Chinese team launches new CAR-T clinical trial to provide more options for children with acute myeloid leukemia

Writing | Pei Kunlin Zhang Hui Editing | Zhou Yebin

Although conventional chemotherapy can cure approximately 60% of children with primary acute myeloid leukemia (AML), treatment for refractory or relapsed AML (R/R-AML) remains the same. lack. When a child with AML unfortunately relapses, parents always ask their doctors: Are there any new drugs or treatments to choose from? In fact, both scientific research workers and clinical researchers have been making continuous efforts around this problem.

A number of novel targeted agents (eg, sorafenib, giritinib, gemtuzumab, and veneclax) have shown promise in the treatment of children with R/R-AML advantages, but there are also obvious limitations. The success of immunotherapy in B lymphocyte malignancies provides new ideas for the treatment of AML. Among them, chimeric antigen receptor T-cell therapy (CAR-T) is regarded as a highly effective therapy for the treatment of refractory/relapsed hematological malignancies. Previous studies have demonstrated that CD19-targeting CAR-T cell immunotherapy is very effective in R/R B-ALL patients. However, the future of CAR-T in AML is unclear.

Why does this happen? The reason is that AML is a highly heterogeneous group of myeloid malignancies, with many optional targets (CD33, CD123, CD117, CD38, LewisY, TIM3, etc.), immune targeting potentially affecting the function of hematopoietic stem cells, toxic and side effects. Unclear, etc., all limit the application and promotion of CAR-T cells in AML. However, a large number of studies have also shown that C-type lectin-like molecule 1 (CLL1) is a novel AML stem cell-associated antigen, which is highly expressed on AML stem cells, most AML progenitor cells and monocytes, and is highly expressed on normal hematopoietic stem cells and lymphocytes. low expression. This suggests that CAR-T cell immunotherapy targeting CLL1 may be a new approach to AML treatment.

On September 23, 2022, Southern Chunfu (Children) Institute of Hematology as the lead unit, Li ChunfuProfessor as the lead Published in Leukemia in collaboration with Guangzhou Women’s and Children’s Medical Center a titled Characteristics of anti-CLL1 based CAR-T therapy for children with relapsed or refractory acute myeloid leukemia: the multi-center efficacy and safety The article of interim analysisreports the interim research results and preliminary results of a multi-center clinical study of CLL1 CAR-T cells in the treatment of children with R/R-AML.

Before conducting clinical trials, the research team first tried to verify the targeting ability and tumor cell killing potential of CAR-T cells targeting CLL1 through in vitro experiments and animal experiments. The results showed that CAR-T targeting CLL1 exhibited strong antitumor activity in preclinical mouse models.

CAR-T targeting CLL1 exhibits strong antitumor activity in preclinical mouse models. A. B-NDG mice were injected intravenously with 5×105 HL60 cells expressing luciferase. After 2 days, 3×106 or 1×107 anti-CLL1 CAR-T cells were injected intravenously, respectively, and the AML status of the mice before and after treatment was assessed by in vivo mouse imaging system. B-C. Tumor burden and survival analysis in mice treated with anti-CLL1 CAR-T cells. (5 per group)

Based on the results of animal experiments and previous cases of CLL1-targeting CAR-T therapy in R/R-AML, the research team designed the clinical trial and registered it in the China Clinical Trials Registry ( ChiCTR1900027684) and the US Clinical Trials Registry (NCT03222674). The study enrolled 8 children with R/R-AML to participate in a Phase 1/2 clinical trial of autologous anti-CLL1 CAR-T cell immunotherapy, with the aim of evaluating the safety and preliminary efficacy of anti-CLL1 CAR-T cell therapy.

Patients were reinfused with autologous anti-CLL1 CAR-T cells after lymphodepleting therapy. After CAR-T treatment, all patients developed grade 1-2 cytokine release syndrome (CRS) without any fatal event. Four of the eight patients achieved morphological leukemia-free status (MLFS) and minimal residual disease (MRD) negative, one had MLFS with positive MRD, and one achieved complete remission with incomplete hematologic recovery (CRi) but positive MRD, One patient had a partial response (PR), and one patient had a stable (SD) status but CLL1-positive naive AML cells were cleared. These results suggest that anti-CLL1 CAR-T cell immunotherapy is a well-tolerated and effective option for the treatment of children with R/R-AML. Follow-up of patients showed that 5 subjects were still alive, 4 of them were in continuous remission and 1 had relapse at the last follow-up.

Anti-CLL1 CAR-T induces complete remission in AML patients. A. Schematic diagram of clinical trial design. B. Duration of response and overall survival in patients after infusion of anti-CLL1 CAR-T cells. Six of the eight patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CAR-T cell infusion. Patient 2 died of graft-versus-host disease after the second HSCT. Patient 4 relapsed after HSCT and died of disease progression. In the other 2 patients who did not receive hematopoietic stem cell transplantation, patient 5 relapsed after 12 months of complete remission, and patient 6 died of disease progression and severe lung infection. CR/CRi/MLFS: complete remission/complete remission combinedHematologic incomplete recovery/morphologic leukemia-free status, MRD: minimal residual disease, PR: partial response, SD: stable disease.

The research team, while focusing on the efficacy of anti-CLL1 CAR-T cell therapy, systematically evaluated its systemic side effects. The research team recorded adverse events from the onset of lymphocyte depletion to 60 days after CAR-T cell infusion. All patients developed grade 1-2 cytokine release syndrome, and no cardiac, respiratory, liver, renal, gastrointestinal, and skin toxicity were found.

adverse event information record

In summary, the results of this study show that anti-CLL1 CAR-T cells in the treatment of children with R/R-AML are safe, controllable and highly targeted. bright future. However, preliminary results show that anti-CLL1 CAR-T cell therapy cannot achieve the effect of curing R/R-AML, and it may be more appropriate to bridge for better hematopoietic stem cell transplantation. The therapy also needs to be improved to further improve the clinical effect of R/R-AML in children.




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