Anti-PD-1 Therapy Enhances the Efficacy of CD30-Directed Chimeric Antigen Receptor T Cell Therapy in Patients With Relapsed/Refractory CD30+ Lymphoma

Wei Sang, Xiangmin Wang, Hongzhi Geng, Tianci Li, Dashan Li, Bingpei Zhang, Yi Zhou, Xuguang Song, Cai Sun, Dongmei Yan, Depeng Li, Zhenyu Li, Caixia Li, Kailin Xu, Wei Sang, Xiangmin Wang, Hongzhi Geng, Tianci Li, Dashan Li, Bingpei Zhang, Yi Zhou, Xuguang Song, Cai Sun, Dongmei Yan, Depeng Li, Zhenyu Li, Caixia Li, Kailin Xu

Abstract

Anti-CD30 CAR-T is a potent candidate therapy for relapsed/refractory (r/r) CD30+ lymphomas with therapy limitations, and the efficacy needed to be further improved. Herein a multi-center phase II clinical trial (NCT03196830) of anti-CD30 CAR-T treatment combined with PD-1 inhibitor in r/r CD30+ lymphoma was conducted. After a lymphocyte-depleting chemotherapy with fludarabine and cyclophosphamide, 4 patients in cohort 1 and 3 patients in cohort 2 received 106/kg and 107/kg CAR-T cells, respectively, and 5 patients in cohort 3 received 107/kg CAR-T cells combined with anti-PD-1 antibody. The safety and the efficacy of CAR-T cell therapy were analyzed. Cytokine release syndrome (CRS) was observed in 4 of 12 patients, and only 1 patient (patient 9) experienced grade 3 CRS and was treated with glucocorticoid and tocilizumab. No CAR-T-related encephalopathy syndrome was observed. Only two patients in cohorts 2 and 3 experienced obviously high plasma levels of IL-6 and ferritin after CD30 CAR-T cell infusion. The overall response rate (ORR) was 91.7% (11/12), with 6 patients achieving complete remission (CR) (50%). In cohorts 1 and 2, 6 patients got a response (85.7%), with 2 patients achieving CR (28.6%). In cohort 3, 100% ORR and 80% CR were obtained in 5 patients without ≥3 grade CRS. With a median follow-up of 21.5 months (range: 3-50 months), the progression-free survival and the overall survival rates were 45 and 70%, respectively. Of the 11 patients who got a response after CAR-T therapy, 7 patients (63.6%) maintained their response until the end of follow-up. Three patients died last because of disease progression. Taken together, the combination of anti-PD-1 antibody showed an enhancement effect on CD30 CAR-T therapy in r/r CD30+ lymphoma patients with minimal toxicities.

Keywords: CD30; PD-1; chimeric antigen receptor; efficacy; relapsed/refractory CD30+ lymphoma.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Sang, Wang, Geng, Li, Li, Zhang, Zhou, Song, Sun, Yan, Li, Li, Li and Xu.

Figures

Figure 1
Figure 1
Flowchart for anti-CD30 CAR-T trials.
Figure 2
Figure 2
Clinical response and duration for patients after anti-CD30 CAR-T cell infusion. The color and the length of each bar indicate the response to the anti-CD30 CART treatment and the duration of response, respectively. CR, complete remission; PR, partial remission; PD, progressive disease. The black triangle indicates the start time of the second cycle of CAR-T cell infusion. The arrow indicates a sustained response. The star indicates the start time of anti-PD-1 antibody therapy. The original point and the downward pointing arrow represent the death and the start time of hematopoietic stem cell transplantation.
Figure 3
Figure 3
Changes in the patients’ serum cytokine levels after anti-CD30 CAR-T cell infusion. The serum IL-6 and ferritin levels of each patient were assessed before and at serial time points after anti-CD30 CAR-T cell infusion. The red and the blue lines, respectively, represent patient 5 and patient 9 with higher IL-6 and ferritin levels than the others.
Figure 4
Figure 4
Representative clinical response images of the patient after anti-CD30 CAR-T cell infusion (patient 8). The second cycle of anti-CD30 CAR-T cells was infused 2 weeks after the autologous stem cell transplantation (ASCT). Positron emission tomography–computed tomography scans demonstrated a significant shrinkage of masses after the first cycle of anti-CD30 CAR-T cell infusion and complete disappearance of abnormal lymph nodes after ASCT and the second cycle of anti-CD30 CAR-T treatment.
Figure 5
Figure 5
Overall survival and progression-free survival of patients after anti-CD30 CAR-T cell infusion.

References

    1. Barrett DM, Singh N, Porter DL, Grupp SA, June CH. Chimeric Antigen Receptor Therapy for Cancer. Annu Rev Med (2014) 65:333–47. doi: 10.1146/annurev-med-060512-150254
    1. Abramson JS. Anti-CD19 CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma. Transfus Med Rev (2020) 34:29–33. doi: 10.1016/j.tmrv.2019.08.003
    1. Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, et al. . KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med (2020) 382:1331–42. doi: 10.1056/NEJMoa1914347
    1. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. . Long-Term Safety and Activity of Axicabtagene Ciloleucel in Refractory Large B-Cell Lymphoma (ZUMA-1): A Single-Arm, Multicentre, Phase 1-2 Trial. Lancet Oncol (2019) 20:31–42. doi: 10.1016/S1470-2045(18)30864-7
    1. Chen W, Ma Y, Shen Z, Chen H, Ma R, Yan D, et al. . Humanized Anti-CD19 CAR-T Cell Therapy and Sequential Allogeneic Hematopoietic Stem Cell Transplantation Achieved Long-Term Survival in Refractory and Relapsed B Lymphocytic Leukemia: A Retrospective Study of CAR-T Cell Therapy. Front Immunol (2021) 12:755549. doi: 10.3389/fimmu.2021.755549
    1. Anagnostou T, Riaz IB, Hashmi SK, Murad MH, Kenderian SS. Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy in Acute Lymphocytic Leukaemia: A Systematic Review and Meta-Analysis. Lancet Haematol (2020) 7:e816–e26. doi: 10.1016/S2352-3026(20)30277-5
    1. Bansal R, Reshef R. Revving the CAR - Combination Strategies to Enhance CAR T Cell Effectiveness. Blood Rev (2021) 45:100695. doi: 10.1016/j.blre.2020.100695
    1. Grover NS, Savoldo B. Challenges of Driving CD30-Directed CAR-T Cells to the Clinic. BMC Cancer (2019) 19:203. doi: 10.1186/s12885-019-5415-9
    1. Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, et al. . Aggressive Conventional Chemotherapy Compared With High-Dose Chemotherapy With Autologous Haemopoietic Stem-Cell Transplantation for Relapsed Chemosensitive Hodgkin’s Disease: A Randomised Trial. Lancet (2002) 359:2065–71. doi: 10.1016/S0140-6736(02)08938-9
    1. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. . Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin’s Lymphoma. J Clin Oncol (2012) 30:2183–9. doi: 10.1200/JCO.2011.38.0410
    1. Chen R, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. . Five-Year Survival and Durability Results of Brentuximab Vedotin in Patients With Relapsed or Refractory Hodgkin Lymphoma. Blood (2016) 128:1562–6. doi: 10.1182/blood-2016-02-699850
    1. Wang CM, Wu ZQ, Wang Y, Guo YL, Dai HR, Wang XH, et al. . Autologous T Cells Expressing CD30 Chimeric Antigen Receptors for Relapsed or Refractory Hodgkin Lymphoma: An Open-Label Phase I Trial. Clin Cancer Res (2017) 23:1156–66. doi: 10.1158/1078-0432.CCR-16-1365
    1. Ramos CA, Ballard B, Zhang H, Dakhova O, Gee AP, Mei Z, et al. . Clinical and Immunological Responses After CD30-Specific Chimeric Antigen Receptor-Redirected Lymphocytes. J Clin Invest (2017) 127:3462–71. doi: 10.1172/JCI94306
    1. Ramos CA, Grover NS, Beaven AW, Lulla PD, Wu MF, Ivanova A, et al. . Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma. J Clin Oncol (2020) 38:3794–804. doi: 10.1200/JCO.20.01342
    1. Wang D, Zeng C, Xu B, Xu JH, Wang J, Jiang LJ, et al. . Anti-CD30 Chimeric Antigen Receptor T Cell Therapy for Relapsed/Refractory CD30(+) Lymphoma Patients. Blood Cancer J (2020) 10:8. doi: 10.1038/s41408-020-0274-9
    1. Li F, Zhang Z, Xuan Y, Zhang D, Liu J, Li A, et al. . PD-1 Abrogates the Prolonged Persistence of CD8(+) CAR-T Cells With 4-1BB Co-Stimulation. Signal Transduct Target Ther (2020) 5:164. doi: 10.1038/s41392-020-00277-6
    1. Rafiq S, Yeku OO, Jackson HJ, Purdon TJ, van Leeuwen DG, Drakes DJ, et al. . Targeted Delivery of a PD-1-Blocking scFv by CAR-T Cells Enhances Anti-Tumor Efficacy. vivo Nat Biotechnol (2018) 36:847–56. doi: 10.1038/nbt.4195
    1. Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, et al. . PD-1 Blockade Modulates Chimeric Antigen Receptor (CAR)-Modified T Cells: Refueling the CAR. Blood (2017) 129:1039–41. doi: 10.1182/blood-2016-09-738245
    1. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. . ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated With Immune Effector Cells. Biol Blood Marrow Transplant (2019) 25:625–38. doi: 10.1016/j.bbmt.2018.12.758
    1. 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. doi: 10.1016/S0140-6736(14)61403-3
    1. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. . Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med (2017) 377:2531–44. doi: 10.1056/NEJMoa1707447
    1. Gudipati V, Rydzek J, Doel-Perez I, Goncalves VDR, Scharf L, Konigsberger S, et al. . Inefficient CAR-Proximal Signaling Blunts Antigen Sensitivity. Nat Immunol (2020) 21:848–56. doi: 10.1038/s41590-020-0719-0
    1. Liu S, Deng B, Yin Z, Lin Y, An L, Liu D, et al. . Combination of CD19 and CD22 CAR-T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia After Allogeneic Transplantation. Am J Hematol (2021) 96:671–9. doi: 10.1002/ajh.26160
    1. Yan Z, Cao J, Cheng H, Qiao J, Zhang H, Wang Y, et al. . A Combination of Humanised Anti-CD19 and Anti-BCMA CAR T Cells in Patients With Relapsed or Refractory Multiple Myeloma: A Single-Arm, Phase 2 Trial. Lancet Haematol (2019) 6:e521–e9. doi: 10.1016/S2352-3026(19)30115-2
    1. Rupp LJ, Schumann K, Roybal KT, Gate RE, Ye CJ, Lim WA, et al. . CRISPR/Cas9-Mediated PD-1 Disruption Enhances Anti-Tumor Efficacy of Human Chimeric Antigen Receptor T Cells. Sci Rep (2017) 7:737. doi: 10.1038/s41598-017-00462-8
    1. 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. doi: 10.1158/1078-0432.CCR-17-0867

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