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172 Increasing activation of human tumor-reactive T cells (CD39+CD103+CD8+) by gene silencing of PD1 with self-delivering RNAi INTASYL(TM)
  1. Colin Thalhofer1,
  2. Ryan Montler1,
  3. Melissa Maxwell2,
  4. Dingxue Yan2,
  5. James Cardia2,
  6. Simon Fricker2,
  7. Jacob Moses1,
  8. Joshua Rios1,
  9. Tarsem Moudgil3,
  10. Bernard Fox3,
  11. Nick Morris1,
  12. B Bell3 and
  13. Andrew Weinberg4
  1. 1Agonox Inc., Portland, OR, USA
  2. 2Phio Pharmaceuticals, Marlborough, MA, USA
  3. 3EACRI, Providence Cancer Center, Portland, OR, USA
  4. 4AgonOx, EACRI Providence Cancer Center, Portland, Oregon, USA

Abstract

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.

http://creativecommons.org/licenses/by-nc/4.0/

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