Optimization of Adoptive Cellular Immunotherapy for Rare Melanomas
Abstract
The fiscal year 2022 Melanoma Research Program (MRP) Focus Area addressed by this proposal is research across the entire spectrum for rare melanomas in patients and model organisms. Overall, this proposal will address the MRP Challenge Statement to prevent melanoma progression for rare melanomas. Melanoma is the fifth most common cancer in the U.S. and case numbers are increasing. Military personnel spend long periods of time outside exposed to the sun, increasing their risk of melanoma. Rare melanomas, which are about 10% of total melanomas, occur in places on the body with less exposure to the sun, such as the eyes (uveal melanoma) and the hands and feet (acral melanoma). Of note, acral melanomas are the most common among people with darker skin (e.g., 70% of melanomas in African Americans and 46% of melanomas in Asians), and approximately 40% of the U.S. active-duty Service Members are from racial and ethnic minority groups. Recently, there have been dramatic improvements in the treatment of melanoma by releasing the brakes on the immune system and allowing it to attack and kill the melanoma cells using agents known as immune checkpoint inhibitors. Unfortunately, these have not been successful for rare melanomas. Another type of immunotherapy that shows promise involves taking immune cells directly from the patient s tumor, where they are likely recognizing and trying to kill the cancer cells. These tumor infiltrating lymphocytes (TILs) are grown to very high numbers in the laboratory. Recharged and amplified, the TILs are injected back into the patient to fight the melanoma. In clinical trials, TIL therapy decreased tumor size in up to a third of patients with rare melanomas as opposed to half of patients with non-rare melanomas. Current understanding of the mechanism of action for TILs suggests three important factors that must be improved to enhance their ability to kill tumor cells: (1) the ability of the T cells to recognize the tumor, (2) the ability of the T cells to immediately survive and kill once given back to the patient, and (3) the ability of the T cells to maintain their functionality for a long time. In the first aim, we will use an advanced mouse model of acral melanomas to determine the key features of T cells that recognize melanoma cells. In the second and third aims, we will boost TIL short-term and long-term survival, respectively, by reprogramming them based on molecular pathways we have identified in our prior work as critical for these functions. In order to reprogram the TILs and enhance their function, we have developed a method using RNA. This approach has many benefits, including increased safety, speed, control, and the ability to deliver multiple helpful properties at the same time. The flexibility to accurately adjust the therapy and introduce different proteins into T cells at different times according to the needs of the patient makes this a useful tool for tailoring medical care to each person. Moreover, RNA reprogramming only lasts for a short time. After the treatment is finished, all of the RNAs, the proteins they make break down, and the T cells return to their normal state, which limits any possible side effects of the treatment. By the end of the award period, our goal is to have validated a novel approach to improve the efficacy of TILs for the treatment of rare melanomas. Importantly, all of the necessary technology is already clinically approved, making it easier to translate our findings into clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310739
Entities
People
- Samuel Katz
Organizations
- United States Army
- Yale University