Decreasing HPK1 expression in CD19 CAR-T cells: A novel strategy to overcome challenges of cell therapy for adult (r/r) B-ALL.
Authors: Zhang Na , SI Jingwen , LI Guang , WANG Yu , LONG Fei , WANG Tantan , Song Yanping , Liao Xuebin , Gao Guangxun , Dimitrov Dimiter Stanchev 
Published: June 2022

7041 Background: Since the FDA approved the first CD19 CAR T cell therapy (Kymriah) for pediatric and young adult patients with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (ALL), cytokine release syndrome (CRS) has still been a life-threatening toxicity that limits the full therapeutic potential in adults [1,2]. So far, Tecartus was the first and only approved CAR-T cell therapy for adult r/r B ALL, which was based on results from ZUMA-3 study. CRS occurred in 92% patients, and neurologic toxicities occurred in 87% patients in ZUMA-3 study[3], suggesting that therapeutic developments are needed to ensure more safe options for adult B-ALL. Our preclinical data demonstrated that CAR-T cells with decreased HPK1 expression had enhanced antitumor effects and did not induce higher grade CRS [4]. Thus, the first-in-human clinical study is ongoing to test CD19 CAR-T cells with decreased HPK1 expression (XYF19 CAR-T cells) for adult (r/r) B-ALL (NCT04037566). Methods: Dose-escalation study was initiated to explore the safety and efficacy of XYF19 CAR-T cells in adult r/r B-ALL. 11 eligible adult r/r B-ALL patients were enrolled. The cell dosage of XYF19 was significantly lower than Tecartus and Kymriah, participants were infused with XYF19 CAR-T cells: 3 at low dose (2.0×105/kg), 5 at medium dose (5.0×105/kg), and 3 at high dose (1.0×106/kg). All patients received a conditioning regimen of IV fludarabine (30mg/m2/d) for 4 days and cyclophosphamide (500mg/m2/d) for 2 days. Results: 30 days after infusion with XYF19 CAR-T cells, 8 of the 11 (72.7%) patients had achieved complete remission (CR) or CR with incomplete count recovery (CRi). Considering the low dosage of XYF19 and that the CR/CRi rate is 71% with Tecartus [2] and 69% with Kymriah [3], the clinical response of XYF19 is similar or even the highest in these three studies. Strikingly, in this clinical trial, no patient has yet experienced dose-limiting toxicity. No grade 3 or higher CRS occurred in XYF19 treated patients, while Grade 3 or higher CRS was observed in 26% of patients with Tecartus [2], and 72% of patients with Kymriah[3]. No neurologic events occurred in the current study, while the incidence of neurological events was 51% with Tecartus [2] and 43% with Kymriah[3]. Thus, XYF19 is a strong potential novel treatment for CD19 CAR-T cell therapy in adult B-ALL. Conclusions: Treatment with XYF19 CAR-T cells promises a novel treatment that can alleviate some of the stern challenges of CD19 CAR-T cell therapy for adult patients with r/r B-ALL. In the current study, this treatment showed robust activity against adult (r/r) B-ALL without > Grade 2 toxicity. This efficacy and safety will be demonstrated in further trials with larger sample sizes. References: [1] Blood. 2021; 19;138 (7): 531–543. [2] Lancet.398(10299):491-502. [3] J. Biol. Chem. 287,34091–34100. [4] Cancer Cell. 2020; 38; 1-16. Clinical trial information: NCT04037566.