Can the body be taught to fight cancer with therapeutic proteins?
Resistance is a defining characteristic of many diseases in people, one of the most well known of which is cancer. Patients must repeat a cycle of treatment, remission, relapse, and treatment again until either an effective treatment is found or the patient succumbs to the cancer. Because cancer specifically is devious in nature, patients are only said to be “cured” of the disease if they have been free of it for ten years. This is, of course, very frustrating and frightening for patients, their loved ones, and their care providers. There must be a push for us to do better.
Enter immunotherapy, which uses a patient’s immune system as a tool to fight the disease by reprogramming it to attack cancer cells. Cancer is a progressive disease in which these cells hide in plain sight and evade the immune system. Immunotherapy aims to engage the patient’s immune system with therapeutic proteins in a battle with the cancer and if it does, the patient may have a chance at eliminating the disease.
Strategies to Reverse the Resistance
In order for the immune system to be able to fight cancer, the cause of the immunotherapeutic resistance must first be found. If tumors have an effective resistance mechanism in play, monotherapy cannot eradicate the cancer cells – but combination therapy may be able to.
Combination therapy might include a drug that targets the resistance factor and another to attack the cancer itself. Immunotherapy would work the same way: The system would attack the resistance, then would be able to do its job and attack the cancer. As it stands now, on its own, the immune system doesn’t “see” cancer cells. Finding a way to make them “discoverable” by the immune system is the key because the body won’t attack what it doesn’t find.
Types of Resistance So Far
There are three types of resistance so far that are being studied further: resistance to immune checkpoint inhibitors, resistance to trastuzumab, and resistance to select kinase inhibitors. What do all three of these have in common?
A little something called soluble TNF (sTNF).
sTNF is a complicated cytokine that causes resistance to immunotherapy, and also unfortunately exacerbates the cancer by promoting tumor growth, neovascularization, and metastasis. Therefore, it makes sense to target sTNF because of its direct relationship with tumor biology.
Inmune Bio is currently developing a therapeutic protein called INB03™ to target the causes of immunologic resistance. INB03™ is a protein that is able to neutralize sTNF without affecting TNF receptors or the TNF trans-membrane. It accomplishes this by using dominant-negative technology. Trans-membrane TNF (tmTNF) is beneficial to the patient because it improves the oligodendrocyte function and immune response. Currently, while it’s good that approved TNF inhibitors block the effects of sTNF, unfortunately, they also block the beneficial properties of tmTNF, making it a poor choice as a drug to give cancer patients. However, since INB03™ is able to neutralize the bad sTNF without affecting the good tmTNF, it improves patients’ immune response to cancer cells.
How Does this Targeting Affect Resistance Mechanisms?
Cancer uses sTNF as a tool to trick a person’s immune system to not work against it – incredibly, in some cases, it works to trick the immune system to actually protect the cancer! The sTNF causes myeloid derived suppressor cells to proliferate. These cells are unique to cancer patients, and they migrate to the tumor’s microenvironment where they prevent immunotherapy and the immune system from attacking. These cells require sTNF to survive – if INB03™ is able to neutralize the sTNF, the patient should respond to treatment that eliminates resistance to checkpoint inhibitors.
INB03™ was shown to reverse trastuzumab resistance in an animal at a recent Breast Cancer Symposium in San Antonio, TX. Trastuzumab resistance is present in almost 50% of women with breast cancer. Treatment with INB03™, however, allows women to become sensitive to trastuzumab – it’s believed that MUC4, a substance expressed by resistant tumors, causes the resistance to trastuzumab and “hides” receptor cells. Treatment can’t bind and kill receptor cells that are hiding. This is what happens in HER2 positive breast cancer. There is hope that INB03™ exposes those receptor cells, allowing binding between HER2 cells and trastuzumab.
But what about in people?
The most promising part of these pre-clinical findings is that they can and will be tested on humans. The hypothesis involving checkpoint inhibitors and MDSC will be tested by INmune Bio in the near future, with patients showing inflammation and elevated MDSC being treated with combination therapy using INB03™. In addition, the trastuzumab/MUC4 mechanism will also be tested.
Critical Point: You Can’t Treat What You Don’t Find
Using biomarkers to determine which patients need anti-resistance therapy prior to first-line treatment is vital. No matter how much chemotherapy is given to a patient with immunoresistance, it will never find or destroy cancer cells as long as they are hidden. It is the ultimate goal of combination immunotherapy to first reveal the cancer cells in a way so the body can “see” them and then administer the appropriate treatment to destroy the cells once and for all.
There is still much work to be done, but progress is promising and the next breakthrough in immunotherapy could be just around the corner.
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