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.

Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

“…Ipilimumab, a fully human mAb directed against cytotoxic Contribution of B-cell responses after chemotherapy D Hannani et al T-lymphocyte antigen-4 that improves overall survival in metastatic melanoma patients, slightly increased antibody levels against tumor antigens (NY-ESO-1, MART-1, SSX2, p53 and MAGE-A4) and boosted humoral immune responses against tetanus, pneumococcal and influenza vaccines. 31,32 However, NY-ESO-1 seropositivity was only predictive of clinical benefit in cases of the concomitant elicitation of NY-ESO1-specific CD8 þ T cell responses. 32 Repeated vaccination with NY-ESO-1 protein in the adjuvants (Montanide plus CpG ODN) induced an integrated Th1 CD4 þ T cell and antibody response against NY-ESO-1 that was eventually completed by CD8 þ T cell immunity.…”

“…31,32 However, NY-ESO-1 seropositivity was only predictive of clinical benefit in cases of the concomitant elicitation of NY-ESO1-specific CD8 þ T cell responses. 32 Repeated vaccination with NY-ESO-1 protein in the adjuvants (Montanide plus CpG ODN) induced an integrated Th1 CD4 þ T cell and antibody response against NY-ESO-1 that was eventually completed by CD8 þ T cell immunity. Vaccine-induced antibodies facilitated cross-presentation of NY-ESO-1 epitopes by DCs to CD8 þ T cells.…”

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

“…These kind of double producers are well known to control tumor progression in mice and men. 5,6,39,40 Collectively, these results show that CTLA-4 deficiency in vivo or absence of CTLA-4 signals in vitro enhances the functional and transcriptional plasticity of Tc17 cells and thus profoundly augments their antitumor activity.…”

“…44 It is likely that this mechanism occurs in response to anti-CTLA-4 therapy (Ipilimumab) in melanoma patients. 5,6 In addition, strategies that enhance the plasticity of Tc17 cells in tumor-bearing subjects and the development of Tc1-like cytokine patterns have been shown to result in stronger antitumor immunity due to increased cell persistence and cytotoxicity. 20,21 Efforts to inhibit Tc17 cell activity are likely to result in a valuable strategy for treating cancer; 52 indeed, CTLA-4 blockade is well known to augment the antitumor activity of T cells in patients with advanced melanoma.…”

“…3 In mice and humans, Tc1 cells coexpressing two or three of their signature cytokines are correlated with reduced bacterial load and tumor burden. [4][5][6] Nevertheless, depending on the activation conditions, a cytokine milieu containing transforming growth factor b (TGF-b) and IL-6 7,8 drives CD8 C T cells to differentiate into IL-17-producing Tc17 cells, which have only limited cytotoxic activity. 9 In addition to TCR and co-stimulation-mediated signals, a third signal provided by cytokine receptor engagement with its respective cytokine, strongly determines the outcome of T cell differentiation as well as the stability of the initial phenotype.…”