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
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
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
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.
pemetrexed have immune modulating properties?
pemetrexed induce ICD leading to an immune response against tumors?
and how does pemetrexed work with immunotherapy?3
MC38 syngeneic mouse tumor model, pemetrexed monotherapy
frequency of tumor-infiltrating lymphocytes, and
expression of genes associated with the enrichment of
helper cells, and
monotherapy showed more differentially expressed genes compared to
paclitaxel, cisplatin or carboplatin monotherapy, and combination
with carboplatin therapy.3,7
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
T cell signaling and cytokine signaling, and
of CD4+ T cell-mediated immunity.3,7,8
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
both MC38 and Colon26 tumor cells, treatment with pemetrexed induced
a robust release of HMGB1 indicative of immunogenic cell death.3,7
slightly reduced proliferation of primary human T cells, and lead to
T cell-intrinsic effects as evidenced by
mitochondrial respiratory capacity
oxidative respiration, and
surface molecules, and
T cells primed in the presence of pemetrexed displayed improved
antigen specific in vitro cytotoxic activity.7
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.
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.
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.
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.
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.
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.
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.
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.
= high mobility group box 1 protein
= immunogenic cell death
= major histocompatibility complex
cells = Natural Killer cells
= non-small cell lung cancer
= programmed death-1
= programmed death-ligand 1