Novel GUCY2C targeting CAR-T therapy: Efficacy in advanced colorectal cancer

3559 Background: Chimeric antigen receptor (CAR) T cells have shown remarkable success in treating patients with hematologic malignancies. However, the majority of CAR-T cell clinical trials in solid tumors have limited success which is partially attributed to the detrimental tumor microenvironment and the lack of ideal target. Recently, GUCY2C emerges as an ideal therapeutic target which is highly expressed in colorectal cancer (CRC). Here, a novel nanobody-based GUCY2C targeting CAR-T cell developed by us is applied to treat advanced colorectal cancer patients who failed third-line therapy. Methods: In this open-label, single-arm, investigator-initiated exploratory trial (ChiCTR2100044831), we primarily explore the safety and the low-dose efficacy of the autologous anti-GUCY2C CAR-T cells. All patients screened by IHC met our criteria for GUCY2C positivity. All enrolled patients had received at least 3 prior lines of therapy and had multiple metastases at baseline. Totally, 13 advanced CRC patients aged 18 to 65 years were infused with the anti-GUCY2C CAR-T cells at a dose range of 0.5-3 x10e6/kg after standard Cy-Flu lymphodepletion. Adverse events (AE) were graded according to CTCAE 5.0, and objective tumor responses were assessed per RECIST 1.1 criteria. Results: Between November 2021 and December 2022, 13 subjects with refractory metastatic CRC (mCRC) were treated with the anti-GUCY2C-CAR-T cells infusions at a dose range of 0.5-3 x10e6/kg. There were no dose-limiting toxicities, treatment-related death or any form of neurotoxicity occurred in this study. The most common TEAEs were diarrhea in 9/13 (69%) subjects (Grade 1: 2/13 (15.38%) Grade 2: 3/13 (23.07%) Grade 3: 4/13 (30.77%)). 8/13 (62%) mCRC subjects experienced grade1 or grade 2 mouth ulcer generally appear as a single lesion lasting for a few days. All cytokine release syndromes (CRS) observed were grade 1. Totally 9 pts (69%) experienced grade 1 CRS and all resolved by supportive care without the need of tocilizumab. No grade 4 AEs except for decreased lymphocytes in 12/13 pts (92%), decreased white blood cells in 1/13 pts (7.7%) and decreased platelet in 1/13 pts (7.7%). Among 10 evaluable patients, 6 partial responses, 2 stable disease and 2 progressive disease were achieved. At all dose levels ORR and DCR were 60% and 80% respectively. Notably, all 3 patients infused at the dose level above 2x10e6/kg reached partial responses. Among the 3 non-evaluable patients, 1 patient lost follow-up, 1 patient died of bone marrow failure and 1 patient died of COVID-19 related complications before the first efficacy evaluation. Additional data will be presented at the meeting. Conclusions: This clinical study indicated that the anti-GUCY2C CAR-T cell therapy was well tolerated and had promising efficacy in heavily pretreated mCRC patients. Clinical trial information: ChiCTR2100044831 .