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.
Editor’s Note:
The 2023 European Society for Medical Oncology (ESMO) Annual Meeting took place in Madrid, Spain, from October 20th to 24th. The Oncology Frontier team delved into the frontline, capturing international advancements and witnessing the strides made by China in the global oncology arena. Professor Changsong Qi from Peking University Cancer Hospital delivered a crucial oral presentation (Abstract No: 1018O) at this conference. In an exclusive interview with Oncology Frontier, Professor Qi shared insights from his reported research and thoughts on colorectal cancer studies presented at this year’s ESMO. This article compiles relevant content for readers.
01. Oncology Frontier: You presented a Phase I study on CAR-T therapy IM96 targeting GCC for the treatment of advanced colorectal cancer at this year’s ESMO. Could you discuss the background, key findings, and your future research plans for this study?
Professor Changsong Qi: Currently, immunotherapy, particularly immune checkpoint inhibitors, is widely used. However, its efficacy in certain solid tumors, especially in digestive system cancers, is not significant. In such cases, exploring additional immunotherapies becomes essential. Hence, we conducted a Phase I study on CAR-T therapy IM96 targeting GCC (guanylyl cyclase C) for the treatment of advanced colorectal cancer.
02.Oncology frontier: Why did we choose colorectal cancer for this exploration?
Professor Changsong Qi: Firstly, colorectal cancer is a prevalent global malignancy, ranking among the top five in both incidence and mortality among malignant tumors. Therefore, focusing on colorectal cancer as an indication could potentially benefit a large number of patients. Secondly, colorectal cancer is unique, categorized into MSI-H and MSS types based on molecular subtyping. While MSI-H colorectal cancer significantly benefits from immune checkpoint inhibitors, these patients constitute only about 5% of advanced colorectal cancer cases. The remaining approximately 95% fall under MSS type, posing challenges in deriving benefits from immune checkpoint inhibitors. We needed to find alternative effective therapies for these patients, leading us to explore cell immunotherapy targeting GCC.
GCC is highly expressed in over 80% of metastatic colorectal cancers, with both primary and metastatic lesions showing high GCC expression. Moreover, normal tissues exhibit lower expression, with only the normal intestinal mucosa showing some degree of expression. Therefore, GCC is a promising CAR-T target, and this was validated in the clinical trial. IM96 demonstrated excellent safety, with no severe cytokine release syndrome (CRS) or neurotoxicity reported. Among the nine patients, six experienced diarrhea, mostly mild to moderate, and they recovered well within ten days post-cell infusion. In terms of efficacy, this study involved dose escalation, with a decrease in tumor markers observed in some patients at the first two dose levels, and significant tumor regression in the third patient. The high-dose group achieved excellent efficacy, correlating positively with GCC expression.
Future research plans include exploring the efficacy and safety of higher doses and investigating the effectiveness and safety of IM96 in patients with higher GCC expression. Additionally, due to the controllable adverse reactions of IM96, which are entirely different from the adverse reaction spectrum of targeted therapy, immunotherapy, and chemotherapy, we plan to explore combination therapy with IM96 and other treatments, such as PD-1 monoclonal antibodies, CTLA-4 monoclonal antibodies, tumor vaccines, or oncolytic viruses, to achieve a synergistic effect. Lastly, we plan to explore drugs targeting other antigens. In summary, our goal is to continuously explore ways to bring better benefits to patients with digestive system tumors.
03. Oncology Frontier: This year’s ESMO conference unveiled several studies in the field of colorectal cancer. Could you share your thoughts on the research presented at this conference?
Professor Changsong Qi:
The colorectal cancer studies presented at this year’s ESMO conference focused on perioperative chemoradiotherapy combined with immunotherapy and immunotherapy for advanced colorectal cancer. While these treatments are promising, they ultimately revolve around exploring immunotherapy, particularly immune checkpoint inhibitors, in colorectal cancer. These explorations may show progress in early-stage colorectal cancer, but overall efficacy remains limited in advanced cases. Nevertheless, some studies left a profound impression, particularly those investigating biomarkers, the immune microenvironment, etc. These contribute to our understanding of how colorectal cancer responds to treatment mechanisms, resistance mechanisms to corresponding drugs, and are crucial for the development of future drugs or improvements in therapy.
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.
