MUC1-specific Th1 immunotherapy induce differential levels and proportions of "inducible" and "natural" CD4 TReg cell subpopulations that results in enhanced tumor immunity and increased ovarian cancer patient survival (131.38)

Abstract

Abstract Adoptive T cell therapy is a viable treatment for cancer patients and optimally requires participation of CD4 T cells. Here, we assessed the therapeutic effects of adoptively transferred autologous MUC1 peptide-stimulated CD4+ effector cells in patients with ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4+/Th1 effector cell generation, we show that 3 monthly treatment cycles of T cell restimulation and intraperitoneal re-infusion modulated T cell mediated immune responses that correlated with diminished serum CA125 tumor marker levels and enhanced patient survival. One patient remains disease free, another patient survived long-term for nearly 18 months with recurrent disease and two patients expired within 3-5 months following final infusion. Long term survivors showed elevated levels of systemic CD3/CD4/CD25+ and CD3/CD4/CD25- T cells when compared to that of pre-treatment levels and similarly treated short-term survivors. Such cells co-expressed different levels of "Inducible" Tr1 (CD4/CD25-/FoxP3-/IL-10+) and "Natural" (CD4/CD25+/FoxP3+) TReg cell ratios that further correlated with disease-free survival. These patients showed elevated levels of Th1 cells and MUC1-specific T cells expressing chemokine receptors associated with T cell differentiation/memory. This suggests that MUC1-stimulated CD4 T cells induce differential levels and proportions of systemic TReg subpopulations that influence long term tumor immunity in such patients following treatment.