Journal
CLINICAL IMMUNOLOGY
Volume 133, Issue 3, Pages 333-352Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.clim.2009.08.007
Keywords
Tumor immunity; Regulatory T cells; Th1 effector cells; Chemokines; T effector/memory cells; Adoptive T cell immunotherapy
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Funding
- Harrington Cancer Research Foundation, Amarillo, TX
- Department of Veterans Affairs Medical Research Program
- Institutional Research Program of the Texas Tech School of Medicine
- National Institutes of Health [1R21CA89883-01A1]
- Department of Defense Medical Research Development Command [DAMD 17-01-1-0429]
- Don and Sybil Harrington Foundation, Amarillo, TX
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Adoptive T cell immunotherapy using autologous lymphocytes is a viable treatment for patients with cancer and requires participation of Ag-specific CD4 and CD8 T cells. Here, we assessed the immunotherapeutic effects of autologous MUC1 peptide-stimutated CD4(+) effector cells following adoptive transfer in patients with ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4(+)/Th1 effector cell generation, we show that three monthly treatment cycles of peripheral blood T cell restimulation and intraperitoneal re-infusion selectively modulated endogenous 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 16 months with recurrent disease and two patients expired within 3-5 months following final infusion. Although PBL from all patients showed elevated MUC1 cytolytic activity following therapy, such responses did not correlate with therapeutic efficacy. Long-term survivors showed elevated levels of systemic memory (CD45RO) and naive (CD45RA) 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 Foxp3 and CTLA-4 that resulted in progressively tower systemic Foxp3/CTLA-4 memory T cell ratios that further correlated with disease-free survival. Lastly, these patients showed elevated levels of MUC1-specific T cells expressing the CCR5 and CCR1 chemokine receptors and the chemokine CCL4 associated with Th1 cell differentiation/memory. We suggest that effective immunotherapy with autologous MUC1 stimulated CD4(+) effector cells induces differential levels of systemic Ag-experienced and Ag-inexperienced CD4/CD25(+) TReg cell subpopulations that influence tong-term tumor immunity in ovarian cancer patients. (C) 2009 Elsevier Inc. All rights reserved.
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