Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab.

Abstract

Ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte antigen 4 (CTLA-4), has been shown to improve survival in patients with advanced metastatic melanoma. It also enhances immunity to NY-ESO-1, a cancer/testis antigen expressed in a subset of patients with melanoma. To characterize the association between immune response and clinical outcome, we first analyzed NY-ESO-1 serum antibody by ELISA in 144 ipilimumab-treated patients with melanoma and found 22 of 140 (16%) seropositive at baseline and 31 of 144 (22%) seropositive following treatment. These NY-ESO-1-seropositive patients had a greater likelihood of experiencing clinical benefit 24 wk after ipilimumab treatment than NY-ESO-1-seronegative patients (P = 0.02, relative risk = 1.8, two-tailed Fisher test). To understand why some patients with NY-ESO-1 antibody failed to experience clinical benefit, we analyzed NY-ESO-1-specific CD4(+) and CD8(+) T-cell responses by intracellular multicytokine staining in 20 NY-ESO-1-seropositive patients and found a surprising dissociation between NY-ESO-1 antibody and CD8 responses in some patients. NY-ESO-1-seropositive patients with associated CD8(+) T cells experienced more frequent clinical benefit (10 of 13; 77%) than those with undetectable CD8(+) T-cell response (one of seven; 14%; P = 0.02; relative risk = 5.4, two-tailed Fisher test), as well as a significant survival advantage (P = 0.01; hazard ratio = 0.2, time-dependent Cox model). Together, our data suggest that integrated NY-ESO-1 immune responses may have predictive value for ipilimumab treatment and argue for prospective studies in patients with established NY-ESO-1 immunity. The current findings provide a strong rationale for the clinical use of modulators of immunosuppression with concurrent approaches to favor tumor antigen-specific immune responses, such as vaccines or adoptive transfer, in patients with cancer.

• Authors: Jianda Yuan, Matthew Adamow, Brian A Ginsberg, Teresa S Rasalan, Erika Ritter, Humilidad F Gallardo, Yinyan Xu, Evelina Pogoriler, Stephanie L Terzulli, Deborah Kuk, Katherine S Panageas, Gerd Ritter, Mario Sznol, Ruth Halaban, Achim A Jungbluth, James P Allison, Lloyd J Old, Jedd D Wolchok, Sacha Gnjatic
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 40 Pg. 16723-8 (Oct 04 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21933959 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigens, Neoplasm
• CTAG1B protein, human
• CTLA-4 Antigen
• Ipilimumab
• Membrane Proteins

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (immunology, pharmacology)
• Antigens, Neoplasm (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• CTLA-4 Antigen (immunology)
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunohistochemistry
• Ipilimumab
• Melanoma (immunology)
• Membrane Proteins (immunology)
• Middle Aged
• Proportional Hazards Models
• Survival Analysis