CD38-directed CAR-T cell therapy: a novel immunotherapy strategy for relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation

Qingya Cui, Chongsheng Qian, Nan Xu, Liqing Kang, Haiping Dai, Wei Cui, Baoquan Song, Jia Yin, Zheng Li, Xiaming Zhu, Changju Qu, Tianhui Liu, Wenhong Shen, Mingqing Zhu, Lei Yu, Depei Wu, Xiaowen Tang, Qingya Cui, Chongsheng Qian, Nan Xu, Liqing Kang, Haiping Dai, Wei Cui, Baoquan Song, Jia Yin, Zheng Li, Xiaming Zhu, Changju Qu, Tianhui Liu, Wenhong Shen, Mingqing Zhu, Lei Yu, Depei Wu, Xiaowen Tang

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for acute myeloid leukemia (AML). However, most patients experience relapse after allo-HSCT, with a poor prognosis, and treatment options are limited. The lack of an ideal targetable antigen is a major obstacle for treating patients with relapsed AML. CD38 is known to be expressed on most AML and myeloma cells, and its lack of expression on hematopoietic stem cells (HSCs) renders it a potential therapeutic target for relapsed AML. To investigate the clinical therapeutic efficacy and safety of CD38-targeted chimeric antigen receptor T (CAR-T-38) cells, we enrolled 6 AML patients who experienced relapse post-allo-HSCT (clinicaltrials.gov: NCT04351022). Prior to CAR-T-38 treatment, the blasts in the bone marrow of these patients exhibited a median of 95% (92-99%) CD38 positivity. Four weeks after the initial infusion of CAR-T-38 cells, four of six (66.7%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi); the median CR or CRi time was 191 (range 117-261) days. The cumulative relapse rate at 6 months was 50%. The median overall survival (OS) and leukemia-free survival (LFS) times were 7.9 and 6.4 months, respectively. One case relapsed 117 days after the first CAR-T-38 cell infusion, with remission achieved after the second CAR-T-38 cell infusion. All six patients experienced clinically manageable side effects. In addition, multiparameter flow cytometry (FCM) revealed that CAR-T-38 cells eliminated CD38 positive blasts without off-target effects on monocytes and lymphocytes. Although this prospective study has a limited number of cases and a relatively short follow-up time, our preliminary data highlight the clinical utility and safety of CAR-T-38 cell therapy in treating relapsed AML post-allo-HSCT.

Keywords: Allogeneic hematopoietic stem cell transplantation; CAR-T-38; Chimeric antigen receptor T cells; Cytokine release syndrome; Relapsed acute myeloid leukemia.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
CAR-T-38 therapy regimen and treatment response among 6 relapsed AML patients post-allo-HSCT. a Schematic of the CAR-T-38 structure. b Schematic of the CAR-T-38 therapy regimen (* and ** supplementary file). c Variation in donor chimerism in the bone marrow (BM) and peripheral blood (PB) was measured by short tandem repeat-polymerase chain reaction (STR-PCR). d Patients 1, 2, 4, and 5 achieved complete remission (CR) or CR with incomplete count recovery (CRi) at 4 weeks after CAR-T-38 infusion. Patients 1 and 4 relapsed within six months. Patient 4 experienced relapse 117 days after the first CAR-T-38 infusion but exhibited remission after the second CAR-T-38 treatment. The 6-month OS and LFS rates were both 50%. CD38-positive blasts were reduced, and CD38-positive granulocytes and monocytes gradually increased at 1 and 4 weeks after CAR-T-38 infusion. e The CD38-positive blast population is shown in the upper right (red) of the CD34/CD38 plot. f, g CD38-positive granulocytes and monocytes, based on forward versus side scatter and CD38 expression, are shown in the upper left (crimson) and the lower left (green), respectively

References

    1. Schmid C, Labopin M, Nagler A, Niederwieser D, Castagna L, Tabrizi R, et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood. 2012;119:1599–1606. doi: 10.1182/blood-2011-08-375840.
    1. Bejanyan N, Weisdorf DJ, Logan BR, Wang HL, Devine SM, de Lima M, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a center for international blood and marrow transplant research study. Biol Blood Marrow Transplant. 2015;21:454–459. doi: 10.1016/j.bbmt.2014.11.007.
    1. Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449–459. doi: 10.1056/NEJMoa1709919.
    1. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–448.
    1. Walter RB, Appelbaum FR, Estey EH, Bernstein ID. Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood. 2012;119:6198–6208. doi: 10.1182/blood-2011-11-325050.
    1. Jin L, Lee EM, Ramshaw HS, Busfield SJ, Peoppl AG, Wilkinson L, et al. Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell. 2009;5:31–42. doi: 10.1016/j.stem.2009.04.018.
    1. Wei J, Han X, Bo J, Han W. Target selection for CAR-T therapy. J Hematol Oncol. 2019;12:62. doi: 10.1186/s13045-019-0758-x.
    1. Huang R, Li X, He Y, Zhu W, Gao L, Liu Y, et al. Recent advances in CAR-T cell engineering. J Hematol Oncol. 2020;13:86. doi: 10.1186/s13045-020-00910-5.
    1. Konopleva M, Rissling I, Andreeff M. CD38 in hematopoietic malignancies. Chem Immunol. 2000;75:189–206. doi: 10.1159/000058769.
    1. Overdijk MB, Verploegen S, Bögels M, van Egmond M, Lammerts van Bueren JJ, Mutis T, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7:311–321. doi: 10.1080/19420862.2015.1007813.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться