Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner. We demonstrate that co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer. Furthermore, we demonstrate that these T cells can be used to assess the efficiency of killing of matched tumor organoids. This platform provides an unbiased strategy for the isolation of tumor-reactive T cells and provides a means by which to assess the sensitivity of tumor cells to T cell-mediated attack at the level of the individual patient. Display omitted •Induction of tumor-reactive T cells by co-culture of PBMCs and tumor organoids•Induced T cell populations do not recognize healthy organoids or tissue•This platform can be used to assess the efficiency of T-cell-mediated tumor killing A modified patient-derived tumor organoids system allows the expansion of tumor-specific T cells from blood for personalized analysis of their anti-cancer properties.