Alimta® (Pemetrexed)

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Pemetrexed: Preclinical Study With PD-1 Pathway Blockade

Pemetrexed aumenta la eficacia antitumoral del bloqueo de la vía PD-1 a través de la muerte inmunogénica de las células tumorales y los mecanismos intrínsecos de las células T.

Introduction

Clinical data from cohort G of the KEYNOTE-021 trial and more recently from the phase 3 KEYNOTE-189 trial revealed compelling activity of pemetrexed/platinum chemotherapy in combination with pembrolizumab, a PD-1 antibody, in NSCLC patients. These results suggest a potential positive interaction between these therapeutics.1,2

Pemetrexed inhibits enzymes in the folate pathway and disrupts cellular processes that are required for cell division. Rapidly dividing cancer cells are the favored targets of pemetrexed.3

The folate pathway is a component of the one-carbon metabolism that plays a critical role during T cell activation. Antifolate treatment like pemetrexed could thus interfere with the one-carbon metabolism and have a detrimental effect on effector T cells in the tumor microenvironment.4,5 

Preclinical studies were completed to better understand the effects of pemetrexed on tumor immune microenvironment. The following key questions were evaluated using MC38 or Colon26 murine tumor models.

  • Does pemetrexed have immune modulating properties?

  • Does pemetrexed induce ICD leading to an immune response against tumors?

  • Why and how does pemetrexed work with immunotherapy?3

In Vivo Data

In MC38 syngeneic mouse tumor model, pemetrexed monotherapy

  • increased frequency of tumor-infiltrating lymphocytes, and

  • increased expression of genes associated with the enrichment of 

    • macrophages 

    • dendritic cells/NK cells

    • T helper cells, and

    • interferon signaling.3,6,7

Pemetrexed monotherapy showed more differentially expressed genes compared to paclitaxel, cisplatin or carboplatin monotherapy, and combination with carboplatin therapy.3,7

The combination of pemetrexed and anti-PD-L1 improved the antitumor efficacy in MC38 and Colon26 syngeneic mouse tumor models.6-8 Pathway analysis of gene expression in Colon26 tumors revealed that the combinatorial effect of pemetrexed and anti-PD-L1 was associated with a pronounced inflamed/immune activation phenotype characterized by

  • improved antigen presentation

  • enhanced T cell signaling and cytokine signaling, and

  • engagement of CD4+ T cell-mediated immunity.3,7,8

These changes correlated with an upregulation of MHC-I and MHC-II on monocytes, macrophages, and tumor cells, suggesting increased immune priming. Supporting this, blockade of T cell priming in lymph nodes after initiation of combination therapy resulted in a loss of combination efficacy.7

In Vitro Data

In both MC38 and Colon26 tumor cells, treatment with pemetrexed induced a robust release of HMGB1 indicative of immunogenic cell death.3,7

Pemetrexed slightly reduced proliferation of primary human T cells, and lead to T cell-intrinsic effects as evidenced by

  • enhanced mitochondrial respiratory capacity

  • enhanced oxidative respiration, and

  • increased expression of

    • cell surface molecules, and

    • immune-related genes.3,6,7

Murine T cells primed in the presence of pemetrexed displayed improved antigen specific in vitro cytotoxic activity.7

References

1. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508. https://doi.org/10.1016/S1470-2045(16)30498-3

2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. http://dx.doi.org/10.1056/NEJMoa1801005

3. Schaer D, Geeganage S, Amaladas N, et al. Pemetrexed enhances anti-tumor efficacy of PD-L1 blockade by promoting intra-tumor immune response via tumor and T cell-intrinsic mechanisms. Poster presented at: International Association for the Study of Lung Cancer (IASLC) 19th World Conference on Lung Cancer (WCLC); September 23-26, 2018; Toronto, Canada. Abstract P1.04-07. https://library.iaslc.org/virtual-library-search?product_id=10&author=Schaer&category=

4. Ron-Harel N, Santos D, Ghergurovich JM, et al. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab. 2016;24(1):104-117. https://www.sciencedirect.com/science/article/pii/S1550413116302935?via%3Dihub

5. Tan H, Yang K, Li Y, et al. Integrative proteomics and phosphoproteomics profiling reveals dynamic signaling networks and bioenergetics pathways underlying T cell activation. Immunity. 2017;46(3):488-503. https://www.sciencedirect.com/science/article/pii/S1074761317300729?via%3Dihub

6. Novosiadly R, Schaer D, Lu Z, et al. P3.07-006 Pemetrexed exerts intratumor immunomodulatory effects and enhances efficacy of immune checkpoint blockade in MC38 syngeneic mouse tumor model. J Thorac Oncol. 2017;12(11, Supplement 2):S2300. http://dx.doi.org/10.1016/j.jtho.2017.09.1697

7. Schaer DA, Amaladas N, Lu ZH, et al. The folate pathway inhibitor pemetrexed pleiotropically enhances effects of cancer immunotherapy via immunogenic tumor cell death and T cell-intrinsic mechanisms. Poster presented at: 110th Annual Meeting of the American Association for Cancer Research (AACR); March 29-April 3, 2019; Atlanta, GA. https://www.abstractsonline.com/pp8/#!/6812/presentation/2706

8. Novosiadly RD, Schaer DA, Amaladas N, et al. Pemetrexed enhances anti-tumor efficacy of PD-1 pathway blockade by promoting intra-tumor immune response via immunogenic tumor cell death and T cell-intrinsic mechanisms. Presented as an abstract and poster at: 109th Annual Meeting of the American Association for Cancer Research (AACR); April 14-18, 2018; Chicago, IL. Abstract #4549.

Glossary

HMGB1 = high mobility group box 1 protein

ICD = immunogenic cell death

MHC = major histocompatibility complex

NK cells = Natural Killer cells

NSCLC = non-small cell lung cancer

PD-1 = programmed death-1

PD-L1 = programmed death-ligand 1

Fecha de la última revisión: 2019 M04 04


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