Phase I study of functionally enhanced CD33 CAR T cells in patients with relapsed or refractory acute myeloid leukemia.
Authors: Pan Jing , Zuo Shiyu , Li Chuo , Ling Zhuojun , Xu Jinlong , Duan Jiajia , Wang Zelin , Wu Tong , Feng Xiaoming 
Published: June 2024

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Background: Chimeric antigen receptor (CAR) T-cell therapy has shown promising efficacy in B-cell malignancies (Majzner RG, et al. Nat Med. 2019 Sep;25(9):1341-1355). However, its feasibility in acute myeloid leukemia (AML) is not fully established. CD33 CAR T-cell therapy in relapsed or refractory (r/r) AML have reported limited or no significant anti-leukemic effects (Tambaro FP, et al. Leukemia. 2021 Nov;35(11):3282-3286; Wang QS, et al. Mol Ther. 2015 Jan;23(1):184-91). CD123 CAR T-cell therapy has weak proliferation and low CR rates (Wermke M, et al. Blood. 2021 Jun 3;137(22):3145-3148; Cummins, Katherine D. et al. Blood. 2017; 130: 1359), while CLL1 CAR T-cell therapy has induced anti-leukemic responses in a small subset of patients without sustained expansion (Pei K, et al. Cancer Med. 2023 Apr;12(8):9655-9661; Jin X, et al. J Hematol Oncol. 2022 Jul 7;15(1):88). Here, we present early safety and efficacy of functionally enhanced CD33 CAR T cells in AML. Methods: We improved the performance of CD33 CAR T cells by adding a potentiating molecule linked to human CD33 scFv by P2A. The study was registered with ClinicalTrials.gov (NCT04835519). The trial used the “3+3” approach, starting with an initial dose of 5×105 (±20%)/kg. The primary endpoint was safety with efficacy secondary. Results: Four relapsed patients, including three who underwent stem cell transplantation, were enrolled and received initial dose of CAR T cells between April 13, and July 28, 2021. The Data and Safety Monitoring Committee approved the preliminary report. Three patients (75%) experienced grade 1−2 cytokine release syndrome (CRS), while one (25%) had grade 4 CRS. One developed grade 2 CRS after the second infusion. One patient had dose-limiting toxicity. Two patients (50%) had grade 1 neurotoxicity, and two (50%) developed grade 1–2 graft-versus-host disease. All patients experienced grade 2–4 neutropenia, monocytopenia, and thrombocytopenia. One patient developed sepsis. Two patients achieved CR with incomplete hematologic recovery (CRi) and were MRD-negative at day 30, while two had no response. Of these, one patient received a second infusion and achieved MRD+ CRi. Two patients have remained disease free for over two years. One patient remained disease free for one year before CD33+ relapse. The two patients with CRi had peak CAR T cell counts of 192 and 23.5 cells/μl, while the two without CRi had lower peak counts of 2.12 and 10.3 cells/μl. One patient peaked at 1.73 cells/μl after the second infusion. The two patients with CRi also had a higher proportion of CAR T cells among the lymphocytes (46.8% and 53.0%). As expected, peripheral blood CD33+ cells decreased. Conclusions: We report the safety and efficacy of functionally enhanced CD33 CAR T cells. While some patients had CRi, there was also depletion of CD33-positive normal cells. Thus, further research is needed to address the issue of normal cell depletion. Clinical trial information: NCT04835519 .