Immunotherapy with IL-10- and IFN-[gamma]-producing CD4 effector cells modulate "Natural" and "Inducible" CD4 TReg cell subpopulation levels: observations in four cases of patients with ovarian cancer

• Published in: Cancer immunology, immunotherapy immunotherapy, 2012-06, Vol.61 (6), p.839
• Main Authors: Dobrzanski, Mark J, Rewers-felkins, Kathleen A, Samad, Khaliquzzaman A, Quinlin, Imelda S, Phillips, Catherine A, Robinson, William, Dobrzanski, David J, Wright, Stephen E
• Format: Article
• Language: English
• Subjects: Ovarian cancer
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-011-1128-x

Adoptive T cell therapy for cancer patients optimally requires participation of CD4 T cells. In this phase I/II study, we assessed the therapeutic effects of adoptively transferred IL-10- and IFN-γ-producing CD4 effector cells in patients with recurrent ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4 effector cell generation, we show that three monthly treatment cycles of autologous T cell restimulation and local intraperitoneal re-infusion-modulated T cell-mediated immune responses that were associated with enhanced patient survival. One patient remains disease-free, another patient experienced prolonged survival for nearly 16 months with recurrent disease, and two patients expired within 3-5 months following final infusion. Prolonged survivors showed elevated levels of systemic CD3^sup +^CD4^sup +^CD25^sup +^ and CD3^sup +^CD4^sup +^CD25^sup -^ T cells when compared to that of pre-treatment levels and similarly treated short-term survivors. Such cell populations among these patients contained variable levels of "Inducible" Tr1 (CD4^sup +^CD25^sup -^FoxP3^sup -^IL-10^sup +^) and "Natural" (CD4^sup +^CD25^sup +^CD45RO^sup +^FoxP3^sup +^) TReg cell numbers and ratios that were associated with prolonged and/or disease-free survival. Moreover, peptide-restimulated T cells from these patients showed an elevation in both IFN-γ production, memory cell phenotype, and select TNF family ligands associated with enhanced T cell survival and apoptosis-inducing activities. This suggests that intraperitoneally administered Th1-like cells, producing elevated levels of IL-10, may require and/or induce differential levels of distinct systemic TReg subpopulations that influence, in part, long-term tumor immunity and enhanced memory/effector CD4-mediated therapeutic potentials. Furthermore, treatment efficacy and enhanced memory cell phenotype did not appear to be dependent on TReg cell numbers but upon ratios of "Inducible" and "Natural" TReg subpopulations.[PUBLICATION ABSTRACT]