A Neoepitope Subunit Vaccine Targeting the Mutated Estrogen Receptor Ligand Binding Domain to Treat and Prevent Endocrine-Resistant ER+ Breast Cancer
Abstract
Approximately 75% of all breast cancers are classified as estrogen receptor positive (ER+), which use estrogen as their source of “fuel.” Over the past several decades, multiple drugs have been developed to block estrogen production to deprive these cancers of this critical fuel. While these drugs have been very successful, up to 50% of these cancers will eventually develop resistance to them. As such, drugs targeting different pathways have been developed as secondary therapies for resistant ER+ breast cancer, but these are not universally effective and many elicit significant toxicities and side effects. The majority of these resistant tumors will eventually metastasize, at which point there are no effective treatments. While there are many ways resistance can occur, recent research has uncovered a surprisingly simple mechanism to account for a large percentage (~30%) of resistant metastases. These studies found that the estrogen receptor gene was mutated, or changed, in very specific places that made it able to function without estrogen. This mutated gene could thus fuel these cancers even when the fuel supply (i.e., estrogen) is cut using endocrine therapy. Remarkably, a handful of virtually identical mutations account for these endocrine-resistant metastases, suggesting that targeting these types of mutations could effectively block this type of resistance. Thus, despite decades of research that have identified and effectively targeted estrogen receptor (ESR1) in ER+ breast cancer, its recently discovered ability to mutate to evade certain therapies reveals a new opportunity for immunologic-based treatment. While the body’s immune cells (its proverbial cellular army) typically protect the body from foreign pathogens (foreign invaders), immunotherapy redirects immune cells to attack cancer cells. As mutant forms of ESR1 are highly overexpressed and essential to ER+ breast cancer cells, it is an ideal target for the immune system to focus its attack. Moreover, mutated genes are easier for the immune system to target due their changed “non-self” mutant nature, which marks them as different and immunologically distinct from other non-cancer cells. This affords a unique therapeutic opportunity, as it is normally difficult to predict the development of specific mutations in cancer to immunologically target. As such, it is possible that this approach could be specifically utilized to safely and effectively target ~30% of metastatic resistant ER+ breast cancers, if a viable vaccine was generated that could elicit ESR1-mutant “non-self” specific immunity. Our studies have revealed that the mutated portions of ESR1 are actually presented by cell to the immune system, which spurred our developed of vaccines targeting this mutant portion. Critically, we have found that our ESR1mut vaccines can elicit robust ESR1-mutant specific immunity and that vaccines targeted to a specific mutation work equally well against other ESR1 mutations (which makes sense, due to their structural similarities). This strongly suggests that a universal ESR1mut vaccine is achievable. Our research team has extensive experience in this area, having successfully developed a novel viral vaccine platform (now in clinical trials) which uses a modified virus to train immune cells to specifically target highly expressed cancer genes. In this application, we wish to validate and extend these findings in our ER+ endocrine-resistant ER+ breast cancer model and additionally determine if Food and Drug Administration (FDA)-approved antibodies that boost the immune response will enhance our vaccine. Finally, we will also determine if FDA-approved drugs that help degrade ESR1 would similarly enhance our vaccine by allow more presentation of the mutated ESR1 peptides by ER+ breast cancer cells, thus more effectively marking them for destruction. Thus, our study will capitalize on a novel vaccine platform and recent immunotherapy advances to strat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810057
Entities
People
- Zachary C Hartman
Organizations
- Duke University
- United States Army