Immunotherapy with IL-10- and IFN-γ-producing CD4 effector cells modulate “Natural” and “Inducible” CD4 TReg cell subpopulation levels: observations in four cases of patients with ovarian cancer

Abstract

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 3 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+CD4+CD25+ and CD3+CD4+CD25− 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+CD25−FoxP3−IL-10+) and “Natural” (CD4+CD25+CD45RO+FoxP3+) 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.

RETRACTED ARTICLE: Targeted immune therapy of ovarian cancer

“…While the infusions were found to be safe, no clinical activity was observed, likely due to the observation that the infused T cells did not persist for long periods of time in large numbers [241] and potentially an inhibitory factor which developed in a half of the patients. In another trial patients were infused with non-modified MUC1-specific Th1 effector T cells [243, 244]. MUC1-specific T cells were derived by repeated stimulation and expansion of leukapheresis-derived cells with the 20mer MUC1 peptide, GSTAPPAHGVTSAPATAPAP.…”

Peripheral Tr1 and Foxp3+ Treg as Markers of Recurrent Malignancies in Patients with Hepato-Biliary Pancreatic Cancers

“…Tr1 cells were found to be a strong regulator of T cells (26) and to secrete IL-10 (17, 27). Because Tr1 cells do not express Foxp3, they are defined as CD4 + CD25 − Foxp3 − IL-10 + cells (16). These cells in murine and human peripheral blood can be sorted as CD4 + CD49b + LAG3 + T cells (17), enabling their recognition by FACS.…”

Natural and Induced T Regulatory Cells in Cancer

“…There are a number of studies showcasing the importance of these cells in tempering anti-tumor response, some dating back to pre-Foxp3 years (25–30). In a cohort of Hodgkins lymphoma patients, an argument was made by Marshall and colleagues for a contributory role of CD4+ IL-10+ Tr1 cells toward ineffective clearance of Hodgkins lymphoma.…”