CELL INTELLIGENCE · 肿瘤细胞治疗研究

Despite advances in the molecular characterization of mature T and NK cell lymphomas, outcomes for these patients is poor especially those with relapsed/refractory (R/R) disease. These tumors possess mutations that often result in tonic T cell receptor (TCR) signaling and an immunosuppressive tumor microenvironment. Interleukin-2-inducible T cell kinase (ITK) plays an important role in TCR signaling and T cell differentiation. Soquelitinib is a covalent oral selective ITK inhibitor that blocks Th2 differentiation while sparing Th1 cells (Th1 skewing). We conducted a phase 1 trial with soquelitinib for the treatment of R/R peripheral T cell lymphomas to determine safety, target occupancy and antitumor activity. A dose escalation design was followed by an expansion cohort to confirm dosing and identify predictive characteristics. Seventy-five patients were enrolled. No dose-limiting toxicities were observed with doses up to 600mg BID and target occupancy exceeding 80% was established for 200mg BID dose. At the 200mg BID dose, number of prior lines of therapy was found to affect antitumor activity as durable complete and partial responses were seen in 37% patients with 1-3 prior therapies; no responses were seen in patients with >3. Objective and durable tumor responses were observed in various histologic subtypes. Blood and tumor biopsies indicated that soquelitinib treatment leads to Th1 skewing, reduction of T cell exhaustion and blockade of Th2 cells. These studies demonstrate soquelitinib is active in T cell lymphomas with a mechanism related to effects on malignant T cells and/or normal T effector cells. Trial registration: NCT03952078 at www.ClinicalTrials.gov.