# Cancer Vaccine Targeting Mutated GNAQ-Expressing Uveal Melanoma

## TL;DR

This study explores DNA vaccines to activate the immune system against a common mutation in uveal melanoma, aiming to prevent metastatic spread.

## Contribution

A novel DNA vaccine design that enhances T cell responses against mutated GNAQ in uveal melanoma is proposed.

## Key findings

- DNA vaccines containing immune-enhancing epitopes activated T cells that reduced lung metastases in animal models.
- Optimized vaccine constructs generated cytolytic T cells that killed mutated GNAQ-expressing tumor cells in vitro.
- The vaccine's effectiveness suggests potential for preventing metastatic uveal melanoma progression.

## Abstract

Most effective immunotherapeutics rely on activation of a patient’s immune system to fight cancer; however, they are only somewhat effective against metastatic uveal melanoma (MUM). This study explored DNA vaccination as a way to teach the immune system to recognize tumors and prevent the progression of metastatic lesions from dormant malignant cells and tumor seeds. Our findings indicate that cancer-fighting immune cells activated by DNA vaccines in animals and human cells can recognize and attack tumor cells characterized by the common UM-associated cancer-driving mutation. An enhanced form of this vaccine containing multiple parts and improved structure was even more effective in activating cancer-fighting immune cells. These data suggest that such a vaccine could be further improved toward the design of a novel MUM-preventive strategy.

Background/Objectives: Uveal melanoma (UM) is the most common intraocular malignancy in adults. Although brachytherapy of the primary tumor provides an approximate 80% five-year survival, with time, nearly half of patients experience predominant liver metastases. It was proposed that malignant cells migrate early and stay dormant as they adapt to the liver microenvironment. We propose that cancer vaccine-mediated activation of UM-targeted immunity in primary UM patients could prevent progression of metastatic disease from dormant cells or malignant seeds. Thus, this study explored DNA vaccination as a measure to educate the immune system to recognize the most common UM-associated Q209L tumor driver mutation in GNAQ and GNA11 G-alpha proteins. Methods: Several DNA constructs encoding mutated GNAQ were developed and tested for activation of UM-reactive T cells in HLA-A2/Hd transgenic mice and human T cells ex vivo. Results: Constructs containing immune-enhancing PADRE and VP22-derived epitopes boosted T cell responses against mutant GNAQ, which correlated with reduced experimental lung metastases. Ex vivo dendritic cell-mediated T cell activation with vaccine constructs containing optimized structure produced cytolytic T cells that secreted IFN gamma and killed mutated GNAQ-expressing UM cells in vitro. Conclusions: These findings propose the utility of the fusion DNA vaccines in eliciting T cell immunity against UM cells bearing the Q209L mutation in GNAQ/GNA11 protein to prevent the establishment and progression of metastatic disease.