A novel adoptive synthetic TCR and antigen receptor (STAR) T‐Cell therapy for B‐Cell acute lymphoblastic leukemia

Abstract

We developed a T-cell-receptor (TCR) complex-based chimeric antigen receptor (CAR) named Synthetic TCR and Antigen Receptor (STAR). Here, we report preclinical and phase I clinical trial data (NCT03953599) of this T-cell therapy for refractory and relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL) patients. STAR consists of two protein modules each containing an antibody light or heavy chain variable region and TCR α or β chain constant region fused to the co-stimulatory domain of OX40. T-cells were transduced with a STAR-OX40 lentiviral vector. A leukemia xenograft mouse model was used to assess the STAR/STAR-OX40 T cell antitumor activity. Eighteen patients with R/R B-ALL were enrolled into the clinical trial. In a xenograft mouse model, STAR-T-cells exhibited superior tumor-specific cytotoxicity compared with conventional CAR-T cells. Incorporating OX40 into STAR further improved the proliferation and persistence of tumor-targeting T-cells. In our clinical trial, 100% of patients achieved complete remission 4 weeks post-STAR-OX40 T-cell infusion and 16/18 (88.9%) patients pursued consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twelve of 16 patients (75%) remained leukemia-free after a median follow-up of 545 (433-665) days. The two patients without consolidative allo-HSCT relapsed on Day 58 and Day 186. Mild cytokine release syndrome occurred in 10/18 (55.6%) patients, and 2 patients experienced grade III neurotoxicity. Our preclinical studies demonstrate super anti-tumor potency of STAR-OX40 T-cells compared with conventional CAR-T cells. The first-in-human clinical trial shows that STAR-OX40 T-cells are tolerable and an effective therapeutic platform for treating R/R B-ALL. | INTRODUCTIONOver the past decades, several chimeric antigen receptor (CAR) T-cell therapies targeting distinct cancer types have received regulatory approvals. [1][2][3][4] While early CAR-T approaches were associated with relatively severe cytokine release syndrome (CRS), CAR-T-related neurotoxicity, and infectious complications, 5,6 second-generation CARs composed of a target-specific single-chain variable fragment (scFv), a flexible hinge region, a transmembrane domain, a costimulatory domain and a CD3ζ intracellular signaling domain have shown remarkable efficacy in patients with B-cell malignancies. 7,8 However, many studies have demonstrated that strengthening the Jiasheng Wang, Xian Zhang, and Zhixiao Zhou contributed equally to this work.

IL-6 translation is a therapeutic target of human cytokine release syndrome

“…1 H ), recapitulating the observation in patient #0 and rendering the KS culture a suitable system for further mechanistic investigations. To generalize the observation to conventional CD19-targeting CAR T, we generated KS by killing Raji B cells with previously described BBz-CAR T cells ( Wang et al, 2022 ). Consistently, both prophylactic and conditional metoprolol treatment impaired BBz-KS–induced IL-6 protein production in human monocytes ( Fig.…”

“…BBz-CAR was generated as previously described ( Wang et al, 2022 ). Briefly, the sequences of FMC63 scFv, the CD8 transmembrane domain, and CD3ζ plus 4-1BB signaling chains constituted the CD19 + CAR construct.…”

Essentials of CAR-T Therapy and Associated Microbial Challenges in Long Run Immunotherapy

“…The results showed that although third-generation CARs' in vivo persistence was generally improved in preclinical mouse xenograft models of pancreatic cancer, the anti-tumor potency of the secondgeneration CARs still outperformed the third-generation formats [81]. In a different study, third-generation anti-GD2 CARs with CD28-OX40-CD3ζ domains produced better in vitro cytokine secretion (IL-2, TNFα) and proliferation than second-generation (CD28-CD3ζ or OX40-CD3ζ) and firstgeneration (CD3ζ) forms [82]. Apart from structural variations in co-stimulatory domains, patient heterogeneity and different therapies may potentially contribute to the dearth of advantages of third-generation CARs.…”

T-cell engineering strategies for tumors with low antigen density, and T-cell survival in the immunosuppressive tumor microenvironment of relapsed/refractory diffuse large B-cell lymphoma

“…Moreover, mutSTAT co-stimulated with OX40 significantly prolongs the in vivo persistence. CD19 specific mutSTAR-OX40 has been found to have a 100% CR rate in treating 18 patients with r/r B-ALL 4 weeks post infusion in a phase I clinical trial: 75% (12/16) patients remained leukemia-free after a median follow-up of 545 (433-665) days; 55.6% patients (10/18) had mild CRS; and two patients had grade III neurotoxicity [206]. In another preclinical study, V L and V H domain of the Fab of human anti-CD19 (ET190L1, clone) were fused with the δ chain and γ chain of TCR respectively to direct CD19 antigen specificity and antigen dependent CD3γε/CD3δε/ CD3ζζ signaling, cytokine production, degranulation.…”