Phase 1 study of guanylyl cyclase 2C-targeted CAR T-cell therapy in patients with metastatic colorectal cancer

The clinical efficacy of third- or later-line therapies for metastatic colorectal cancer (mCRC) is limited. A phase 1 trial at Peking University Cancer Hospital and Institute (Beijing, China) evaluated IM96, a guanylyl cyclase 2C (GUCY2C)-targeted autologous CAR T-cell therapy, in patients with third- or later-line mCRC that expressed GUCY2C. In the 3+3 pattern dose-escalation phase, four dose levels were tested: 3 x 10⁸ (DL1), 6 x 10⁸ (DL2), 12 x 10⁸ (DL3), and 20 x 10⁸ (DL4) CAR T cells. No dose-limiting toxicity was observed, and DL3 was chosen for the dose-expansion study. A total of 20 patients were infused after lymphodepletion, and only one patient (5%) showed grade 3 CRS and neurotoxicity. Grade 3 diarrhea occurred in 11 patients (55%). Among 19 evaluable patients, the objective response rate (ORR) was 26.3%, with all responding patients in de DL3 and DL4 groups. Among 10 patients in the DL3 group, the ORR was 40% and the median progression-free survival (mPFS) was 7.0 months. Among patients showing medium-to-high GUCY2C expression in the DL3 group, the ORR was 50.0% and the mPFS was 9.0 months. The authors conclude that IM96 showed an acceptable safety profile and high response rate in patients with third- or later-line mCRC, with clinical efficacy associated with CAR T dose level.