Melanoma is the most aggressive primary skin cancer affecting adolescents and adults. The incidence of melanoma of the skin has been steadily increasing over the past 10 years (76,100 estimated new cases in the United States alone in 2014). Despite the improvements in outcome over the last decade for those with early-stage disease, the outcome remains extremely poor for those with advanced stage disease at diagnosis.
With the current standard therapy, 10-year survival for patients with metastatic melanoma is less than 10%. It is therefore desirable to develop novel therapies that could improve these disappointing outcomes. Immune system-based therapies have the potential to fulfill this dire need. The high specificity of such immune-based therapies will also make them less toxic, reducing the organ toxicities and other long-term adverse effects endured by cancer survivors.
Melanoma cells express tumor-specific molecules on their surface referred to as ‘antigens’. Some of these antigens can be used for developing targeted therapies that will specifically recognize and kill the tumor cells without affecting the other healthy cells in the body. We are working on generating immune cells (T cells) from melanoma patients that are specific for two antigens, HER2 and GD2 expressed on melanoma tumor cell surface. Expression of these surface antigens is variable from one patient to the other and in fact, within a single tumor (e.g., some cells will be both HER2 and GD2 positive while others may express either HER2 or GD2 only).
We and others have found that using T cells specific for a single antigen can hence result in selective survival of those tumor cells that do not express the targeted antigen. This leads to cancer recurrence after therapy. We have previously shown that simultaneous targeting of two tumor-specific antigens using bispecific T cell products improves tumor control. We now propose to target two melanoma antigens, HER2 and GD2, simultaneously, with the goal of decreasing the risk of tumor recurrence.
To achieve this, we will genetically modify the T cells with a novel bispecific molecule that we have designed and constructed in our laboratory, called ‘TanCAR’. We will further test the function of these bispecific T cells against melanoma cells in the lab and in animal models. Knowledge gained from the current proposal will be used to justify and develop a clinical trial to treat patients with melanoma. Furthermore, the obtained information could have applicability for T cell therapy of other cancers as well.
