Background Tumor Infiltrating Lymphocyte (TIL) therapy has proven effective for patients with stage IV melanoma, however there are critical issues that can limit the efficacy of standard TIL therapy across a wide range of different malignancies. We and others have shown that some tumor types contain a low percentage of tumor-specific T cells. We hypothesize that most of the patients that do not respond to TIL therapy are likely receiving a low percentage of tumor-reactive T cells and therefore a high percentage of non-therapeutic bystander TIL. We have developed a streamlined method that expands a highly enriched fraction of tumor-reactive T cells contained within the CD39+CD103+CD8+ TIL in greater than 90% of patient samples from a wide variety of malignancies (melanoma, colon cancer, head and neck cancer, etc.). This TIL product displays a broad repertoire of tumor-specific TCRs. The expanded CD39/CD103 TIL can kill autologous tumors in vitro, but the possibility remains that they could revert to a suppressed or exhausted state when they reach the tumor microenvironment upon transfer back into patients. To mitigate the suppressive effects of the tumor microenvironment we have evaluated Phio Pharmaceutical’s self-delivering RNAi INTASYL(TM) platform to silence PD-1 in the expanded TIL product.
Methods The TIL product was treated during the rapid expansion phase of the protocol with either nontargeting control compounds or PD-1 targeting INTASYL™ compounds. PD-1 protein levels and TIL functionality were assessed via flow cytometry and cytokine bead array.
Results Silencing of PD-1 expression in the expanded TIL product was obtained by adding the self-delivering RNAi compounds to the cell culture media, without needing transfection media, delivery formulations or electroporation. The RNAi-treated TIL product showed increased IFN-?? TNF-α and Granzyme B expression.
Conclusions These data highlight a promising combination to improve the activity of tumor-reactive TIL in future human clinical trials.
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