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Q&A: Harnessing the power of the immune system to combat cancer

Currently, monoclonal antibodies targeting immune checkpoint proteins are a mainstay of cancer therapy and cancer drug development.

French scientists work on a cancer vaccine, one of several in development that raises hopes of coming breakthroughs
French scientists work on a cancer vaccine, one of several in development that raises hopes of coming breakthroughs - Copyright AFP Abdul MAJEED
French scientists work on a cancer vaccine, one of several in development that raises hopes of coming breakthroughs - Copyright AFP Abdul MAJEED

Immunotherapy promises to deliver significant results in the battle against different forms of cancer. To learn about the types of activities that a startup company is involved with in this area of pharmaceutical development, Digital Journal spoke with RJ Tesi MD, CEO of INmune Bio, Inc., a clinical-stage immunology company focused on developing treatments that harness the patient’s innate immune system to fight disease.

Digital Journal: Can you provide a brief background on INmune Bio?

RJ Tesi: INmune Bio was formed in 2015 as a private biotech company focused on harnessing the power of the innate immune system to treat disease. The Company went public in 2019 is listed on Nasdaq under the ticker symbol INMB.

The Company has two product platforms – Dominant-Negative negative tumour necrosis factor (TNF) inhibitor and INKmune. INB03 is a dominant-negative TNF inhibitor that is different from currently-approved TNF inhibitors because it only binds soluble TNF (sTNF) without affecting trans membrane TNF (tmTNF). This gives it a safety and efficacy profile that is unique. INKmune is a program targeting natural killer (NK) cells in patients with cancer. INKmune converts that patient’s resting NK cells into tumour killing memory like NK cells.

DJ: What are your product platforms that are currently in clinical trials?

Tesi: Both XPro and INKmune are currently in clinical trials. XPro, a DN-TNF compound being developed to treat neuroinflammation that causes neurodegenerative disease is in a blinded randomized Phase II trial treating patients with Alzheimer’s Disease (AD).   INB03 is a DN-TNF compound that has complete a Phase I clinical trial in patients with solid tumours and is the drug used in the posters presented at the AACR.  INKmune is an open label Phase I/II trial in patients with metastatic castration-resistant prostate cancer (mCRPC). The AD trial is a global trial enrolling patients in Australia, the U.S., the UK, and the EU. The mCRPC trial is enrolling patients in the U.S.

DJ: You just demonstrated that INB03 down regulates immune checkpoint proteins on T cells and macrophages and decreases metastatic potential of MUC4 expressing breast cancer. Can you share what INB03 is and insight into your data? What is the importance of understanding MUC4 status for women with breast cancer?

Tesi: Despite significant advancements in the treatment of women with high-risk breast cancer (HER2+ and TNBC), relapse is common due to resistance, primary or secondary, to therapy. Determining biomarkers of resistance to allow precision medicine approach for patient treatment is needed to improve results.  MUC4 expression in woman with one of these high risk breast cancers predicts resistance to therapy, metastasis and early death.  If clinical teams  know a woman’s MUC4 status, they can adjust the therapy to  better suit the tumour. This is the definition of precision cancer care.

There are three main insights we would like to share from our recent work:

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 tumours to immunotherapy sensitive tumours.

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 tumour metastasis, decreases the number of metastasis and improves response to anti-PD1 therapy. Early use of INB03 may prevent distal disease and improve tumour control.

DJ: Considering your data, what recommendations do you have for practitioners moving forward?

Tesi: We recommend that women with high-risk breast cancer should be tested for the MUC4 biomarker during their diagnostic panel. 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 tumour 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.

DJ: What is next for INmune Bio for use of INB03 in treatment of cancer?

Tesi: We are looking for a partner to help support our efforts around INB03 and have three recommendations for what our ideal next steps would be together:

  • 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, oesophageal, 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 tumours 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.
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Written By

Dr. Tim Sandle is Digital Journal's Editor-at-Large for science news. Tim specializes in science, technology, environmental, business, and health journalism. He is additionally a practising microbiologist; and an author. He is also interested in history, politics and current affairs.

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