Turning the Tide: How to Make Breast & Pancreatic Cancer Respond to Immunotherapy
"New research reveals how a drug called entinostat can reprogram cancer cells to respond to treatments they were once resistant to."
Immunotherapy, particularly immune checkpoint inhibition (ICI), has transformed cancer treatment, especially for cancers easily recognized by the immune system. However, breast and pancreatic cancers, with their complex and suppressive tumor microenvironments (TMEs), remain challenging, showing low response rates to ICI. These tumors often recruit myeloid-derived suppressor cells (MDSCs), which hinder T-cell activation and infiltration, critical for successful immunotherapy.
A promising strategy involves epigenetic modulation to target MDSC trafficking and function, creating a TME that's more receptive to immune attack. This approach aims to make these stubborn tumors more responsive to ICI, boosting the chances of effective treatment.
New research explores using entinostat (ENT), a histone deacetylase inhibitor, in combination with ICI, such as anti-PD-1 and anti-CTLA-4. The results indicated significantly improved tumor-free survival in models of HER2/neu transgenic breast cancer and metastatic pancreatic cancer, offering hope for overcoming treatment resistance.
Entinostat and Nivolumab in Metastatic PDA
A phase 2 clinical trial reported results for entinostat, a histone deacetylase inhibitor, combined with nivolumab, an anti-PD-1 inhibitor, in patients with metastatic PDA. The available source material does not provide trial outcomes or population statistics, so no response rate or impact estimate can be stated.
Entinostat’s Epigenetic Rationale
Entinostat was developed as an approach to target epigenetic dysregulation in cancer. A technical guide describes it as inhibiting class I HDACs, which promotes histone hyperacetylation, chromatin relaxation, and transcriptional activation of silenced genes, including tumor suppressors. In 2018, a report described entinostat’s long half-life and predicted sustained gene expression as reasons it was an appealing candidate for combination with immunotherapies, and said this rationale supported early-phase clinical trials of entinostat alone in ovarian cancer and in combinations.
Reprogramming Immune Cells: How Entinostat Changes the Game
The study used mouse models to mimic breast and pancreatic cancers, employing flow cytometry, gene-expression profiling, and functional assays to deeply analyze tumor-infiltrating lymphocytes (TILs) and MDSCs. The goal was to understand how entinostat, when combined with checkpoint inhibition, affects these immune cell populations and their functions within the TME.
- Reduced Suppression: Entinostat decreases the suppressive effects of granulocytic MDSCs, key cells that normally shut down the immune response in tumors.
- T Cell Activation: The treatment boosts the activity of CD8+ T effector cells, which are essential for directly attacking and destroying cancer cells.
- Gene Expression Changes: Both MDSCs and TILs showed significant changes in immune-related pathways, indicating a reprogramming of their functions.
Entinostat and Antitumor Immunity
A review reports that entinostat can promote tumor-intrinsic immunogenicity by increasing MHC class I expression, tumor antigen presentation, and PD-L1 expression. It also describes effects on systemic and intratumoral immunity, including reducing immunosuppressive myeloid populations and promoting T-cell-permissive immune states. Separately, a study of a syngeneic model of spontaneously metastatic HER2-positive breast cancer notes that adding epigenetic modulators to therapies has reduced tumor growth and improved response in multiple cancer models.
Hope for the Future: What This Means for Cancer Treatment
This research highlights the potential of entinostat to transform immune-resistant cancers into more manageable and treatable conditions. By altering the tumor microenvironment and enhancing the effectiveness of immune checkpoint inhibitors, entinostat opens new avenues for combination therapies.
Resistance and Other Immunotherapy Challenges
Resistance is a major challenge for cancer immunotherapy: cancers may evade immunosurveillance through mechanisms that produce intrinsic or acquired resistance. Acquired resistance, also called secondary resistance, describes cancers that initially respond to immunotherapy but later adapt and progress despite treatment. Immunotherapy also faces affordability concerns and immune-associated adverse events, alongside the difficulty of initiating an antitumor response or tempering tumor-induced immunosuppression when resistance is present.
These findings have significant implications for clinical trials and patient care, suggesting that combining epigenetic modulators like entinostat with immunotherapy could improve outcomes for those with breast and pancreatic cancers. Current clinical trials (NCT02453620 and NCT03250273) are underway to further explore combining entinostat with immunotherapeutic agents.
Ultimately, this approach aims to harness the body's immune system more effectively, providing new hope for patients with some of the most challenging cancers to treat. Further research and clinical application promise a future where even the most resistant tumors can be made vulnerable to the power of immunotherapy.