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应用CAR转导的自然杀伤细胞治疗CD19阳性淋巴肿瘤
Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors


Enli Liu ... 肿瘤 • 2020.02.06
相关阅读
• 嵌合抗原受体疗法 • 悲剧、坚持和机遇——CAR-T疗法的故事 • 慢性淋巴细胞白血病的CAR-T细胞疗法

摘要


背景

抗CD19嵌合抗原受体(CAR)T细胞疗法治疗B细胞肿瘤的临床疗效显著。然而,CAR T细胞可产生显著的毒性作用,并且细胞的制备非常复杂。经改造后可表达抗CD19 CAR的自然杀伤(NK)细胞有可能克服这些局限性。

 

方法

在这项1期和2期试验中,我们将来自脐带血的HLA不匹配的抗CD19 CAR-NK细胞用于11例复发性或难治性CD19阳性肿瘤(非霍奇金淋巴瘤或慢性淋巴细胞白血病[CLL])患者。我们使用表达抗CD19 CAR、白细胞介素-15和可诱导型半胱天冬酶9(inducible caspase 9,作为安全开关)编码基因的反转录病毒载体转导NK细胞。对细胞进行体外扩增,并在淋巴细胞清除性化疗之后给患者单次输入以下三种剂量之一(1×105、1×106或1×107 CAR-NK细胞/kg体重)。

 

结果

输入CAR-NK细胞后未伴发细胞因子释放综合征、神经毒性或移植物抗宿主病,而且与基线水平相比,炎性细胞因子(包括白细胞介素-6)水平也未增加。本试验未达到最大耐受剂量。在接受治疗的11例患者中,8例(73%)达到缓解;其中7例(4例淋巴瘤患者和3例CLL患者)达到完全缓解,1例患者的Richter转化达到缓解,但CLL持续。患者达到缓解的速度快,所有剂量水平均在输入后30日内观察到缓解。输入的CAR-NK细胞发生扩增,并以低水平持续至少12个月。

 

结论

在11例复发性或难治性CD19阳性肿瘤患者中,大部分接受CAR-NK细胞治疗后达到缓解,且未发生主要毒性作用(由M.D.安德森癌症中心[M.D. Anderson Cancer Center] CLL和淋巴瘤登月计划[CLL and Lymphoma Moonshot]和美国国立卫生研究院资助,在ClinicalTrials.gov注册号为NCT03056339)。





作者信息

Enli Liu, M.D., David Marin, M.D., Pinaki Banerjee, Ph.D., Homer A. Macapinlac, M.D., Philip Thompson, M.B., B.S., Rafet Basar, M.D., Lucila Nassif Kerbauy, M.D., Bethany Overman, B.S.N., Peter Thall, Ph.D., Mecit Kaplan, M.S., Vandana Nandivada, M.S., Indresh Kaur, Ph.D., Ana Nunez Cortes, M.D., Kai Cao, M.D., May Daher, M.D., Chitra Hosing, M.D., Evan N. Cohen, Ph.D., Partow Kebriaei, M.D., Rohtesh Mehta, M.D., Sattva Neelapu, M.D., Yago Nieto, M.D., Ph.D., Michael Wang, M.D., William Wierda, M.D., Ph.D., Michael Keating, M.D., Richard Champlin, M.D., Elizabeth J. Shpall, M.D., and Katayoun Rezvani, M.D., Ph.D.
From the Departments of Stem Cell Transplantation and Cellular Therapy (E.L., D.M., P.B., R.B., L.N.K., B.O., M. Kaplan, V.N., I.K., A.N.C., M.D., C.H., P.K., R.M., Y.N., R.C., E.J.S., K.R.), Nuclear Medicine (H.A.M.), Leukemia (P. Thompson, W.W., M. Keating), Biostatistics (P. Thall), Laboratory Medicine (K.C.), Hematopathology (E.N.C.), and Lymphoma and Myeloma (S.N., M.W.), University of Texas M.D. Anderson Cancer Center, Houston. Address reprint requests to Dr. Rezvani at the Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 448, Houston, TX 77030, or at krezvani@mdanderson.org.

 

参考文献

1. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018;378:439-448.

2. Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 2018;378:449-459.

3. 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;365:725-733.

4. 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):303ra139-303ra139.

5. Turtle CJ, Hay KA, Hanafi LA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol 2017;35:3010-3020.

6. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377:2531-2544.

7. Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 2017;377:2545-2554.

8. Schuster SJ. Tisagenlecleucel in diffuse large B-cell lymphoma. N Engl J Med 2019;380:1586-1586.

9. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019;25:625-638.

10. 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 2014;6(224):224ra25-224ra25.

11. Neelapu SS, Tummala S, Kebriaei P, et al. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit ‘ALL.’ Nat Rev Clin Oncol 2018;15:218-218.

12. Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 2008;9:495-502.

13. Wu J, Lanier LL. Natural killer cells and cancer. Adv Cancer Res 2003;90:127-156.

14. Shah N, Li L, McCarty J, et al. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Br J Haematol 2017;177:457-466.

15. Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005;105:3051-3057.

16. Rubnitz JE, Inaba H, Ribeiro RC, et al. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol 2010;28:955-959.

17. Tagaya Y, Bamford RN, DeFilippis AP, Waldmann TA. IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity 1996;4:329-336.

18. Liu E, Tong Y, Dotti G, et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 2018;32:520-531.

19. Mehta RS, Rezvani K. Can we make a better match or mismatch with KIR genotyping? Hematology Am Soc Hematol Educ Program 2016;2016:106-118.

20. Hallek M, Cheson BD, Catovsky D, et al. iwCLL Guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018;131:2745-2760.

21. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-3068.

22. Hoyos V, Savoldo B, Quintarelli C, 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;24:1160-1170.

23. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014;371:1507-1517.

24. Muftuoglu M, Olson A, Marin D, et al. Allogeneic BK virus–specific T cells for progressive multifocal leukoencephalopathy. N Engl J Med 2018;379:1443-1451.

25. Felices M, Lenvik AJ, McElmurry R, et al. Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight 2018;3(3):e96219-e96219.

26. Olson JA, Leveson-Gower DB, Gill S, Baker J, Beilhack A, Negrin RS. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood 2010;115:4293-4301.

27. Ruggeri L, Mancusi A, Burchielli E, et al. NK cell alloreactivity and allogeneic hematopoietic stem cell transplantation. Blood Cells Mol Dis 2008;40:84-90.

28. Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med 2018;24:731-738.

29. Rezvani K, Rouce R, Liu E, Shpall E. Engineering natural killer cells for cancer immunotherapy. Mol Ther 2017;25:1769-1781.

30. Lin JK, Muffly LS, Spinner MA, Barnes JI, Owens DK, Goldhaber-Fiebert JD. Cost effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma. J Clin Oncol 2019;37:2105-2119.

31. Campbell JD, Whittington MD. Paying for CAR-T therapy amidst limited health system resources. J Clin Oncol 2019;37:2095-2097.

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