1018O - Phase I study of GCC CAR-T therapy IM96 in patients with advanced colorectal cancer

Background

The clinical outcomes of metastatic colorectal cancer (mCRC) therapies are limited. Guanylyl cyclase 2C (GCC) is ectopically expressed in mCRC and intestinally-restricted. A GCC-targeted CAR-T (IM96) was developed and phase I study was conducted to evaluate the safety and efficacy (NCT05287165).

Methods

In this open-label, 3+3 dose-escalation study, IM96 was evaluated in GCC-positive mCRC patients (pts) failed to ≥3 lines of therapies. Bridging therapies were allowed. Pts were pre-treated with fludarabine and cyclophosphamide, and received a single infusion of IM96 at the dose of 3×10⁸ (DL1), 6×10⁸ (DL2), 12×10⁸ (DL3), or 20×10⁸ (DL4) CAR-T cells. The primary objectives were safety and toxicity, and the secondary objectives were efficacy and pharmacokinetic profile.

Results

As of December 2022, 9 pts were enrolled and infused with IM96. The median age was 52.6, and 5/9 cases were male. Bridging therapies were used in 8 pts. Neurotoxicity and ≥grade 3 cytokine release syndromes (CRS) were not observed. Grade 1-2 CRS occurred in 5/9 pts (55.6%) with dramatic increase of interleukin-6. In 4/9 pts (44.4%), grade 1-3 diarrhea and rash were observed. Grade 3 diarrhea occurred in 2/9 pts (22.2%), and grade 2-3 oral mucositis occurred in 3/9 pts (33.3%), only in DL2 and DL3 groups. Dose-limiting toxicity and maximum tolerated dose were not achieved. The disease control rate (DCR) was 66.7%, and the objective response rate (ORR) was 11.1%. After CAR-T infusion, 5/9 (55.6%) patients showed a significant decrease in CEA level which was aberrantly high in all pts at baseline. CAR-T proliferated in all pts and reached peak at 7-10 days after infusion. Two pts showed persisting tumor reduction and declination of CEA level within 3 months, coinciding with CAR-T expansion to 10⁸/L. The response in pts with moderate-to-strong GCC expression in ≥30% of tumor cells was 100% DCR, and with this prerequisite, tumor reduction was observed in 100% pts when the IM96 dose was ≥6×10⁸.

Conclusions

IM96 was well tolerated and showed encouraging efficacy. The clinical response is correlated with tumor GCC expression, infusion dose, and CAR-T expansion level. This study is ongoing, and dose extensive investigation will also be performed.

Clinical trial identification

NCT05287165.

Editorial acknowledgement

Legal entity responsible for the study

Peking University Cancer Hospital and Institute.

Funding

Beijing Imunopharm Technology Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.