11 Apr AACR24: MUC4 is a Biomarker of Metastasis in Triple Negative Breast Cancer and Can Help Improve Treatment Results
Dr. Tesi
MedicalResearch.com Interview with:
RJ Tesi M.D.
CEO and Founder of INmune Bio
MedicalResearch.com: What is the background for this study? What are the main findings?
- MUC4 expression by high-risk breast cancer (HER2+ or TNBC) is a biomarker that predicts resistance to therapy and an increased risk a metastasis. MUC4 expression can be determined at time of biopsy and therapeutic decisions should be adjusted to optimize the chance of response to first line therapy.
This biomarker is easily determined using immunohistochemistry in the diagnostic breast biopsy tissue similar to testing for HER2 expression. Testing for MUC4 can be easily added to the current panel of routine stains obtained at the time of the diagnostic biopsy. Knowing MUC4 status in women with high-risk breast cancer will improve results.
- Soluble TNF causes the up regulation of immune checkpoint proteins of cells of the TME. This includes CD47 and SIRPa on tumor based macrophages and CTLA4, PD1, LAG3 and TIGIT on T cells in the TME. INB03 is a pan immune checkpoint modulator. Treatment with INB03 downregulates all immune checkpoint proteins on the cells. Downmodulation of all immune checkpoint proteins improves response to immunotherapy.
Currently, monoclonal antibodies targeting immune checkpoint proteins are a mainstay of cancer therapy and cancer drug development. These strategies target one immune checkpoint protein at a time. To date, combination therapy targeting two immune checkpoint proteins has been tried (e.g.: anti-PD1 and anti-CTLA4 combination therapy) with mixed results. Combination immune checkpoint strategies may increase therapeutic response but increase toxicity. INB03 downregulates all immune checkpoint proteins. This is equivalent to giving a patient a 6 antibody cocktail – something that cannot be done in man. As expected, decreased immune checkpoint expression improves response to therapy by converting immunotherapy resistant tumors to immunotherapy sensitive tumors.
- In TNBC, MUC4 expression predicts both resistance to anti-PD1 therapy and increased risk of distant metastasis. Treatment with INB03 decreases expression of proteins associated with tumor metastasis, decreases the number of metastasis and improves response to anti-PD1 therapy. Early use of INB03 may prevent distal disease and improve tumor control.
MedicalResearch.com: What should readers take away from your report?
- The MUC4 biomarker is easily determined by immunohistochemistry to breast biopsy tissue similar to testing for HER2 expression. The test can be easily added to the current panel of diagnostic stains routinely used on the diagnostic breast biopsy. Knowing MUC4 status in women with high-risk breast cancer will improve results especially if MUC4 status is known, and acted on, at the start of therapy.
- Resistance to immunotherapy can be predicted based on histology. Waiting to define treatment resistance by tumor progression should be considered a dated treatment strategy. Determining a resistance profile at the time of biopsy will allow for a precision medicine approach in women with high-risk breast cancer
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
- Recommendation #1: Additional animal studies are not needed for use of INB03 in combination with immunotherapy in women with MUC4 expressing high-risk breast cancer (HER2+TNBC). Clinical studies are needed to demonstrate the pre-clinical data are relevant in women with high-risk breast cancer. We believe the ideal studies would be addition of INB03 to standard of care in women with advanced HER2+ breast cancer and addition of INB03 and an immune checkpoint inhibitor to standard of care in women with TNBC.
- Recommendation #2: Demonstrate in animal models that downregulation of MUC4 in MUC4 expressing GI malignancies (pancreas, gastric, esophageal, colon) improves response to therapy. If these studies are positive, the strategy should be translated to man in Phase II clinical trials.
- Recommendation #3: More than 90% of pancreas tumors express MUC4. Because of the futility of immunotherapy in treatment of patients with pancreatic cancer, a study in patients with pancreatic cancer is justified. The ideal therapy will be the addition of INB03 and an immune checkpoint inhibitor to standard-of-care.
Disclosures: I am a founder, CEO, and full-time employee of INmune Bio, the company developing INB03.
Citations: AACR April 2024: Poster Abstracts:
PO.IM01.02 – Immune Checkpoints and Inhibitory Molecules 1
INB03: a new immune checkpoint inhibitor that reprograms macrophage polarization, boosts ADCP and reverts T-cell exhaustion markers by Sofia Bruni, Maria Florencia Mercogliano and Roxana Schillaci
PO.TB04.02. Biomarkers and Expression Differences in Metastatic Progression 1.30 pm
MUC4 is a biomarker of metastasis in TNBC and its downregulation by blocking soluble TNF prevents metastasis in combination with immunotherapy by Mauro, Florencia; Bruni, S; Dupont, A; Inurrigarro, G; Figurelli, S; Barchuk, S, Lopez Della Vecchia, D; Cordo Russo, R;Gil Deza, E; Mercogliano, M; Schillaci, Roxana
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Last Updated on April 11, 2024 by Marie Benz MD FAAD