YIA20-004: Altering the Local Immune Landscape in Lung Cancer to Improve Checkpoint Inhibitor Therapy

Authors: Nancy Danielle Ebelt BS, PhD1, Edith Zuniga BS1, and Edwin Ramos Manuel PhD1
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  • 1 Beckman Research Institute of the City of Hope, Duarte, CA

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Immune checkpoint blockers (ICBs) composed of antibodies targeting programmed death 1 (anti-PD1) and cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) have shown great promise in treating NSCLC, but these responses are not universal among patients and are often met with high risk for developing resistance. A key feature of NSCLC is a tumor infiltrate dominated by suppressive immune subsets such as regulatory T cells, NK cells, macrophages and neutrophils, which have been associated with significant immune suppression and overall poor survival. While the preponderance of infiltrating suppressive immune subsets likely contributes to checkpoint inhibitor resistance, new studies highlight how reprogramming the immune microenvironment can overcome resistance mechanisms to immunotherapy. Our central hypothesis is that by enhancing the overall anti-tumor immune phenotype within NSCLC tumors, we can enhance response rates to ICBs. To convert and/or expand anti-tumor subsets within an ICB non-responsive model of NSCLC, we utilized our Salmonella typhimurium -based platform targeting indoleamine 2,3-dioxygenase (shIDO-ST), which we have confirmed is specifically engulfed by neutrophils and induces hyperactivation of their anti-tumor (N1) functions. Following shIDO-ST treatment, we observed broader changes in intratumoral immune repertoire and phenotype, in addition to N1 neutrophils, which likely contributed to enhancement of ICB efficacy in controlling NSCLC tumor growth. Given the need for synergistic combinations with ICBs, shIDO-ST treatment is an attractive approach that could augment response rates in NSCLC patients by reprogramming intratumoral suppressive immune subsets to a more immunostimulatory state.

Corresponding Author: Edwin Ramos Manuel, PhD
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