Approaches to Enhance Vaccine-Induced Tumor-Infiltrating Lymphocytes (viTILs) in Melanoma
Abstract
FY22 MRP Topic Area(s): This proposal will address the FY22 MRP Focus Area: Identify how the tumor microenvironment (e.g., stromal, immune, microbiome) impacts tumor initiation, response to therapy, progression, recurrence, and/or dormancy. The proposed study addresses the FY22 MRP Challenge Statement by identifying obstacles in melanoma that prevent immune cells from entering them, and developing new methods to treat melanomas with melanoma vaccines plus intratumoral treatment to enable the immune cells to enter the melanoma and to destroy it and to inhibit the development of metastases. Scientific Rationale, Objective and Aims: Melanoma vaccines induce circulating T cell responses against melanoma antigens, with promise to eliminate primary melanomas and their metastases. In murine models, circulating vaccine-induced T lymphocytes (cVILs) readily infiltrate experimental tumors and mediate tumor control. However, the promise of cancer vaccines has not yet been realized in humans. Human melanoma vaccines induce circulating T cell responses, but clinical responses have been rare. Failure of T cells to infiltrate tumors is likely the major obstacle to clinical efficacy of cancer vaccines. Many melanoma tumors lack tumor-infiltrating lymphocytes which are crucial to immune- mediated control. Thus, a likely explanation for the low rates of clinical benefit with immunogenic vaccines is that vaccine-induced immune cells fail to infiltrate melanoma deposits. Our preliminary data show that immune cells induced by melanoma vaccines do infiltrate a subset of melanomas, but at very low frequencies, but that addition of either of two treatments directly to the melanoma tumor can cause vaccine-induced immune cells to infiltrate melanomas in all patients evaluated and can increase the numbers of those immune cells in the tumors. We also have discovered that combination of two treatments can increase the ability of melanoma cells to secret a key molecule that attracts immune cells (CXCL10), and we propose to understand the mechanism of the synergy of those two treatments and to perform pre-clinical studies in mouse models to enable a future clinical trial of this combination therapy plus a melanoma vaccine. The specific aims are: Aim 1. To understand the impacts of intratumoral or systemic agents on melanoma tumor microenvironments that may enhance infiltration, function, and retention of viTILs. Aim 2. To evaluate combination therapy of IFN-gamma and a TLR2 agonist (IFN- gamma/TLR2) for enhancing production of CXCL10 and other HRLs, viTILs, and tumor control in preclinical models. Applicability to Melanoma Patients and Survivors: The study will increase understanding of factors limiting immune cell infiltration in melanoma, which will be assessed primarily in the setting of melanoma vaccines, but which has relevance for a wide array of immune therapies including cell therapies and checkpoint blockade therapy. The patients who may ultimately benefit from this research are those with early metastatic disease, and even those with locally advanced primary melanomas. If the approaches tested here are effective, they will support a future clinical trial in patients with early metastatic melanoma, which may include neoadjuvant therapy of locally advanced primary melanomas, cutaneous in-transit metastases, and regional lymph node metastases. Military Relevance: This project will address critical questions about obstacles in the tumor microenvironment that limit immune-mediated tumor control and will provide new options for combination immune therapy to overcome those obstacles. If successful, these studies will pave the way for further development of this approach which may melanoma progression and enhance melanoma control, thus enhancing the quality of life of melanoma patients. All of these benefits would enhance mission readiness of active military and their families by avoiding melanoma and/or treating it with lo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311060
Entities
People
- Ileana Mauldin
Organizations
- United States Army
- University of Virginia