Autologous MUC1-specific Th1 effector cell immunotherapy induces differential levels of systemic TReg cell subpopulations that result in increased ovarian cancer patient survival.

Abstract

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-stimulated 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 naïve (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 lower 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 long-term tumor immunity in ovarian cancer patients.

• Authors: Mark J Dobrzanski, Kathleen A Rewers-Felkins, Imelda S Quinlin, Khaliquzzaman A Samad, Catherine A Phillips, William Robinson, David J Dobrzanski, Stephen E Wright
• Journal: Clinical immunology (Orlando, Fla.) (Clin Immunol) Vol. 133 Issue 3 Pg. 333-52 (Dec 2009) ISSN: 1521-7035 [Electronic] United States
• PMID: 19762283 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antigens, CD
• CA-125 Antigen
• CTLA-4 Antigen
• CTLA4 protein, human
• Cytokines
• FOXP3 protein, human
• Forkhead Transcription Factors
• MUC1 protein, human
• Mucin-1
• Leukocyte Common Antigens

Topics

• Aged
• Amino Acid Sequence
• Antigens, CD (blood, immunology)
• CA-125 Antigen (blood, immunology)
• CD4-Positive T-Lymphocytes (cytology, immunology)
• CTLA-4 Antigen
• Cytokines (genetics, immunology)
• Female
• Flow Cytometry
• Forkhead Transcription Factors (blood, immunology)
• Humans
• Immunotherapy, Adoptive (methods)
• Leukocyte Common Antigens (blood, immunology)
• Middle Aged
• Molecular Sequence Data
• Mucin-1 (immunology)
• Ovarian Neoplasms (immunology, therapy)
• T-Lymphocyte Subsets (immunology)
• T-Lymphocytes, Regulatory (cytology, immunology)
• Th1 Cells (cytology, immunology)