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Darin Chin



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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.04-07 - Pemetrexed Enhances Anti-Tumor Efficacy of PD-L1 blockade by Promoting Intra-Tumor Immune Response via Tumor and T Cell-Intrinsic Mechanisms (ID 14269)

      16:45 - 18:00  |  Author(s): Darin Chin

      • Abstract
      • Slides

      Background

      The combination of pemetrexed/carboplatin with the PD-1 antibody pembrolizumab demonstrates a substantial increase in overall survival in NSCLC patients (hazard ratio 0.49) based on KEYNOTE-189 Phase III data (Gandhi et al., 2018), and represents the first chemoimmunotherapy combination ever approved in Oncology. However, the mechanisms underlying the efficacy of this combination remain largely unknown. Many chemotherapies in general and antifolates in particular have detrimental effects on immune homeostasis, and differ in their ability to induce immunogenic tumor cell death. Nevertheless, KEYNOTE-189 results suggest a positive interaction between pemetrexed-based chemotherapy and immunotherapy highlighting the importance to understand the role of pemetrexed in modulating antitumor immune response to assure rational application of this therapy to the appropriate patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To characterize the effects of pemetrexed on intra-tumor immune response, murine syngeneic tumor models (MC38 and Colon 26) were treated with pemetrexed, paclitaxel with or without carboplatin, or anti-mouse PD-L1. Immune cell subsets and immune-related changes in tumor tissue and T cells were assessed by flow cytometry and gene expression analysis. Tumor and T cell-intrinsic effects of pemetrexed including ability to induce immunogenic cell death of tumor cells and enhance immune function through changes in mitochondrial respiration and gene expression in T cells were also evaluated.

      4c3880bb027f159e801041b1021e88e8 Result

      In MC38 syngeneic mouse tumor model, pemetrexed increases frequency of intratumor leukocytes and cycling (Ki67+) T cells accompanied by gene expression changes indicative of T cell inflamed phenotype. In contrast, paclitaxel exerts quantitatively and qualitatively different immune effects mainly associated with modest upregulation of myeloid cell-related genes whereas carboplatin barely exhibits any immune-related changes in monotherapy and appears to attenuate immunomodulatory effects induced by pemetrexed in MC38 tumors. Pemetrexed in combination with PD-L1 antibody demonstrates enhanced antitumor efficacy and pronounced inflamed/immune activation phenotype in Colon26 syngeneic mouse tumor model. In vitro data indicate that pemetrexed is a potent inducer of immunogenic tumor cell death as exemplified by marked release of HMGB1 in MC38 and Colon26 tumor cells and suggest T cell-intrinsic effects exemplified by enhanced mitochondrial content, oxidative respiration and increased expression of cell surface molecules and immune-related genes indicative of T cell activation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Pemetrexed promotes intra-tumor T cell-mediated immune response through immunogenic tumor cell death and increased activation and metabolic fitness of T cells leading to an enhanced anti-tumor efficacy in combination with PD-L1 antibody.

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