T‐cell receptor–like chimeric antigen receptor T cells targeting mesothelin: A first‐in‐human dose‐escalation trial for platinum‐resistant advanced ovarian cancer

Background

Ovarian cancer remains a formidable therapeutic challenge due to late diagnosis, high recurrence rates, and limited treatment options. Mesothelin (MSLN) is highly expressed in ovarian cancer, making it a promising target for immunotherapy. Given this target profile, the authors developed a novel T‐cell receptor (TCR)‐like chimeric antigen receptor (CAR) T‐cell therapy targeting MSLN, designated KT127.

Methods

A first‐in‐human, dose‐escalation trial of KT127 was conducted following preclinical evaluation in vitro and in vivo. A combination of rapid titration and a standard “3 + 3” dose‐escalation design was implemented. Eleven patients received KT127 at doses ranging from 1 × 10 ⁶ to 2 × 10 ⁷ cells/kg following lymphodepletion. The primary objectives were to assess the safety and tolerability of KT127. Secondary objectives included overall survival, disease control rate (DCR), and progression‐free survival as efficacy measures. Quality of life (QOL) was assessed using the European Organisation for Research and Treatment of Cancer QLQ‐OV28 questionnaire.

Results

No dose‐limiting toxicities, cytokine release syndrome, or immune effector cell‐associated neurotoxicity syndrome were observed. The DCR was 80% (95% confidence interval, 44.4%–97.5%). QOL assessments indicated improvement in abdominal/gastrointestinal symptoms post‐treatment ( p  = .037), with no significant deterioration in other domains. Proteomic analysis identified differential expression of kallikrein‐related peptidases (KLK13, KLK14) and chemokine CXCL17 at baseline, potentially linked to treatment outcomes.

Conclusions

This study highlights that KT127 has a manageable safety profile and shows preliminary biological activity in patients with advanced ovarian cancer, particularly those who have failed multiple lines of therapies.