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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

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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 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+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.

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Abbreviations

Th1:

CD4+ T cells producing IFN-γ

TReg:

Regulatory T cells

Foxp3:

Forkhead box protein p3

TR1:

CD4+ CD25−FoxP3− T cells producing IL-10

nTRegs:

Ag-experienced natural TReg CD4+CD25+CD45RO+FoxP3− cells

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Acknowledgments

The authors are grateful to those mentioned in the text for supplying materials, Coffee Memorial Blood Bank, Amarillo, TX, under the direction of Mary Townsend, for leukaphereses. Robin McWherter and Beth Vertin for technical assistance and the Clinical Trials Department of the Harrington Cancer Center, Amarillo, TX, for data collection. This work was supported by grants through the Harrington Cancer Research Foundation, Amarillo, TX (to M.J.D.), Department of Veterans Affairs Medical Research Program (to S.E.W.), Institutional Research Program of the Texas Tech School of Medicine (to M.J.D.), National Institutes of Health Grant 1R21CA89883-01A1 (to W.R. and S.E.W), Department of Defense Medical Research Development Command DAMD 17-01-1-0429 (to M.J.D.) and the Don & Sybil Harrington Foundation, Amarillo, TX (to S.E.W. and C.A.P.).

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None of the authors have any potential financial conflict of interest related to this manuscript.

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Authors and Affiliations

  1. Department of Internal Medicine, Texas Tech University School of Medicine, Amarillo, TX, 79106, USA

    Mark J. Dobrzanski, Kathleen A. Rewers-Felkins, Khaliquzzaman A. Samad, Imelda S. Quinlin, Catherine A. Phillips & Stephen E. Wright

  2. Amarillo Veterans Affairs Health Care System, Amarillo, TX, USA

    Catherine A. Phillips & Stephen E. Wright

  3. Harrington Cancer Center, Amarillo, TX, USA

    William Robinson

  4. Department of Obstetrics and Gynecology, School of Medicine, Texas Tech University Health Science Center, Amarillo, TX, USA

    William Robinson

  5. Clinical Research Department, Bristol Hospital Cancer Care Center, Bristol, CT, USA

    Mark J. Dobrzanski & David J. Dobrzanski

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  1. Mark J. Dobrzanski
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Dobrzanski, M.J., Rewers-Felkins, K.A., Samad, K.A. et al. 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. Cancer Immunol Immunother 61, 839–854 (2012). https://doi.org/10.1007/s00262-011-1128-x

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