Baseline levels of innate and adaptive immune cell functions were studied in patients with pancreatic cancer. The effects of pemetrexed were measured at 7 and 14 days after initial therapy then 14 days after combination therapy with gemcitabine. Pretherapy levels of absolute numbers of natural killer (NK) cells positively correlated with survival. Cytolytic units of NK activity correlated positively with NK cell numbers. Pemetrexed decreased NK cytolytic units to significance when combined with gemcitabine. Pemetrexed increased intracellular accumulation of interferon gamma (IFNγ) in NK cells that correlated negatively with survival. Addition of gemcitabine decreased IFNγ-producing NK cells to baseline. Memory (CD45RO*) T cells enumerated at baseline correlated negatively with survival but were decreased by pemetrexed therapy. Memory T cells were increased in subjects with greater B7-H3 expression in tumor tissue, whereas OX40*-activated total T cells and helper T-cell subset were decreased. FoxP3*, CD8* T cells correlated positively with progression-free interval and survival. In conclusion, innate NK-cell immunity and FoxP3*, CD8* T cells seemed beneficial to pancreatic cancer patients. Higher levels of B7-H3 expression in pancreatic tumors were detrimental to effective immunity. Although pemetrexed therapy increased activation of a subset of NK cells to produce IFNγ, addition of gemcitabine abated those responses, decreasing IFNγ-producing NK cells, whereas NK cells producing interleukin-2 without IFNγ at this timepoint positively correlated with survival. Innate immunity and adaptive immunity thus are important in defense against pancreatic cancer. Progression-free interval and survival were longer than observed in a phase III trial where gemcitabine preceded pemetrexed suggesting that a larger trial of pemetrexed preceding gemcitabine is warranted.
5 O), were prepared and copolymerized with styrene. The monomers were synthesized by the piperidine catalyzed Knoevenagel condensation of ring-substituted benzaldehydes and N-cyanoacetylurethane, and characterized by CHN analysis, IR, 1 H-and 13 C-NMR. All the ethylenes were copolymerized with styrene (M 1 ) in solution with radical initiation (ABCN) at 70 • C. The compositions of the copolymers were calculated from nitrogen analysis and the structures were analyzed by IR, 1 H-and 13 C-NMR. The order of relative reactivity (1/r 1 ) for the monomers is 3-C 2 H 5 O (2.1) > 4-CH 3 (CH 2 ) 3 (1.7) > 2-C 2 H 5 O (1.5) ≈ 4-CH 3 CH 2 (1.5) > 4-CH 3 (CH 2 ) 2 O (0.9) > 2,5-(CH 3 ) 2 (0.5) ≈ 4-CH 3 (CH 2 ) 3 O (0.5) > 2,4-(CH 3 ) 2 (0.4) > 4-CH 3 (CH 2 ) 4 O (0.3) ≈ 4-(CH 3 ) 2 CH (0.3). High T g of the copolymers, in comparison with that of polystyrene, indicates decrease in chain mobility of the copolymer due to the high dipolar character of the trisubstituted ethylene structural unit. Decomposition of the copolymers in nitrogen occurred in two steps, first in 270-420 • C with a residue (3-10% wt), which then decomposed in the 550-700 • C range.
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
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