Abstract LB-380: Novel coupledCARTMtechnology for treating colorectal cancer
Authors: Li Song , Pu Chengfei , Cao Zhiyuan , Lu Cheng , Yang Hang , Huang Xi , Shen Xiaogang , Wang Xiuwen , Wu Zhao , Xiao Lei 
Published: September 2020

Abstract
Chimeric antigen receptor (CAR) T cell therapy has made significant progress in the treatment of blood cancers such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges in treating solid tumors. These challenges include physical barriers, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and limited reactive cell expansion in vivo. Here, we developed CAR -T cells based on a novel CoupledCARTM technology to treat solid tumors. CoupledCAR T cells significantly improved the expansion of the CAR-T cells in vivo and enhanced the CAR-T cells' migration ability and resistance to immunosuppression by the tumor microenvironment, allowing the CAR-T cells to infiltrate to tumor tissue sites and increase anti-tumor activities.Specifically, we engineered CoupledCAR-T cells with lentiviral vectors encoding an anti-GUCY2C (guanylate cyclase 2C) CAR molecule. To verify the safety and efficacy of CoupledCAR T cells for treating solid tumors, we conducted several clinical trials for different solid tumors, including two patients with colorectal cancer. After the infusion of anti-GUCY2C CoupledCAR T cells, these two patients showed rapid expansion of CoupledCAR T cells and the killing of tumor cells. Spherically, we observed that CoupledCAR T cells expanded significantly in the patients and infiltrated tumor tissue sites, demonstrating enhanced anti-tumor activities. Patient Profile: Patient 1: Male, 55Y, Colon Adenocarcinoma. In May 2016, 8 cycles of XELOX chemotherapy and 1 dose of radiotherapy were performed. In Step 2016, “radical rectal resection and terminal ileum double ileostomy” was performed. After surgery, gemcitabine chemotherapy was performed for 2 cycles. In January 2018, relapse and metastasis of prostate and left lung were observed. Starting from March 2018, seven cycles of "Iritican + Retitrazepam + Epitope Chemotherapy," one cycle of "Iritican + Retitrazepam," implantation of radioactive particles, and three cycles of "Oxaliplatin + Capecitabine" were performed. In April 2019, relapse and metastasis were observed. Patient 2: Female, 57Y, Colon Adenocarcinoma. In December 2014, DT46Gy/2Gy/23 radiotherapy was performed. In December 2014 and January 2015, the single drug chemotherapy of Xeloda was taken orally. In February 2015, laparoscopic radical resection of rectal cancer was performed. In April, May, June, and July 2015, mFOLFOX6 chemotherapy was performed. In June 2019, CT showed tumor metastasis. In June, July, August 2019, irinotecan + fluorouracil regimen chemotherapy was performed. Observations and Results: Patient 1: One month after infusion (M1), the patient was evaluated as PR (Partial Response); most of the target lesions were significantly reduced by more than 50%, and the primary tumor volume was reduced by ~45%. Patient 2: M1, the patient was also evaluated as PR; the tumor in the left upper lobe tip posterior segment was reduced by approximately 75%. The clinical data demonstrated that CoupledCAR-T cells effectively expanded, infiltrated tumor tissue sites, and killed tumor cells in patients with colorectal cancer. We are recruiting more colorectal cancer patients to further test the safety and efficacy of anti-GUCY2C CoupledCAR T cells. Further, since our CoupledCARTM technology is a platform technology, we are developing it to treat other solid tumors using different target markers.
Citation Format: Song Li, Chengfei Pu, Zhiyuan Cao, Cheng Lu, Hang Yang, Xi Huang, Xiaogang Shen, Xiuwen Wang, Zhao Wu, Lei Xiao. Novel coupledCARTMtechnology for treating colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-380.