Optimized T cells for personalized immunotherapy for solid cancer - OptiCAN

Abstract

The OptiCAN project aims to enhance CAR T cell therapies to treat solid tumors more effectively through advanced genetic engineering of patient-derived T cells. During the project, 37 advanced-stage pancreatic cancer patients were recruited. An efficient workflow involving surgeons, pathologists, and oncologists was established to quickly process and ship fresh tumor samples to partner sites. The project demonstrated that CD137+ enrichment can generate sufficient T cells for clinical treatment. A novel CD276 adaptor was developed, showing promising results in enhancing T cell function. Additionally, a systematic screening of over 20 candidates identified a lead binder, which performed well in vivo, either matching or surpassing the direct CAR moiety. The consortium shifted its focus to developing an on-tumor targeted CAR to work synergistically with endogenous TIL activity, as the originally planned "boost-CAR" approach proved more challenging and less promising pre-clinically. The project also confirmed that inducing IFNγ secretion in tumors can modulate the tumor microenvironment before CAR T cell treatment. Significant progress was made in developing and validating the new 3D ex vivo tumor model assay as an additional read out of the already established preclinical 3D model, particularly in assessing the cytotoxic effects of HER2 CAR T cells on patient-derived xenograft (PDX) samples. Pancreatic tumors from 18 patients were transplanted into mice, with 7 successfully establishing as PDX models, meeting the project’s milestones. Additionally, 17 out of 18 tumors successfully yielded yTILs for further optimization. A novel method for transducing TILs with lentivirus in the presence of feeder cells was developed, bypassing the need for an additional expansion phase, which marks a significant innovation in the field. Regulatory and ethical considerations were also addressed through three advisory board meetings, focusing on clinical trial designs, ethical implications, patient representation, and fair inclusion in early clinical trials. Patient surveys were conducted to incorporate broader patient perspectives into the project. In conclusion, the OptiCAN project has made substantial strides in advancing CAR T cell therapies, providing a promising pathway toward personalized immunotherapy for solid tumors.