Post-vaccination CTLA-4 expression correlates inversely with survival in patients vaccinated with allogeneic melanoma cell vaccine

Abstract

2565 Background: Immunologic endpoints are often utilized in cancer vaccine trials as surrogates to clinical outcomes. However validation of these endpoints, particularly in adjuvant vaccine trials, is not yet thoroughly explored. Signaling through CTLA-4 has been associated with a diminished T cell response, and this cell surface molecule is now a target in some melanoma immunotherapy trials. We examined CTLA-4 expression in T cells upon stimulation with autologous tumor before and after vaccination with an allogeneic melanoma cell vaccine. Methods: T cells isolated from cryopreserved PBMC were co-cultured with autologous melanoma cells (isolated from surgically resected metastases) for 3 days. After culture, cells were harvested and stained with fluorochrome labeled antibodies for CD3 and CTLA-4. The percentage of T cells expressing CTLA-4 was determined using flow cytometry. Survival of patients expressing CTLA-4 in greater than 1% of T cells was compared to those with less than 1% before and after vaccination. Results: Lymphocytes from 15 patients were examined. Median overall survival for the group was 42.6 months. Mean percent of T cells expressing CTLA-4 was 1.01% prior to vaccination and 0.78% 2–3 months post-vaccination (p=0.11). Survival did not correlate significantly with CTLA-4 expression by pre-vaccination T cells (p=0.51), but there was a strong correlation with post-vaccination T cell CTLA-4 expression (Wilcoxon p=0.04).Median survival for patients with CTLA-4 >1%post-vaccination was 15.9 months, while median survival for those <1% was 74 months. Conclusions: In patients undergoing vaccine therapy for melanoma, relatively high levels of CTLA-4 expressing T cells after stimulation with autologous tumor correlates with decreased overall survival. This measurement may be a prognostically important immunologic surrogate measure in adjuvant vaccine trials. It also suggests that there may be a clinical benefit to CTLA-4 blockade in conjunction with melanoma immunotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cancervax Corp. Cancervax Corp. Cancervax Corp.