Novel Combination Immune Therapy Regimens for Metastatic Breast Cancer
Abstract
Overarching Challenge: The proposal addresses two challenges: (a) eliminate the mortality associated with metastatic breast cancer and (b) revolutionize existing treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. Immunotherapy with agents called immune checkpoint inhibitors (ICIs) has provided new promise for cancer patients. However, ICI therapy showed low response rates in breast cancer (BC), including metastatic BC (MBC). This problem was linked to the highly immune suppressive environment that detracts the positive benefits of ICI therapy. New approaches to improve ICI therapy are needed such as targeting myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), major immune suppressive cells in the immune environment. Most MBCs carry mutations inactivating the tumor suppressor p53. Mutant p53 drives cancer progression and metastasis in part by promoting inflammation and the build-up of immune suppressive MDSC/TAM cells. At present, there are no effective treatment options for p53-mutant BC. We developed a novel therapeutic strategy for selective damaging p53-mutant tumors that takes advantage of DNA repair dysregulation in those tumors. Our data demonstrate that this novel anti-mutant-p53 regimen effectively blocks tumor growth and metastasis in p53-mutant MBC models without adverse effects. This new anti-mutant-p53 strategy is now being tested in the first-in-human phase 1 clinical trial for advanced colorectal cancer (CRC) (NCT04511039). The results from the first six patients showed good tolerance to this treatment. New data suggest that our anti-mutant-p53 treatment may affect immune suppressive cells and improve response to ICI therapy. The current study will test the hypothesis that this anti-mutant-p53 regimen can stimulate antitumor immune responses and improve the ICI efficacy by acting via both tumor-intrinsic and tumor-extrinsic mechanisms affecting the immune environment in p53-mutant MBC. The proposal includes three specific aims. Aim 1 will define the effects of our anti-mutant-p53 regimen on the various immune cell populations in p53-mutant MBC models. Aim 2 will assess the contribution of anti-tumor immune cells and immune suppressive cells to the antitumor action of our anti-mutant-p53 therapy. Aim 3 will test this anti-mutant-p53 treatment in combination with ICI agents in p53-mutant MBC. This work matters for thousands of patients with advanced BC, such as MBC, which is presently incurable. The results of this work may lead to a new treatment option for breast cancers with mutant p53 accounting for majority of MBC. Excitingly, our new therapeutic strategy can be quickly translated into the clinical trials as all components are already approved for cancer treatment but never been combined, to the best of our knowledge.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310059
Entities
People
- Andrei Bakin
Organizations
- United States Army