Hiệu quả tiền lâm sàng của tế bào T thể hiện thụ thể kháng nguyên chimeric nhằm vào CD20 cho bệnh bạch cầu không Hodgkin

Wen Hu1, Xiaoyan Lou2, Zhe Qu1, Chao Qin1, Hua Jiang1, Ying Yang1, Liqing Kang2, Xin Geng1, Lei Yu2, Ying Huang1
1Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control, Beijing, 100176, People’s Republic of China
2Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd, No 1525 Minqiang Road, Shanghai, People’s Republic of China

Tóm tắt

Tóm tắt Nền tảng Tế bào CAR-T chống lại CD20 (CAR-T20) được kích thích bởi 4-1BB/CD3-ζ đã được đánh giá hiệu quả hệ thống trong một mô hình đồng văn hóa tế bào, và chuột NOD-SCID IL-2 receptor gamma null (viết tắt là chuột NSG) đã được ghép xenograft với tế bào Burkitt's lymphoma Raji của người. Phương pháp Các tế bào CAR-T20 được ủ với các tế bào mục tiêu (K562, K562 CD20 hoặc tế bào Raji) theo tỷ lệ 10:1 và 5:1 trong 24 giờ, và tỷ lệ tiêu diệt được ước lượng qua xét nghiệm độc tính LDH. Để đánh giá tác động của CAR-T20 lên thời gian sống sót của động vật mang khối u, 30 con chuột NSG đã được sử dụng, và các tế bào Raji-Luc (5 × 105 tế bào mỗi chuột) đã được tiêm trước khi sử dụng CAR-T20. Thời gian sống sót, cường độ ánh sáng của tế bào Raji-Luc, các triệu chứng lâm sàng và khối lượng cơ thể của động vật đã được quan sát. Thêm vào đó, 144 con chuột đực NSG đã được sử dụng để điều tra sự phát triển và hiệu ứng chống khối u của CAR-T20. Nghiên cứu đã phát hiện ra cytokine của người và cytokine của chuột ở 1, 7, 14, 21, 28, 42, 56 và 90 ngày sau khi tiêm CAR-T, trong khi phân tích chỉ số sinh hóa, phát hiện tế bào T và tế bào CAR-T trong máu ngoại vi, và kiểm tra mô bệnh học được thực hiện ở 14, 28, 56 và 90 ngày sau khi tiêm.

Từ khóa

#CAR-T #CD20 #lymphoma #pre-clinical #efficacy

Tài liệu tham khảo

Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49.

Tilly H, Morschhauser F, Sehn LH, et al. The POLARIX study: polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) therapy in patients with previously untreated diffuse large B-cell lymphoma. Blood. 2021;138(Supplement 2):LBA-1.

Hutchings M, Mous R, Clausen MR, et al. Subcutaneous epcoritmab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma: safety profile and anti-tumor activity. Hematol Oncol. 2021;39(S2):42–3.

Caimi P, Ai WZ, Alderuccio JP, et al. Duration of response to loncastuximab tesirine in relapsed/refractory diffuse large B-cell lymphoma by demographic and clinical characteristics: subgroup analyses from LOTIS 2. J Clin Oncol. 2021;39(suppl 15):abstr7546.

Song Y, Zhou K, Jin C, et al. A phase II study of penpulimab, an anti-PD-1 antibody, in patients with relapsed or refractoryclassic Hodgkin lymphoma (cHL). J Clin Oncol. 2021;39(15):7529.

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):2709–20.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.

Ansell SM, Lin Y. Immunotherapy of lymphomas. J Clin Invest. 2020;130(4):1576–85.

Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69.

Davenport AJ, Jenkins MR, Cross RS, et al. CAR-T cells inflict sequential killing of multiple tumor target cells [published correction appears in Cancer Immunol Res. 2018 Mar;6(3):370]. Cancer Immunol Res. 2015;3(5):483–94.

Abramson JS, Gordon LI, Palomba ML, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J Clin Oncol. 2018;36(15_suppl):7505.

Till BG, Jensen MC, Wang J, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008;112(6):2261–71.

Neelapu SS, Locke FL, Bartlett N, et al. Axicabtagene Ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44.

Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell Lymphoma. N Engl J Med. 2019;380(1):45–56.

Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331–42.

Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839–52.

Westin JR, Kersten MJ, Salles G, et al. Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: observations from the JULIET, ZUMA-1, and TRANSCEND trials. Am J Hematol. 2021;96(10):1295–312.

Marshall MJE, Stopforth RJ, Cragg MS. Therapeutic antibodies: what have we learnt from targeting CD20 and where are we going? Front Immunol. 2017;8:1245.

Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14(8):517–34.

Klein C, Jamois C, Nielsen T. Anti-CD20 treatment for B-cell malignancies: current status and future directions. Expert Opin Biol Ther. 2021;21(2):161–81.

Kumar A, Planchais C, Fronzes R, et al. Binding mechanisms of therapeutic antibodies to human CD20. Science. 2020;369(6505):793–9.

Till BG, Jensen MC, Wang J, et al. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4–1BB domains: pilot clinical trial results. Blood. 2012;119(17):3940–50.

Chu Y, Hochberg J, Yahr A, et al. Targeting CD20+ aggressive B-cell non-hodgkin lymphoma by anti-CD20 CAR mRNA-modified expanded natural killer cells in vitro and in NSG Mice. Cancer Immunol Res. 2015;3(4):333–44.

Wen H, Qu Z, Yan Y, et al. Preclinical safety evaluation of chimeric antigen receptor-modified T cells against CD19 in NSG mice. Ann Transl Med. 2019;7(23):735.

Smith JB, Lanitis E, Dangaj D, et al. Tumor regression and delayed onset toxicity following B7–H4 CAR T cell therapy. Mol Ther. 2016;24(11):1987–99.

Yin Z, Zhang Y, Wang X. Advances in chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. Biomark Res. 2021;9(1):58.

Salles G, Barrett M, Foà R, et al. Rituximab in B-cell hematologic malignancies: a review of 20 years of clinical experience. Adv Ther. 2017;34(10):2232–73.

Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125(1):22–32.

Pytlik R, Polgarova K, Karolova J, et al. Current immunotherapy approaches in non-hodgkin lymphomas. Vaccines (Basel). 2020;8(4):708.

Benmebarek MR, Karches CH, Cadilha BL, et al. Killing mechanisms of Chimeric Antigen Receptor (CAR) T cells. Int J Mol Sci. 2019;20(6):1283.

Chu Y, Yahr A, Huang B, et al. Romidepsin alone or in combination with anti-CD20 chimeric antigen receptor expanded natural killer cells targeting Burkitt lymphoma in vitro and in immunodeficient mice. Oncoimmunology. 2017;6(9): e1341031.

Rufener GA, Press OW, Olsen P, et al. Preserved activity of CD20-specific chimeric antigen receptor-expressing T cells in the presence of Rituximab. Cancer Immunol Res. 2016;4(6):509–19.

Cheng Q, Tan J, Liu R, et al. CD20-specific chimeric antigen receptor-expressing T cells as salvage therapy in rituximab-refractory/relapsed B-cell non-Hodgkin lymphoma. Cytotherapy. 2022;24(10):1026–34.

Nishimoto KP, Barca T, Azameera A, et al. Allogeneic CD20-targeted γδ T cells exhibit innate and adaptive antitumor activities in preclinical B-cell lymphoma models. Clin Transl Immunology. 2022;11(2): e1373.

Seder RA, Ahmed R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat Immunol. 2003;4(9):835–42.

Jiang H, Li C, Yin P, et al. Anti-CD19 chimeric antigen receptor-modified T-cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia: An open-label pragmatic clinical trial. Am J Hematol. 2019;94(10):1113–22.

Turtle CJ, Berger C, Sommermeyer D, et al. Anti-CD19 Chimeric antigen receptor-modified T Cell Therapy for B Cell Non-hodgkin lymphoma and chronic lymphocytic leukemia: fludarabine and cyclophosphamide lymphodepletion improves in vivo expansion and persistence of CAR-T cells and clinical outcomes. Blood. 2015;126(23):184.

Shedlock DJ, Shen H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science. 2003;300(5617):337–9.

Wen H, Huo G, Hou T, et al. Preclinical efficacy and safety evaluation of interleukin-6-knockdown CAR-T cells targeting at CD19. Ann Transl Med. 2021;9(23):1713.

Wang Z, Wu Z, Liu Y, et al. New development in CAR-T cell therapy. J Hematol Oncol. 2017;10(1):53.

Salomao M, Dorritie K, Mapara MY, et al. Histopathology of graft-vs-host disease of gastrointestinal tract and liver: an update. Am J Clin Pathol. 2016;145(5):591–603.

Kang L, Tang X, Zhang J, et al. Interleukin-6-knockdown of chimeric antigen receptor-modified T cells significantly reduces IL-6 release from monocytes. Exp Hematol Oncol. 2020;9:11.

Shah NN, Maatman T, Hari P, et al. Multi targeted CAR-T cell therapies for B-cell malignancies. Front Oncol. 2019;9:146.