Redirecting Viral Immunity to Eradicate Low Tumor Mutation Burden Lung Cancers
Abstract
Immunotherapies that stimulate the immune system to attack tumors have revolutionized the treatment of lung cancer. However, while these therapies work well in some patients, not all tumors respond. Lung cancers that harbor low numbers of gene mutations (low tumor mutation burden, or TMB), such as those with EGFR mutations or ALK gene fusions, or those that occur in the absence of cigarette smoking, are especially difficult for the immune system to recognize. As a result, these patients have very few T cells that are capable of attacking the cancer. In contrast, most patients have large numbers of T cells that are capable of recognizing viruses such as CMV, EBV, or Flu that are commonly encountered in the context of normal life. These bystander T cells are functional but unable to participate in anti-tumor responses because the specificity of their T-cell receptor does not allow them to recognize tumor cells. In this project, we will develop a novel therapy that is capable of reprogramming tumor cells to look like they are infected by virus so that viral-specific T cells will attack them. These molecules, called Antibody Epitope Peptide Conjugates (APEC), use antibodies to deliver viral peptide antigens to the surface of the tumor cell, where they are displayed to nearby viral T cells. APECs can be tuned to match the specific viral T cells and tumor characteristics of each patient. In this project, we will develop APECs specifically designed for non-small cell lung cancers. Using patient-derived models of low mutation burden tumors and tumor explant cultures, we will test whether APECs can activate viral T cells to selectively kill cancer cells, while sparing normal tissue. We will also investigate how cancer-associated fibroblasts in the tumor microenvironment may enhance or suppress the ability for APECs to redirect bystander viral T cells. This approach of using antibodies to deliver viral antigens to tumor cells to render them immunogenic is a departure from other immunotherapy approaches that typically seek to reinvigorate existing anti-tumor T cells and has the potential to open up broad new therapeutic opportunities lung cancer patients with that do not respond to current immunotherapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311000
Entities
People
- Aaron N Hata
Organizations
- Massachusetts General Hospital
- United States Army