Uveal Melanoma Cell-Based Vaccines Activate CD4+ T Lymphocytes That Cross-React With Primary and Metastatic Uveal Melanoma Cells

Abstract

Purpose:: We are exploring cell-based immunotherapy as an alternative or adjunctive treatment against uveal melanoma metastases. Uveal melanoma may be particularly appropriate for immunotherapy because primary tumors arise in an immune privileged site, and may express antigens to which the host is not tolerized. Because of the key role of CD4⁺ T cells in optimizing CD8⁺ T cell immunity, facilitating immune memory, and preventing tolerance, we are developing cell-based uveal melanoma vaccines that target the activation of CD4⁺ T lymphocytes. Our previous studies showed that tumor cells genetically modified to express MHC class II and costimulatory molecules are potent inducers of anti-tumor immunity. Because these MHC II vaccine cells do not express the MHC II accessory molecule, Invariant Chain, they preferentially process and present MHC II-restricted peptides derived from endogenously-encoded tumor antigens and they present these peptides to MHC II-matched CD4⁺ T cells.Methods and

Results:: We now report that MHC II vaccines prepared from primary uveal melanomas activate CD4⁺ T cells from healthy donors and from uveal melanoma patients. As measured by ELISA, activated CD4⁺ T cells produce high levels of IFNγ and cross-react with metastatic and other primary uveal melanomas. These activated CD4+ T cells do not cross-react with similar vaccines made from breast or lung cancer cell lines. Moreover, studies using lactate dehydrogenase (LDH) release as a measure of cytotoxicity indicate that the cell-based uveal melanoma vaccines prepared from primary uveal melanoma cells activate cytotoxic T cells that specifically lyse unmodified primary and metastatic uveal melanoma cells. In contrast, vaccines prepared from metastatic uveal melanomas, or vaccine cells that do not co-express MHC II molecules, are significantly less effective at activating CD4⁺ T cells.

Conclusions:: These data suggest that genetically modified tumor cells originating in immune privileged sites have enhanced capacity to induce anti-tumor immunity and therefore may be highly effective immunotherapeutic agents for treating uveal melanoma metastatic disease.

Keywords: melanoma • tumors • immunomodulation/immunoregulation