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M.D. Kalos
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P3.07 - Immunology and Immunotherapy (ID 723)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.07-006 - Pemetrexed Exerts Intratumor Immunomodulatory Effects and Enhances Efficacy of Immune Checkpoint Blockade in MC38 Syngeneic Mouse Tumor Model (ID 8680)
09:30 - 09:30 | Author(s): M.D. Kalos
- Abstract
Background:
Pemetrexed is a well-known folate pathway inhibitor that is used in the treatment of non-small cell lung cancer (NSCLC) and mesothelioma. Folate pathway is also known to play a critical role during T cell activation. However, the role of pemetrexed in modulating antitumor T cell-mediated immune response is largely unknown. Recent clinical data for cohorts C and G in the KEYNOTE-021 trial revealed compelling activity of pemetrexed-based chemotherapy in combination with PD-1 antibody (pembrolizumab) in NSCLC patients suggesting a potential positive interaction between these two therapeutic modalities. The objective of the present study was to understand the effects of pemetrexed on tumor immune microenvironment and evaluate its efficacy in combination with PD-1 pathway inhibition.
Method:
C57BL/6 mice bearing syngeneic MC38 tumors were treated with pemetrexed with or without platinum agents (cisplatin, carboplatin). Immune cell subsets and immune-related gene expression changes in MC38 tumor tissue were assessed by flow cytometry and Quantigene Plex assay, respectively. Pemetrexed-related effects on energy metabolism were evaluated by Agilent Seahorse XF analysis. Anti-mouse PD-L1 antibody 178G7 was used to evaluate effects of pemetrexed in combination with anti-PD-L1 on MC38 tumor growth.
Result:
Treatment with pemetrexed resulted in an increased frequency of intratumoral leukocytes and T cells accompanied by upregulation of immune-related genes indicative of enhanced antigen presentation and T cell infiltration and/or activation. Immune gene expression signature induced by pemetrexed was largely unaffected by cisplatin or carboplatin. The results of Seahorse XF analysis suggested changes in the bioenergetics of T cells exposed to pemetrexed. Combination of pemetrexed and anti-PD-L1 significantly delayed MC38 tumor growth whereas single agent treatments were largely ineffective.
Conclusion:
Pemetrexed exerts positive effects on the intratumor T cell-mediated immune response independently of platinum agents, and enhances effects of PD-L1 antibody in MC38 syngeneic mouse tumor model.
