Combinatorial Strategies to Overcome Resistance to Immune Checkpoint Blockade in Breast Cancer
Abstract
Harnessing the immune system to treat metastatic cancer is becoming an increasingly promising therapy option. In several solid tumor types that include melanoma, lung, and bladder cancers, the use of antibodies against T cell inhibitory receptors, or immune checkpoint receptors, such as CTLA4 and PD1, is leading to unprecedented response and survival in patients with advanced disease. However, the majority of solid tumor types that include breast cancer (BrCa) appear poorly responsive to immune checkpoint blockade (ICB). Two factors that contribute to this are unidentified resistance mechanisms and a relatively low number of cancer-associated mutations in breast cancer that tends to mask the ability of T cells to recognize the tumor. Potential approaches to address these two factors include the use of combination antibodies against immune checkpoint receptors (for example, the combination of anti-CTLA4 and anti-PD1) and vaccines against tumor antigens. However, knowing what combination therapy to give and what tumor antigen to use for vaccination is often unclear. Moreover, combination ICB can be associated with severe and life-threatening side effects. In this proposal, we seek to examine and develop ways to (1) effectively inhibit resistance to ICB by targeting key signaling pathways that may orchestrate a multifaceted resistance program and (2) enhance the repertoire of T cells that can recognize cancer through methods that promote the expansion of T cells against tumor self-antigens rather than cancer-associated mutations. Mouse models will be used to dissect mechanisms and determine effective ways to target resistance and expand the T cell repertoire. Biospecimens from breast cancer patients will be utilized to corroborate findings from mice. Importantly, this proposal will focus on the use and investigation of drugs that are already clinically available and can inhibit resistance and expand the T cell repertoire in preclinical models. Thus, our objective is to broaden the scope of effective ICB therapy to metastatic BrCa by combining strategies that inhibit multiple resistance mechanisms and enhance the T cell repertoire that can be reactivated against the tumor.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710264
Entities
People
- Andy Minn
Organizations
- United States Army
- University of Pennsylvania