CAR-T Cell Therapy for Rare Melanoma Targeting TYRP-1
Abstract
The Fiscal Year 2020 (FY20) Melanoma Research Program (MRP) challenges the research community to redefine the concept of prevention to include all the steps of melanoma progression, and especially encourages studies for rare subtypes of melanoma, such as acral, mucosal, and uveal melanoma, across the entire melanoma process from initiation to distant macro-metastasis. Here we propose the preclinical development of a new therapy to interrupt disease progression and recurrence for patients with acral, mucosal, and uveal melanoma. The proposed study will address the FY20 Focus Area of therapeutic prevention and is in line with the FY20 MRP Challenge Statement. Acral, mucosal, and uveal melanomas are rare subtypes of melanoma and present significant biological differences from the more common type of melanoma known as cutaneous melanoma. As a result, treatment strategies such as immune checkpoint blockade that have worked well for cutaneous melanoma are less effective in these patients, underscoring a need for new therapeutic approaches. A characteristic trait of a significant subset of acral, mucosal, and uveal melanomas is the high expression of tyrosinase-related protein-1 (TRYP-1), a protein involved in the production of pigment. Adoptive T cell therapy is a new therapeutic approach that uses a specific type of white blood cells, called T cells, to target and kill tumor cells. In one strategy, the patient’s own T cells are genetically modified to express a synthetic protein–called a chimeric antigen receptor, or CAR–that enables engineered T cells to specifically recognize and kill tumor cells. We have developed a new CAR, called 20D7SL, that will redirect the patient’s T cells to target the TYRP-1 protein overexpressed in acral, mucosal, and uveal melanoma and, in a lower proportion of patients, in cutaneous melanoma. We have tested this approach in melanoma cell lines and demonstrated that the engineered T cells are able to completely kill these melanoma layers. Additionally, in mouse models, we have shown that the adoptive transfer of T cells genetically modified to express the 20D7SL CAR leads to a significant slowdown in tumor growth and can even eliminate the tumor. In this grant proposal, we seek funding that will allow us to extend our safety and antitumor efficacy studies in acral, mucosal, and uveal melanoma models. Additionally, this grant, if awarded, will allow us to prepare all the reagents and manufacturing protocols needed to open a phase 1 clinical trial for patients with rare subtypes of melanoma. By the end of the funding period, all the data generated from these studies will be submitted to the Food and Drug Administration (FDA) that will review the results and, if satisfactory, grant approval to open the clinical trial. If we receive the approval from the FDA, we will immediately open a clinical trial to treat patients with acral, mucosal, and uveal melanoma with high expression of TYRP-1. TYRP-1 is expressed at high levels in 58.3% of acral, 60% of mucosal, and 91.7% of uveal melanoma patients. As mentioned above, this therapy could also be used to treat patients with cutaneous melanoma. However, the frequency of TYRP-1 overexpression in these patients is lower, around 30%. As suggested by our preliminary studies in mouse models, we expect this treatment to slow down the tumor growth, decrease the tumor volume, and in some cases, even eliminate the tumor. The potential risks are associated with the chemotherapy required before the administration of the T cells. The CART cells could also lead to excessive activity of the T cells or depigmentation. However, these toxicities are well understood based on previous adoptive T cell therapy clinical trials and can be managed in most cases with immunosuppressive drugs. Moreover, the 20D7SL CAR-T cells that we have designed contain a built-in mechanism that will allow us to eliminate them from the body in case of an adverse reaction. The 20D7SL CART
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110839
Entities
People
- Cristina Puig Saus
Organizations
- United States Army
- University of California, Los Angeles