M, Witt K, Lladser A, Chmielewski M, et al. Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity. J Immunol 2016;196:759-66.

Lohr J, Ratliff T, Huppertz A, Ge Y, Dictus C, Ahmadi R, et al. Effector T-cell infiltration positively impacts survival of glioblastoma patients and is impaired by tumor-derived TGF-beta. Clin Cancer Res 2011;17:4296-308.

Bollard CM, Tripic T, Cruz CR, Dotti G, Gottschalk S, Torrano V, et al. Tumor-specific T-cells engineered to overcome tumor immune evasion induce clinical responses in patients with relapsed Hodgkin lymphoma. J Clin Oncol 2018;36:1128-39.

Grenga I, Donahue RN, Gargulak ML, Lepone LM, Roselli M, Bilusic M, et al. Anti-PD-L1/TGFbetaR2 (M7824) fusion protein induces immunogenic modulation of human urothelial carcinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis. Urol Oncol 2018;36:93.e1-.e11.

Juillerat A, Marechal A, Filhol JM, Valogne Y, Valton J, Duclert A, et al. An oxygen sensitive self-decision making engineered CAR T-cell. Sci Rep 2017;7:39833.

Kawalekar OU, O'Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD, Jr., et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 2016;44:380-90.

Gargett T, Brown MP. Different cytokine and stimulation conditions influence the expansion and immune phenotype of third-generation chimeric antigen receptor T cells specific for tumor antigen GD2. Cytotherapy 2015;17:487-95.

Hoyos V, Savoldo B, Quintarelli C, Mahendravada A, Zhang M, Vera J, et al. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 2010;24:1160-70.

Zhang L, Morgan RA, Beane JD, Zheng Z, Dudley ME, Kassim SH, et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin Cancer Res 2015;21:2278-88.

Mohammed S, Sukumaran S, Bajgain P, Watanabe N, Heslop HE, Rooney CM, et al. Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol Ther 2017;25:249-58.

Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex Genome Editing to Generate Universal CAR T Cells Resistant to PD1 Inhibition. Clin Cancer Res 2017;23:2255-66

Schumann K, Lin S, Boyer E, Simeonov DR, Subramaniam M, Gate RE, et al. Generation of knock-in primary human T cells using Cas9 ribonucleoproteins. Proc Natl Acad Sci U S A 2015;112:10437-42.

Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 2017;543:113-7.

Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, et al. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 2017;8:17002-11.

Ruella M, Kenderian SS. Next-generation chimeric antigen receptor T-cell therapy: going off the shelf. BioDrugs 2017;31:473-81.

Torikai H, Reik A, Soldner F, Warren EH, Yuen C, Zhou Y, et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 2013;122:1341-9.

Kansal R, Richardson N, Neeli I, Khawaja S, Chamberlain D, Ghani M, et al. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Sci Transl Med 2019;1.1.

Ali A, Kitchen SG, Chen ISY, Ng HL, Zack JA, Yang OO. HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies. J Virol 2016;90:6999-7006

Lim WA, June CH. The principles of engineering immune cells to treat cancer. Cell 2017;168:724-40.

Patel S, Burga RA, Powell AB, Chorvinsky EA, Hoq N, McCormack SE, et al. Beyond CAR T cells: other cell-based immunotherapeutic strategies against cancer. Front Oncol 2019;9:196.

How to Cite
Huang, Y., Li, L., Liu, W., Tang, T., & Chen, L. (2020). The progress of CAR-T therapy in cancer and beyond. STEMedicine, 1(3), e47.
Review articles