Immunogenicity and Targeting of Shared Neoantigens in Adenoid Cystic Cancer
Abstract
Background on Adenoid Cystic Carcinoma: In this project, we seek to develop new therapies for adenoid cystic carcinoma (ACC). ACC is a rare cancer, with approximately 1,600 new cases diagnosed and 1,200 deaths recorded annually in the United States. ACCs usually arise in the salivary glands of the head and neck, and less commonly affect the trachea, lung, breast, and other sites. Both men and women are affected. There are no known risk factors for the development of ACC, although salivary cancers have been strongly linked to Agent Orange herbicide exposure among Vietnam War Veterans. Most ACCs are treated with surgery and radiation therapy, but over 50% of patients experience cancer recurrence. In a majority of these cases, cancer recurrences are not able to be successfully treated. At this stage, most patients receive chemotherapy, although there is no clear evidence that any chemotherapy drug is effective. In recent years, cancer immunotherapy has shown great promise; unfortunately, in contrast to some other cancer types, immunotherapy drugs have only been effective in a very small percentage of patients with ACC. The goal of our multidisciplinary ACC research team is to develop new, more effective immunotherapies to treat metastatic ACC, which is otherwise an incurable cancer. Objectives and Rationale: The rationale behind this project is that most ACC tumors contain non-self signals (neoantigens) that result from alterations inside the tumor. Neoantigens can be detected by the immune system. Sometimes, these neoantigens result from a gene mutation in the tumor. In other cases, neoantigens may also come from gene fusions (a combination of parts of two different genes), an alteration that happens to be found in most ACC tumors. Our early data suggest that many ACCs have neoantigens that result from a gene fusion; however, further work is needed to translate these findings into new therapies for patients. Our objective is to identify the neoantigens in ACC that can be recognized by T cells, especially the set of neoantigens that are shared among patients. Such shared neoantigens would be particularly amenable to the development of standardized off-the-shelf immunotherapies based on T cells programmed to identify and kill cells expressing these signals. FY22 RCRP Focus Areas: Our project addresses components of all three Focus Areas of the fiscal year 2022 Rare Cancers Research Program: Biology and Etiology: We will identify new targets in ACC tumors that can stimulate T cell attack. Research Model: We have developed a new approach to screen tumors for immune reactivity in mice, as well as a collection of ACC patient-derived tumor models that have been grown in mice and can be used for drug treatment studies. These new models will be shared with the research community. Therapy: We will establish the feasibility of targeting neoantigens in ACC, a new immunotherapy approach that has the potential to improve upon current drugs that have minimal effectiveness. Applicability to Patients with ACC and Other Rare Cancers: This research will provide unprecedented insight into a common genetic event in ACCs, as well as identifying whether this common genetic event represents an Achilles’ heel that can be targeted with immunotherapy. The findings of this project will facilitate development of a new neoantigen-targeting treatment strategy for ACC which, if successful, would be the first effective therapy for this highly lethal cancer. In addition, there are a number of other rare cancer types that share many biological similarities with ACC, including several types of pediatric cancers and sarcomas that have comparable genetic profiles and low response rates to immunotherapy. We anticipate that the techniques and findings of our study will have applicability to these other cancer types as well. During the 3-year timeline of this project, we expect to generate clear, actionable data in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310716
Entities
People
- Luc Morris
Organizations
- Sloan-Kettering Institute
- United States Army