Clinical response rate of CD19 chimeric antigen receptor modified-T cells in the treatment of B cell hematological malignancies: a single rate meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

XU Hui ¹ , MING Jing ¹ , CHEN Erling ¹ , WANG Jian ¹ , LI Sujun ² , WANG Xiang ² , HU Yan ¹ , HE Caixia ² ,  WANG Xingbing ¹

1. Department of Hematology, Anhui Provincial Hospital, Anhui Medical University, Hefei, 230001, P.R. China;
2. Anhui Medical University, Hefei, 230001, P.R. China;

Corresponding author：

WANG Xingbing, Email: wangxingbing91@hotmail.com

Keywords：

Chimeric antigen receptor T cells; CART; Hematological malignancy; Immunotherapy; Cohort study; Single group rate; Meta-analysis

DOI：

10.7507/1672-2531.201705037

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ObjectivesTo systematically review the clinical response rate of CD19 chimeric antigen receptor modified-T cells (CD19CART) in the treatment of B cell hematological malignancies.MethodsPubMed, EMbase, CNKI, WanFang Data and VIP databases were searched to collect cohort studies about CD19CART in the treatment of B cell hematological malignancies from 2000 to 2016. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then, a single rate meta-analysis was performed by R software and SPSS 16.0 software.ResultsA total of 13 prospective cohort studies were included. The results of single group rate meta-analysis showed that the overall pooled response rate of CD19 CART was 68% (95%CI 0.51 to 0.82). The 6 months and 1-year PFS after CD19 CART infused by Kaplan-Meier were 46% (95%CI 0.35 to 0.56) and 24% (95%CI 0.16 to 0.34), respectively. The median duration was 180 days (95%CI 138 to 222). The COX regression model showed lymphodepletion to be the only influence factor of PFS.ConclusionsCD19 CART has a good clinical response rate in the treatment of B cell hematological malignancies. Lymphodepletion is the only important impact on the response rate and PFS. Due to limited quality and quantity of included studies, more high quality studies are required to verify the above conclusions.

Citation： XU Hui, MING Jing, CHEN Erling, WANG Jian, LI Sujun, WANG Xiang, HU Yan, HE Caixia, WANG Xingbing. Clinical response rate of CD19 chimeric antigen receptor modified-T cells in the treatment of B cell hematological malignancies: a single rate meta-analysis. Chinese Journal of Evidence-Based Medicine, 2018, 18(3): 314-321. doi: 10.7507/1672-2531.201705037 Copy

1.	Gökbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood, 2012, 120(10): 2032-2041.
2.	Schwarzbich MA, Mcclanahan F, Dsc JG. Allogeneic transplantation for chronic lymphocytic leukemia in the age of novel treatment strategies. Oncology, 2016, 30(6): 526-533.
3.	Nivisonsmith I, Bardy P, Dodds AJ, et al. A review of hematopoietic cell transplantation in Australia and New Zealand, 2005-2013. Biol Blood Marrow Transplant, 2015, 22(2): 284-291.
4.	Magenau J, Runaas L, Reddy P. Advances in understanding the pathogenesis of graft-versus-host disease. Br J Haematol, 2016, 173(2): 190-205.
5.	Uckun FM, Jaszcz W, Ambrus JL, et al. Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins. Blood, 1988, 71(1): 13-29.
6.	Kowolik CM, Topp MS, Gonzalez S, et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res, 2006, 66(22): 10995-11004.
7.	Kochenderfer JN, Yu Z, Frasheri D, et al. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood, 2010, 116(19): 3875-3886.
8.	Kochenderfer JN, Feldman SY. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother, 2008, 32(7): 689-702.
9.	Cooper LJ, Topp MS, Serrano LM, et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood, 2003, 101(4): 1637-1644.
10.	Brentjens RJ, Santos E, Nikhamin Y, et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res, 2007, 13(18 Pt 1): 5426-5435.
11.	Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood, 2010, 116(20): 4099-4102.
12.	Savoldo B, Ramos CA, Liu E, 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.
13.	Kalos M, Levine BL, Porter DL, et al. 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.
14.	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 Clin Oncol, 2015, 33(6):540-549.
15.	Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T Cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med, 2011, 6(224): 224ra25.
16.	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. Lancet, 2014, 385(9967): 517-528.
17.	Dai H, Zhang W, Li X, et al. Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Oncoimmunology, 2015, 4(11): e1027469.
18.	Kochenderfer JN, Dudley ME, Feldman SA, 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.
19.	Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med, 2015, 7(303): 303ra139.
20.	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. Blood, 2013, 122(25): 4129-4139.
21.	Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med, 2016, 8(355): 355ra116.
22.	Brentjens RJ, Isabelle R, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood, 2011, 118(18): 4817-4828.
23.	Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J Clin Invest, 2016, 126(6): 2123-2138.
24.	Maude S L, Frey N, Shaw P A, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med, 2014, 371(16): 1507-1517.
25.	Zhang T, Cao L, Xie J, et al. Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis. Oncotarget, 2015, 6(32): 33961-33971.
26.	Kantarjian HM, Thomas D, Ravandi F, et al. Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration. Cancer, 2010, 116(24): 5568-5574.
27.	Police RL, Trask PC, Wang J, et al. Randomized controlled trials in relapsed/refractory chronic lymphocytic leukemia: a systematic review and meta-analysis. Clin Lymphoma Myeloma Leuk, 2015, 15(4): 199-207.
28.	Colosia A, Njue A, Trask PC, et al. Clinical efficacy and safety in relapsed/refractory diffuse large B-cell lymphoma: a systematic literature review. Clin Lymphoma Myeloma Leuk, 2014, 14(5): 343-355.
29.	Geyer MB, Brentjens RJ. Review: current clinical applications of chimeric antigen receptor (CAR) modified T cells. Cytotherapy, 2016, 18(11): 1393-1409.
30.	Rosenberg SA, Restifo NP, Yang JC, et al. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer, 2008, 8(4): 299-308.
31.	Wang LX, Li Y, Yang G, et al. CD122+CD8+ Treg suppress vaccine-induced antitumor immune responses in lymphodepleted mice. Eur J Immunol, 2010, 40(5): 1375-1385.
32.	Shank BR, Do B, Sevin A, et al. Chimeric antigen receptor T Cells in hematologic malignancies. Pharmacotherapy, 2017, 37(3): 334-345.
33.	Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood, 2016, 127(26): 3321-3330.
34.	Uslu U, Schuler G, Dörrie J, et al. Combining a chimeric antigen receptor and a conventional T-cell receptor to generate T cells expressing two additional receptors (TETARs) for a multi-hit immunotherapy of melanoma. Exp Dermatol, 2016, 25(11): 872-879.
35.	Sotillo E, Barrett DM, Black KL, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov, 2015, 5(12): 1282-1295.
36.	Perna F, Sadelain M. Myeloid leukemia switch as immune escape from CD19 chimeric antigen receptor (CAR) therapy. Transl Cance Res, 2016, 5(S2): S221-S225.
37.	Ruella M, Barrett DM, Kenderian SS, et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest, 2016, 126(10): 3814-3826.

1. Gökbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood, 2012, 120(10): 2032-2041.
2. Schwarzbich MA, Mcclanahan F, Dsc JG. Allogeneic transplantation for chronic lymphocytic leukemia in the age of novel treatment strategies. Oncology, 2016, 30(6): 526-533.
3. Nivisonsmith I, Bardy P, Dodds AJ, et al. A review of hematopoietic cell transplantation in Australia and New Zealand, 2005-2013. Biol Blood Marrow Transplant, 2015, 22(2): 284-291.
4. Magenau J, Runaas L, Reddy P. Advances in understanding the pathogenesis of graft-versus-host disease. Br J Haematol, 2016, 173(2): 190-205.
5. Uckun FM, Jaszcz W, Ambrus JL, et al. Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins. Blood, 1988, 71(1): 13-29.
6. Kowolik CM, Topp MS, Gonzalez S, et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res, 2006, 66(22): 10995-11004.
7. Kochenderfer JN, Yu Z, Frasheri D, et al. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood, 2010, 116(19): 3875-3886.
8. Kochenderfer JN, Feldman SY. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother, 2008, 32(7): 689-702.
9. Cooper LJ, Topp MS, Serrano LM, et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood, 2003, 101(4): 1637-1644.
10. Brentjens RJ, Santos E, Nikhamin Y, et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res, 2007, 13(18 Pt 1): 5426-5435.
11. Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood, 2010, 116(20): 4099-4102.
12. Savoldo B, Ramos CA, Liu E, 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.
13. Kalos M, Levine BL, Porter DL, et al. 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.
14. 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 Clin Oncol, 2015, 33(6):540-549.
15. Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T Cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med, 2011, 6(224): 224ra25.
16. 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. Lancet, 2014, 385(9967): 517-528.
17. Dai H, Zhang W, Li X, et al. Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Oncoimmunology, 2015, 4(11): e1027469.
18. Kochenderfer JN, Dudley ME, Feldman SA, 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.
19. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med, 2015, 7(303): 303ra139.
20. 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. Blood, 2013, 122(25): 4129-4139.
21. Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med, 2016, 8(355): 355ra116.
22. Brentjens RJ, Isabelle R, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood, 2011, 118(18): 4817-4828.
23. Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J Clin Invest, 2016, 126(6): 2123-2138.
24. Maude S L, Frey N, Shaw P A, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med, 2014, 371(16): 1507-1517.
25. Zhang T, Cao L, Xie J, et al. Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis. Oncotarget, 2015, 6(32): 33961-33971.
26. Kantarjian HM, Thomas D, Ravandi F, et al. Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration. Cancer, 2010, 116(24): 5568-5574.
27. Police RL, Trask PC, Wang J, et al. Randomized controlled trials in relapsed/refractory chronic lymphocytic leukemia: a systematic review and meta-analysis. Clin Lymphoma Myeloma Leuk, 2015, 15(4): 199-207.
28. Colosia A, Njue A, Trask PC, et al. Clinical efficacy and safety in relapsed/refractory diffuse large B-cell lymphoma: a systematic literature review. Clin Lymphoma Myeloma Leuk, 2014, 14(5): 343-355.
29. Geyer MB, Brentjens RJ. Review: current clinical applications of chimeric antigen receptor (CAR) modified T cells. Cytotherapy, 2016, 18(11): 1393-1409.
30. Rosenberg SA, Restifo NP, Yang JC, et al. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer, 2008, 8(4): 299-308.
31. Wang LX, Li Y, Yang G, et al. CD122+CD8+ Treg suppress vaccine-induced antitumor immune responses in lymphodepleted mice. Eur J Immunol, 2010, 40(5): 1375-1385.
32. Shank BR, Do B, Sevin A, et al. Chimeric antigen receptor T Cells in hematologic malignancies. Pharmacotherapy, 2017, 37(3): 334-345.
33. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood, 2016, 127(26): 3321-3330.
34. Uslu U, Schuler G, Dörrie J, et al. Combining a chimeric antigen receptor and a conventional T-cell receptor to generate T cells expressing two additional receptors (TETARs) for a multi-hit immunotherapy of melanoma. Exp Dermatol, 2016, 25(11): 872-879.
35. Sotillo E, Barrett DM, Black KL, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov, 2015, 5(12): 1282-1295.
36. Perna F, Sadelain M. Myeloid leukemia switch as immune escape from CD19 chimeric antigen receptor (CAR) therapy. Transl Cance Res, 2016, 5(S2): S221-S225.
37. Ruella M, Barrett DM, Kenderian SS, et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest, 2016, 126(10): 3814-3826.

Chinese Journal of Evidence-Based Medicine

Clinical response rate of CD19 chimeric antigen receptor modified-T cells in the treatment of B cell hematological malignancies: a single rate meta-analysis

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