Metastatic Colorectal Cancer CAR-T Therapy GCC19CART Demonstrates Safety and Clinical Activity in US Patients

GCC19CART (Innovative Cellular Therapeutics), an investigational autologous chimeric antigen receptor T-cell (CAR-T) therapy, has demonstrated safety and clinical activity among patients with refractory metastatic colorectal cancerbeing treated in the phase 1 CARAPIA-1 clinical trial (NCT05319314).¹ The data were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 31 to June 4, in Chicago, Illinois.

As of the December 31, 2023 data cutoff, 5 patients had been treated with GCC19CART in CARAPIA-1, which is taking place in the United States. The group includes 4 patients who were treated at dose level 1 (1x10⁶ cells/kg, DL1) and 1 patient who was treated at dose level 2 (2x10⁶ cells/kg, DL2), all of whom had reached the end of the 30 day dose limiting toxicity timeframe. The overall response rate was 40%, with 2 of 5 patients having achieved a partial response to the CAR-T. Furthermore, first author Benjamin L. Schlechter, MD, an instructor in medicine at Harvard Medical School and gastrointestinal oncologist at Dana-Farber Cancer Institute, and colleagues, noted that 1 other patient showed stable disease with a partial metabolic response observed on their PET/CT scan. In the 2 other treated patients, progressive disease was observed; although, it was noted that a falling tumor marker suggesting tumor flare was reported in 1 of these patients.

In terms of safety, cytokine release syndrome (CRS) was reported in all 5 patients, with 2 patients (40%) having grade 1 cases of CRS and 3 patients (60%) having grade 2 cases of CRS. Four of the 5 patients experienced cases of diarrhea, with 1 patient (20%) having a grade 1 case, 2 patients (40%) having grade 2 cases, and 1 patient (20%) having a grade 3 case. A single grade 2 case of immune effector cell-associated neurotoxicity syndrome occurred in 1 patient (20%). The aforementioned adverse events (AEs) constituted the most common AEs related to the CAR-T product and all were noted to have resolved with therapy.

“Preliminary results demonstrate that GCC19CART has an acceptable safety profile and meaningful clinical activity in refractory metastatic colorectal cancer,” Schlechter and colleagues wrote in the ASCO abstract. “This trial is ongoing and updated data will be presented, including from patients treated at DL2.”

GCC19CART has previously been evaluated in an investigator-initiated clinical trial (ChiCTR2000040645) in China for the treatment of relapsed/refractory metastatic colorectal cancer (r/r mCRC).² Data from that trial showing improvements over standard of care (SOC) third-line therapies were presented at the American Association for Cancer Research (AACR) Annual Meeting 2023, held April 14-19, 2023, in Orlando, Florida. Among the 21 patients included in the efficacy analysis, superior results were observed in patients (n=8) who received the higher dose level (2x10⁶ CAR-T cells/kg; DL2) than in patients (n=13) who received the lower dose level (1x10⁶ CAR-T cells/kg; DL1). The objective response rate was 50% (n=4) for DL2, 15% (n=2) for DL1, and 29% (n=6) for all patients.

“The new AE specific to this product is diarrhea because the target is guanylate cyclase 2C (GCC), which plays a role in intestinal homeostasis... So, that's expected, theoretically,” Victor Lu, PhD, the chief technology officer of Innovative Cellular Therapeutics, who presented the data, said during his presentation.2 “Most patients treated with this product experienced diarrhea, but it can be controlled and because of the diarrhea management most of the patients actually recovered very quickly.”

GCC19CART targets both GCC and CD19.¹ It was designed using ICT's CoupledCAR platform, which combines 2 CAR T cells engineered to release cytokines that are thought to promote proliferation and infiltration.³ The platform was designed following observations that CD19-directed CAR T cells also stimulated the immune system, which could lead to increase proliferation for other CAR T cells, specifically those directed toward solid tumor antigens, like GCC.

REFERENCES
1. Schlechter BL, Lieu CH, Fakih M, et al. A phase 1 dose escalation study of a novel coupled CAR T cell therapy, GCC19CART, for patients with metastatic colorectal cancer. Presented at: 2024 (ASCO) Annual Meeting; May 31 - June 4; Chicago, Illinois. Abstract #e15572
2. Lu, V. A phase 1 dose escalation study of GCC19CART - a novel CoupledCAR therapy for subjects with metastatic colorectal cancer. Presented at: AACR Annual Meeting. April 14-19, 2023; Orlando, FL. Abstract 1130.
3. Innovative Cellular Therapeutics Receives FDA Fast Track Designation for GCC19CART, its Lead Solid Tumor Candidate, in the Treatment of Patients with Relapsed or Refractory Metastatic Colorectal Cancer. Innovative Cellular Therapeutics. April 19, 2022. Accessed June 4, 2024. https://www.ictbio.com/news/innovative-cellular-therapeutics-ict-receives-fda-fast-track-designation-for-gcc19cart-its-lead-solid-tumor-candidate-in-the-treatment-of-patients-with-relapsed-or-refractory-metastatic-colorectal/