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

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.

Haploidentical Stem Cell Transplantation for Acute Myeloid Leukemia: Current Therapies, Challenges and Future Prospective

“…There were no off-target effects on monocytes and lymphocytes. Although a limited number of cases and a relatively short follow-up time were presented by Cui et al (139), their preliminary data highlight the clinical utility and safety of CAR-T-38 cell therapy in treating relapsed AML following allo-SCT. Several trials (NCT02782546, 04024761, 03300492) investigating the feasibility of immunotherapy with NK cells are ongoing (Table 4).…”

“…The outcomes of AML patients who relapse after allografts remain poor, with a 5-year OS of less than 20%, and either DLI or second allo-SCT is prescribed (138). More recently, Cui et al (139) enrolled 6 AML patients who relapsed after transplantation. The median percentage of CD38 expression on blasts in the bone marrow of these patients was 95% before CD38-targeted CAR-T cell (CAR-T-38, 4 from autologous and 2 from donors) treatment.…”

Treatment of AML Relapse After Allo-HCT

“…For relapsed AML after allo-HCT, CD19 CAR T cells have proven effective in a number of patients with t(8;21), which often aberrantly expresses CD19 ( 106 , 107 ). While CD19 is rarely expressed in AML cells, CAR T cells targeting CD33; CD38; and CD123 have demonstrated efficacy for the treatment of post-allo-HCT AML relapse ( 108 , 109 ), while CAR T cells targeting CLL1; CD13; and TIM3 among others are in development for the treatment of relapsed/refractory AML ( 110 , 111 ). Thus the early evidence points to the relative safety of CAR T cells for the treatment of relapsed ALL after allo-HCT, and early studies treating relapsed AML after allo-HCT with CAR T cells targeting a variety of different antigens have yielded promising results.…”

Immune-Based Therapeutic Strategies for Acute Myeloid Leukemia

“…Currently, this approach is being evaluated in a phase I/II trial (NCT04351022). Currently, results on six relapsed AML patients after allo-HSCT are available [ 59 ]. All patients exhibited CD38 in more than 90% on their blast cells.…”