A phase 1 dose escalation study of GCC19CART: A novel coupled CAR therapy for patients with metastatic colorectal cancer.
Authors: Xiao Lei , Chen Naifei , Pu Chengfei , Zhao Lingling , Li Ning , Wang Chang , Huang Yusheng , Luo Su-xia , Li Xun , Yang Zhenzhou , Bie Jun , Zhu Ruihong , Liang Tingting , Wang Yizhuo , Jia Beibei , Chen Dongqi , Wu Zhao , Song Yongping , Lu Victor , Cui Jiuwei 
Published: June 2023

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Background: GCC19CART, the first clinical candidate from the CoupledCAR solid tumor platform, is designed to overcome the limitations of conventional CAR T-cells in solid tumor malignancies by pairing solid tumor CAR T-cells with CD19 targeting CAR T-cells to amplify the proliferation and activation of the solid tumor CAR T component. GCC19CART targets guanylate cyclase-C (GCC), which is expressed in the metastatic lesions of 70%-80% of subjects with colorectal cancers and largely restricted to the intestinal tract. A Phase 1 investigator-initiated clinical trial is underway in China for patients with relapsed or refractory metastatic colorectal cancer who have received at least 2 prior lines of therapy. As of a data cutoff on Jan 28, 2023 21 subjects have been enrolled in 2 dose escalation groups at 5 hospitals in China. Methods: Subjects are screened for GCC expression by immunohistochemistry. Eligible subjects undergo leukapheresis, a single dose of lymphodepleting chemotherapy (fludarabine 30mg/m2 and cyclophosphamide 300mg/m2) 3 days prior to infusion, and then administration of a single infusion of GCC19CART at one of two preassigned doses: 1x106 or 2x106 CAR T-cells/kg. All responses were confirmed by an independent third-party imaging contract research organization. Results: 13 subjects have been enrolled to dose level 1 (1x106 cells/kg) and 8 subjects have been enrolled to dose level 2 (2x106 cells/kg). The most common adverse events were cytokine release syndrome (CRS) in 21/21 subjects (Grade 1 19/21 (90.48%) or Grade 2 2/21 (9.52%)) and diarrhea in 21/21 subjects (Grade 1 6/21 (28.57%) Grade 2 5/21 (23.81%) Grade 3 9/21 (42.86%) or Grade 4 1/21 (4.76%)). All patients with grade 3 and higher side effects were well managed. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 2/21 (9.52%) subjects at Grade 3 or 4 and resolved with corticosteroids. The combined overall response rate (ORR) for both dose levels was 28.6% (6/21). For dose level 1, overall response rate (ORR) was 15.4% (2/13). Two subjects demonstrated a partial response (PR) while 3 additional subjects had partial metabolic response (PMR) on PET/CT with stable disease (SD) or progressive disease (PD) per RECIST 1.1. For dose level 2, The ORR was 50% (4/8). 4 subjects demonstrated a PR and 2 additional subjects had PMR on PET/CT with SD per RECIST 1.1.The median PFS was 1.9 months in the dose 1 group and 6.3 months in the dose 2 group. The median overall survival was 13.3 months in the dose 1 group and 18.3 months in the dose 2 group. Conclusions: Preliminary results demonstrate that GCC19CART has meaningful dose-dependent clinical activity and an acceptable safety profile in relapsed or refractory metastatic colorectal cancer. This trial is ongoing and updated data will be presented. A Phase 1 trial of GCC19CART in the US has opened for accrual and is expected to enroll patients in mid-2022. Clinical trial information: ChiCTR2000040645 .