Abstract 527: The effects of pemetrexed on innate and adaptive immune cells in subjects with adenocarcinoma of the pancreas

Abstract

Abstract Fifteen patients with previously surgically resected, or newly diagnosed, non-resectable metastatic adenocarcinoma of the pancreas were consented to an IRB approved study of immune cell functions in subjects treated with pemetrexed followed by gemcitabine. All subjects had a health performance status of 0-1 and no subject had received previous chemotherapy or radiotherapy. Dosages were pemetrexed at 500 mg/m2 followed two weeks later with a second dose of pemetrexed and gemcitabine at 1250 mg/m2. Blood draws were at 5 time-points to investigate baseline levels of innate and adaptive immune cell functions and the effects of pemetrexed on those responses as measured 7 and 14 days after initial therapy as well as the effects of a combination therapy of pemetrexed with gemcitabine. Our study revealed a strong positive correlation between pre-therapy absolute numbers of NK cells and overall survival (p=0.039). Cytolytic units of NK activity positively correlated with numbers of NK cells (p=0.008). Therapy with pemetrexed decreased killing activity with cytolytic units decreasing with each blood draw and reaching significance with combination therapy with gemcitabine (p= 0.02). Expression of Th1-type cytokines were induced and intracellular accumulation measured by flow cytometry. Pemetrexed induced a substantial increase in NK (CD56+) cells producing IFNγ. The increased IFNγ production detected 7 days after initial pemetrexed therapy however had a significant negative correlation with survival (p=0.038) suggesting that NK cell production of IFNγ had a deleterious effect on patient survival. A similar significant negative correlation was obtained when either the combination of anti-CD3, anti-CD28, or Concanavalin A was used to induce cytokine production. Addition of gemcitabine to the therapeutic regimen decreased numbers of cell producing IFNγ to pre-therapy baseline levels. Memory (CD45RO+) T-cells enumerated at baseline also revealed a significant negative correlation with survival (p=0.011) but were decreased by pemetrexed therapy alone or in combination with gemcitabine. FoxP3+, CD8+ T-cells were detected and demonstrated a strong positive correlation with both progression-free interval (p=0.005) and with survival (p=0.026) suggesting that FoxP3+, CD8+ T-cells are beneficial to pancreatic cancer patients. While pemetrexed therapy resulted in a negative correlation with survival by increasing activation of a subset of NK cells to produce IFNγ, addition of gemcitabine abated those responses, decreased IFNγ production thereby resulting in a significant positive correlation between NK cells producing IL-2 and survival (p=0.041). Innate immunity thus is an important defense against pancreatic cancer. In order to eliminate a negative effect of NK cell induction of IFNγ however, pemetrexed should follow rather than precede gemcitabine in initial therapy for pancreatic cancer Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 527. doi:1538-7445.AM2012-527