![]() ![]() This is not the case for almost all target antigens in solid tumors until today and remains one of the central problems of solid tumor CAR T cell therapies. As a consequence, all B cells are depleted, which is regarded as an acceptable side effect since it is otherwise well tolerated 7. They typically rely on pan-B cell antigens such as CD19 or CD20 and do not discriminate between healthy and tumor cells. CAR T cells showed unprecedented efficacy in the treatment of B-cell malignancies 5, 6. A new and promising therapeutic approach is chimeric antigen receptor (CAR) T cells. Thus, there is an unmet need for new therapeutic options. Median overall survival with state-of-the-art treatment ranges from 26 month for patients with resectable disease to less than 6 months when already metastatic 4. Surgery still is the only potentially curative treatment, but only around 20% of patients show a resectable disease stage at diagnosis 3. The 5-year overall survival rates have merely changed for the past decades and it is currently the fourth leading cause of cancer-related deaths in Western countries 1, 2. Pancreatic cancer is a devastating disease. This study reveals potential target candidates for CAR T cell based immunotherapy of PDAC together with a functional set of CAR constructs specific for these molecules. ![]() CAR T cells specific for CD66c, CD318 and TSPAN8 demonstrate efficacies ranging from stabilized disease to complete tumor eradication with CD318 followed by TSPAN8 being the most promising candidates for clinical translation based on functionality and predicted safety profiles. Promising constructs are evaluated in vivo. CAR T cell activity is evaluated in vitro based on target cell lysis, T cell activation and cytokine release. We identify CLA, CD66c, CD318 and TSPAN8 as target candidates among 371 antigens and generate 32 CARs specific for these molecules. To address this challenge, here we combine flow cytometry screenings, bioinformatic expression analyses and a cyclic immunofluorescence platform. A major roadblock prohibiting effective cellular immunotherapy of pancreatic ductal adenocarcinoma (PDAC) is the lack of suitable tumor-specific antigens.
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