Targeting resistance to Immunotherapy with INB03
Provided by INmune Bio
Primary and secondary resistance to therapy is a defining characteristic of progressive cancer in man. Patients and their clinical teams repeat the cycle of treatment, remission, relapse and retreatment until an effective therapy is found or the patient succumbs to the disease. Because of the devious biology of cancer, the “cure” word is rarely used in the patients with cancer until they have been disease free for more than 10 years. This is a frustrating scenario for patients, their families and clinical teams. We need to get smarter. We need to do better.
The new therapeutic “kid-on-the-block” is immunotherapy. Clinicians now realize one of the most potent tools in their therapeutic tool box is the patient’s immune system. Unfortunately, one of the reasons the patient got cancer and has progressive disease the tumor is evading their immune system – the tumor is hiding in plain sight. The goal of immunotherapy is to reengage the patient’s immune system to attack their cancer. If the patient’s immune system enters the fray, the patient has a chance.
One strategy to reverse resistance is to target the cause on the immunotherapeutic resistance. Combination therapy may allow the patient to respond to a treatment that was ineffective when used alone as a monotherapy. Put simply, monotherapy cannot eradicate the cancer if it can’t get at the tumor that has an effective resistance mechanism in play. If the resistance mechanism is countered, the therapy may work! Logically, combination therapy should include one drug to target the resistance factor and one drug to to attack the tumor. In the case of combination immunotherapy, it is all about eliminating immunologic resistance to allow the effector immunotherapy do its job – kill cancer cells!
Inmune Bio is developing INB03TM to target causes of immunologic resistance. We have identified three types of resistance that deserve further study – resistance to immune checkpoint inhibitors, resistance to trastuzumab and resistance to selected kinase inhibitors. The common denominator to this diverse set of resistance mechanisms is soluble TNF (sTNF). sTNF is a cytokine that has complicated roles in biology. TNF’s complex biology that is both good and bad for the patient. In cancer, sTNF is definitely the BAD TNF! In addition to causing resistance to immunotherapy, sTNF makes the cancer worse by promoting tumor growth and dedifferentiation, promoting neovascularization and metastasis. Targeting sTNF makes sense due to direct effects on tumor biology and immunology.
INB03 is protein therapeutic that neutralizes soluble TNF (sTNF) without affecting trans-membrane TNF or TNF receptors (TNFR) using a novel mechanism of action that uses dominant-negative technology to neutralize sTNF without inhibiting trans-membrane TNF (tmTNF). tmTNF is often called the GOOD TNF because it improves the immune response and oligodendrocyte function. Currently approved TNF inhibitors a block the effects of both sTNF and tmTNF. In cancer patients, non-selective TNF inhibitors are both anti-inflammatory (that is good!) and immunosuppressive (that is bad!). Giving a drug with this profile to patients with cancer is problematic. INB03 neutralizes sTNF without affecting tmTNF. In the setting of cancer, INB03 is anti-inflammatory but is not immunosuppressive. In fact, INB03 improves the patient’s immune response to both infection and their cancer.
How does targeting a single cytokine affect 3 different resistance mechanisms? Put simply, sTNF is used by the cancer as a “tool” to trick the immune system to not work and in some cases, actually protect the tumor! sTNF causes differentiation and proliferation of myeloid derived suppressor cells (MDSC), a cell type unique to cancer patients, that migrates to the tumor microenvironment (TME) where it causes an immunosuppressive environment that prevents the patient’s immune system and immunotherapy from attacking the tumor. Elevated levels of MDSC in patients cause resistance to immune checkpoint inhibitors (CPI). Many believe that targeting and eliminating MDSC may improve the response to CPI. Because MDSC require sTNF to survive, if INB03 is used to neutralize sTNF, the MDSC population collapses and the patient should respond to CPI.
At the recent San Antonio Breast Cancer Symposium, INB03 was shown to reverse trastuzumab resistance in an animal model. Primary or secondary, trastuzumab resistance occurs in almost half of women with HER+ breast cancers. These resistant tumors often express MUC4, a complex proteoglycan, on their cell surface. MUC4 expression by cancer cells predicts a worse outcome for the patient. In women with HER2 positive breast cancer, that worse outcome relates to resistance to trastuzumab – a therapeutic monoclonal antibody targeting HER2. Treatment of animals with INB03 eliminates MUC4 expression to allow them to become sensitive to trastuzumab. What is going on? MUC4 expression is up-regulated by sTNF in the TME. Although not yet proven, it is believed the MUC4 expression interferes with trastuzumab-HER2 binding. Think of standing, with dry feet, on a rock at the water’s edge. As the tide comes in, the rock gets covered and your feet get wet. Trastuzumab can’t bind the HER2 if it can’t find the HER2! When sTNF is eliminated from the TME, MUC4 expression declines, HER2 gets exposed allowing the therapeutic benefits of trastuzumab-HER2 binding. (ie: the tide goes out and your feet are dry).
Pharmacologic inhibition of the MAPK pathway was a major advance in the treatment of metastatic melanoma over chemotherapy. Vemuraenib and dabrafenib, small molecule inhibitors of MAPK signaling, have improved survival in previously untreated melanoma patients with the BRAF V600E mutations. Trametinib inhibits MAPK kinase (MEK), which is downstream of BRAF in the MAPK pathway and has been associated with improved progression-free and overall survival. Unfortunately, half of melanoma patients with BRAF V600 mutations who are treated with MEK or MAPK inhibitors develop secondary resistance with disease progression within 6 to 7 months after the initiation of treatment. Why is this? 
Work recently presented at the 33rd annual Society for Immunotherapy of Cancer showed that that co-expression of TNF Receptor 1 (TNFR1) and TNFR2 on melanoma cells lines predicted resistance to MAPK inhibitors in the presence of sTNF  suggesting that TNFR status could be an important predictor of MAPK inhibitor resistance in melanoma patients. Neutralization of sTNF using INB03 prevented acquisition of resistance to MAPK inhibitor by BRAF-V600E mutant melanoma cell lines in vitro.
The thrilling part of all of these pre-clinical findings is that they can be tested in man. The MDSC/CPI resistance hypothesis will be tested by INmune Bio in the Phase II trial planned for the near future. Patients resistant to CPI with biomarkers of inflammation including elevated MDSC will be treated with combination therapy, INB03 plus CPI. We hope these previously resistant patients will respond to CPI. The trastuzumab/MUC4 and TNFR/kinase resistance mechanisms will be tested in the future. Often lost in the excitement is that effectively treating a resistance mechanism requires you know it is there. Determining an effective anti-cancer cocktail for a patient by trial and error is not good enough. We must use biomarkers to determine who needs anti-resistance strategies as part of first-line therapy. In each case presented above, there are readily accessible biomarkers to help choose patients who will benefit for combination therapy with INB03 whether it is elevated MDSC in CPI resistance, tumor MUC4 expression or TNFR expression for trastuzumab and kinase inhibitor resistance. Currently, cancer is smarter than we are, but we are catching up. We believe thoughtful use of biomarker directed combination immunotherapies will have an impact on carefully selected patients. We have work to do, but the future is bright.
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