Immunotherapy and Checkpoint Inhibitors: Can They be More Effective?

Over the last two decades, immunotherapies have significantly improved the standard of cancer care with treatments that focus on improving the immune system. By definition, immunotherapies improve the ability of the patient’s immune system to fight cancer. The newest category of immunotherapy, immune checkpoint inhibitors (CPI), is arguably the single greatest advancement in cancer treatment in the past 20 years.

When the immune system is functioning properly there is a coordinated response that identifies harmful pathogens and triggers the body to fight them. The immune response involves a number of cells that work together in a way that turns on the immune response to eliminate danger. Once the danger is gone, the immune system then turns off the initial immune response to avoid harming itself. T cells play a vital role in this ‘seek and destroy’ mission, activating the immune response when identifying danger. As such, controlling T cells is a vital, yet particularly challenging and complex process. Normally, tissues express immune checkpoints – proteins that help to control the T cell response to prevent them from harming healthy cells. However, cancer cells subvert immune checkpoint proteins to protect it from a patient’s immune response, and by extension, immunotherapy. Thus, the cancer is able to evade the immune system by hiding in plain sight.

The reason CPI are so revolutionary is that they block the immune checkpoints that protect the cancer and prevent the immune system from working properly. In doing so, the patient’s immune system has a chance at eliminating developing cancer. Unfortunately, it is not a bed of roses. CPI are still not the silver bullet in cancer care that we have been hoping for. Current CPI treatments are only effective in helping about 25 percent of patients achieve remission. To be sure, a 25 percent success rate is higher than the success rate before CPI were invented, but three-quarters of patients are still left without hope. Cancer researchers are focused on finding solutions for the 75 percent of patients who are still in need of an effective therapy. There are three fundamental ways to make CPI more effective: combination therapy, using biomarkers to direct therapy and not abandoning failed CPI.

The future is with combination therapies

To use two or more anti-cancer drugs together in an attempt to stop cancer growth is not an unusual approach in cancer therapy. The principle is simple: by combining therapies that attack the cancer in different ways, we improve the likelihood that the therapies will be effective in killing the cancer. The golden age of combination chemotherapy has passed, and we are now in an area of more targeted therapies and immunotherapies. While targeted therapies are demonstrating their effectiveness, they are only beginning to be used in combination with other treatments. There is no question that combination therapy works, but we need to know where to start. For example, if a cancer is sensitive to three types of chemotherapy, three types of targeted therapy and two types of immunotherapy, there are many more than 18 different combinations of therapy. And while this is a challenge, it is one that must be met head on.

The CPI monotherapy era is coming to a close, and combination CPI is the future. Combining CPI with existing therapies to boost therapeutic efficacy will allow some of the 75 percent of those unresponsive to the CPI monotherapies, to benefit from these remarkable drugs. The problem is, what do you combine the CPI with?

Using biomarkers to make treatment choices

In the CPI era, there are two types of biomarkers. The traditional biomarker looks at the tumor to determine what therapy will be most effective. These can be genetic markers, such as KRAS gene mutations, or immunohistochemistry markers, such as ER-positive breast cancer. The clinical community has used these types of biomarkers for years. The new kid on the block is immunologic biomarkers.

It comes as no surprise that every patient’s immune system is different. Therefore, the ability of a patient to respond to an immunotherapy may depend on their immunology. Immunologic biomarkers give us the ability to determine the health of the immune system and identify which immunotherapy would be most effective.

One example of immunotherapy directed by a biomarker is trastuzumab, a common immunotherapeutic drug often used in combination with chemotherapy for HER2-positive  breast cancer. 20 percent of women who have HER2-positive breast cancer are candidates for trastuzumab therapy.  To give the drug to HER2-negative breast cancer patients is a waste of time. Using the HER2-positive tumor biomarker, we are able to identify which patients will benefit from trastuzumab, and which will not.  We are only beginning to understand how to use immunologic biomarkers that are completely independent of the tumor to predict therapeutic effects. The best example is in melanoma patients resistant to CPI ipilimumab. As expected, only 25 percent of the patients respond to monotherapy. The best predictor of resistance is the number of myeloid-derived suppressor cells (MDSC) in the patient’s blood. High numbers of MDSC predicted failure of CPI monotherapy.

With this in mind, clinicians can identify immunologic biomarkers that predict response prior to treatment, making more efficient and effective therapeutic decisions. The truth of the matter is, not all patients will benefit from immunotherapy. Put simply, the decision matrix has become more complicated in a way that will benefit patients. Before treatment, clinicians must look at tumor biomarkers and immunologic biomarkers to determine which treatment combinations to use. By cross-referencing the information available from both systems, there is a chance that better informed decisions will result in better outcomes.

CPI failures: do not abandon ship

Physicians do not use a chemotherapy twice. When a patient becomes resistant to the chemotherapy drug, the clinical team moves to other agents based on the assumption that the tumor has mutated in a way to confer resistance. But this tradition does not apply to immunotherapy. Resistance to immunotherapy does not mean you abandon the therapy, but that you add a therapy that targets the cause of the resistance.

Chemotherapy attacks cancer cells, while CPI improves the immunologic response to allow the patient’s immune cells to attack the cancer cells on their own. Put another way, if you add chemotherapy to cancer cells in a test tube, the cancer cells will die. If you add CPI to cancer cells in a test tube, nothing happens until you add immune cells to the mix. When using CPI, clinicians are focused solely on improving the immune response. This suggests that the best way to treat a patient who has failed CPI treatment is to add drugs that will improve the immune response. Using combination therapies together with CPI can make the treatment more effective.

Looking ahead

The groundwork for successful cancer care has already been laid. CPI show immense promise in bringing cancer into remission, but we have our work cut out for us. The unsolved problem in the immunotherapy space is to find effective treatments for the 75 percent of patients left behind by CPI monotherapy. Fortunately, in the near term, we do not have to find new treatments for cancer; we simply need to refine and use the therapies already in our toolbox in ways that make sense based on biology and experience. The future is bright!

About the author: Raymond J. Tesi, M.D., is CEO of INmune Bio, an immunotherapy drug development company based in La Jolla, California.

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