Characterization Of Invariant Natural Killer T Cells In Patients With Advanced Melanoma Treated With Ctla4 Blockade And Dendritic Cell Vaccination

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background. Invariant CD1d-restricted T cells (iNKT) are a T lymphocyte subset with a key role in the innate and adaptive immune systems and have been implicated in protection against cancer. iNKT cells are activated by lipid antigen presentation by CD1d on myeloid dendritic cells (mDC). Upon activation, iNKT produce Th1 and Th2 cytokines. CD4+ iNKT cells have a Th2 profile, while CD4- and CD4-CD8- (DN) subsets, behave as Th1 T-cells. We studied the phenotype of iNKT in patients treated with the anti-CTLA4 monoclonal antibody tremelimumab alone or combined with MART-126-35 peptide-pulsed dendritic cells (MART-1/DC) to explore possible associations between iNKT with treatment outcomes. Methods: Peripheral blood mononuclear cells (PBMC) were obtained before and after treatment with tremelimumab alone (n=21) or tremelimumab with MART-1/DC (n=8). There were 4 patients with an objective response in the combined therapy group and 3 patients with an objective response in the tremelimumab alone group. The number and phenotype of T cell and iNKT were characterized by multi-color flow cytometry. Results. Approximately one month after the first dose of combined treatment the percentage of iNKT-cells increased over baseline, while the percentage of iNKT cells decreased in patients treated with tremelimumab alone. In patients receiving combined treatment, those with a clinical response had a significantly higher iNKT number than non-responders. Overall, iNKT phenotypes did not change in either treatment group during treatment. However, clinical responders receiving combined therapy exhibited a high percentage of iNKT-CD8+ cells and low percentages of iNKT-CD4+. In contrast, in the non-responders and patients treated with tremelimumab alone, the iNKT CD8 to CD4 subset ratio was inverted. The combined iNKT subsets (CD4+, DN+, and CD8+) shared a common phenotype of CCR5+, CD62L+ and CD45RA+ and the phenotype did not change over time. For the tremelimuamb cohort, a CCR7-CD45RA- phenotype appeared and increased within the iNKT-CD4+ and CD8+ subsets after dosing. Conclusions. Treatment with the anti-CTLA4 antibody tremelimumab induced changes in the percentage of iNKT cells which were more pronounced when co-administered with dendritic cell vaccines. iNKT cells may be a new cell subset mediating in the mechanism of action of CTLA4 blocking antibodies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5518. doi:10.1158/1538-7445.AM2011-5518