Abstract：Nowadays, the 5-year survival rate of childhood cancer patients can be more than 80%, but some patients with relapse and refractory cancers have shown no good response to traditional strategies. Chimeric antigen receptor engineered T (CAR-T) cell therapy is promising for these patients. CAR-T cells recognize the tumor-associated antigens in a non-major histocompatibility complex-restricted manner, so their anti-tumor ability is enhanced. There are four generations of CAR-T cells now. The complete remission rate of pediatric patients with relapse and refractory acute lymphoblastic leukemia can be as high as 90% when treated with CD19-targeting CAR-T cells. Furthermore, CAR-T cell therapy can also be used to bridge to transplantation and donor CAR-T cell infusion can be a strategy to prevent relapse after hematopoietic stem cell transplantation. As to solid tumors, only patients with neuroblastoma present good response to the GD2-targeting CAR-T cell therapy. The toxic or side effects of CAR-T cell therapy include cytokine release syndrome, off-tumor effect, tumor lysis syndrome, and insertion mutation. Although the CD19-targeting CAR-T cell therapy for childhood cancer can result in a high remission rate, the relapse rate is high, including CD19+ and CD19- relapse. The mechanisms for relapse merit further investigation.
NI Ya-Ru,XU Xiao-Jun,TANG Yong-Min. Progress in clinical studies of chimeric antigen receptor engineered T cells for treatment of childhood cancer[J]. CJCP, 2017, 19(11): 1219-1224.
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017[J]. CA Cancer J Clin, 2017, 67(1):7-30.
[2]
Anderson J. Unleashing the immune response against childhood solid cancers[J]. Pediatr Blood Cancer, 2017, 64(10). doi:10.1002/pbc.26548.
[3]
Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy[J]. Science, 2013, 342(6165):1432-1433.
[4]
Chmielewski M, Abken H. TRUCKs:the fourth generation of CARs[J]. Expert Opin Biol Ther, 2015, 15(8):1145-1154.
[5]
Batlevi CL, Matsuki E, Brentjens RJ, et al. Novel immunotherapies in lymphoid malignancies[J]. Nat Rev Clin Oncol, 2016, 13(1):25-40.
[6]
Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia[J]. N Engl J Med, 2013, 368(16):1509-1518.
[7]
Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults:a phase 1 dose-escalation trial[J]. Lancet, 2015, 385(9967):517-528.
[8]
Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia[J]. N Engl J Med, 2014, 371(16):1507-1517.
[9]
Gardner RA, Finney O, Annesley C, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults[J]. Blood, 2017, 129(25):3322-3331.
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[J]. Leuk Lymphoma, 2013, 54(2):255-260.
[12]
Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia[J]. Sci Transl Med, 2013, 5(177):177ra138.
[13]
Lussana F, Intermesoli T, Gianni F, et al. Achieving molecular remission before allogeneic stem cell transplantation in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia:Impact on relapse and long-term outcome[J]. Biol Blood Marrow Transplant, 2016, 22(11):1983-1987.
[14]
Kochenderfer JN, Dudley ME, Carpenter RO, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation[J]. Blood, 2013, 122(25):4129-4139.
[15]
Cruz CR, Micklethwaite KP, Savoldo B, 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[J]. Blood, 2013, 122(17):2965-2973.
[16]
Brudno JN, Somerville RP, Shi V, 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]. J Clin Oncol, 2016, 34(10):1112-1121.
[17]
Anti-CD22 CAR therapy leads to all remissions[J]. Cancer Discov, 2017, 7(2):120.
[18]
Wang QS, Wang Y, Lv HY, et al. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia[J]. Mol Ther, 2015, 23(1):184-191.
[19]
Ritchie DS, Neeson PJ, Khot A, et al. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia[J]. Mol Ther, 2013, 21(11):2122-2129.
[20]
Ruella M, Barrett DM, Kenderian SS, et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies[J]. J Clin Invest, 2016, 126(10):3814-3826.
[21]
Erker C, Harker-Murray P, Burke MJ. Emerging immunotherapy in pediatric lymphoma[J]. Future Oncol, 2016, 12(2):257-270.
[22]
Ramos CA, Heslop HE, Brenner MK. CAR-T Cell therapy for lymphoma[J]. Annu Rev Med, 2016, 67:165-183.
[23]
Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor[J]. J Clin Oncol, 2015, 33(6):540-549.
[24]
Wang CM, Wu ZQ, Wang Y, et al. Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory Hodgkin lymphoma:An open-label phase I trial[J]. Clin Cancer Res, 2017, 23(5):1156-1166.
[25]
Eyquem J, Mansilla-Soto J, Giavridis T, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection[J]. Nature, 2017, 543(7643):113-117.
[26]
Cherkassky L, Morello A, Villena-Vargas J, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition[J]. J Clin Invest, 2016, 126(8):3130-3144.
[27]
Liu X, Zhang Y, Cheng C, et al. CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells[J]. Cell Res, 2017, 27(1):154-157.
[28]
Ren J, Liu X, Fang C, et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition[J]. Clin Cancer Res, 2017, 23(9):2255-2266.
[29]
Chong EA, Melenhorst JJ, Lacey SF, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells:refueling the CAR[J]. Blood, 2017, 129(8):1039-1041.
[30]
Xia AL, Wang XC, Lu YJ, et al. Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors:challenges and opportunities[J]. Oncotarget, 2017, doi:10.18632/oncotarget.19361.
[31]
Pule MA, Savoldo B, Myers GD, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors:persistence and antitumor activity in individuals with neuroblastoma[J]. Nat Med, 2008, 14(11):1264-1270.
[32]
Louis CU, Savoldo B, Dotti G, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma[J]. Blood, 2011, 118(23):6050-6056.
[33]
Brown CE, Badie B, Barish ME, et al. Bioactivity and Safety of IL13Ralpha2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma[J]. Clin Cancer Res, 2015, 21(18):4062-4072.
[34]
Morgan RA, Johnson LA, Davis JL, et al. Recognition of glioma stem cells by genetically modified T cells targeting EGFRvⅢ and development of adoptive cell therapy for glioma[J]. Hum Gene Ther, 2012, 23(10):1043-1053.
[35]
Irving M, Vuillefroy de Silly R, Scholten K, et al. Engineering chimeric antigen receptor T-Cells for racing in solid tumors:Don't forget the fuel[J]. Front Immunol, 2017, 8:267.
[36]
Brentjens R, Yeh R, Bernal Y, et al. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells:case report of an unforeseen adverse event in a phase I clinical trial[J]. Mol Ther, 2010, 18(4):666-668.
[37]
Morgan RA, Yang JC, Kitano M, et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2[J]. Mol Ther, 2010, 18(4):843-851.
[38]
Xu XJ, Tang YM. Cytokine release syndrome in cancer immunotherapy with chimeric antigen receptor engineered T cells[J]. Cancer Lett, 2014, 343(2):172-178.
[39]
Frey NV, Porter DL. Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia[J]. Hematology Am Soc Hematol Educ Program, 2016, 2016(1):567-572.
[40]
Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia[J]. Cancer Discov, 2016, 6(6):664-679.
[41]
Xu XJ, Tang YM, Song H, et al. Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children[J]. J Pediatr, 2012, 160(6):984-990.e1.
[42]
Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia[J]. N Engl J Med, 2011, 365(8):725-733.
[43]
Gross G, Eshhar Z. Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment:Counteracting off-tumor toxicities for safe CAR T cell therapy[J]. Annu Rev Pharmacol Toxicol, 2016, 56:59-83.
[44]
Howard SC, Trifilio S, Gregory TK, et al. Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies:a systematic review[J]. Ann Hematol, 2016, 95(4):563-573.
[45]
Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1[J]. J Clin Invest, 2008, 118(9):3132-3142.
[46]
Newrzela S, Cornils K, Li Z, et al. Resistance of mature T cells to oncogene transformation[J]. Blood, 2008, 112(6):2278-2286.
[47]
Maude SL, Teachey DT, Rheingold SR, et al. Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL[J]. J Clin Oncol, 2016, 34(15):3011.
[48]
Ruella M, Maus MV. Catch me if you can:Leukemia escape after CD19-Directed T Cell Immunotherapies[J]. Comput Struct Biotechnol J, 2016, 14:357-362.
[49]
Fischer J, Paret C, El Malki K, et al. CD19 isoforms enabling resistance to CART-19 immunotherapy are Expressed in B-ALL patients at initial diagnosis[J]. J Immunother, 2017, 40(5):187-195.
