Immunotherapy for Cancer: Why Fight Only Half the Battle?

Immunotherapy has made incredible strides over the past several years. Studies have shown it to be effective in treating many diseases that attack the immune system, such as multiple sclerosis, rheumatoid arthritis and psoriasis, and (most recently) cancer. With the latter in particular, although immunotherapy is proving to be effective for some patients, most do not respond to the treatment. It is time for the industry to reevaluate how it approaches immunotherapy especially for treatment-resistant patients.

In the fight against cancer, the most powerful tool in the clinic is the human immune system. When a person’s immune system is fully functional, cancer rarely occurs. Even when it does occur and gets treated, a fully functional immune system will fight off the residual disease, thus preventing relapse. However, when the immune system is compromised, as often it is in oncology patients, it is unable to control the cancer as it continues to grow. To beat cancer, a patient’s immune system needs to be restored to its fully functional state. By bolstering a failing immune system and optimizing immunologic health, we give patients the best chance at beating this deadly disease.

Two Sides to the Story: The problem with many companies’ approach to immunotherapy in treating cancer is that they address only one half of the immune system. The human immune system is made up of innate and adaptive immune parts, which work together to maintain physical health and fight disease. Our understanding of this sophisticated system has evolved over the years, but we have a lot more yet to grasp. And understand it we must if we want to be successful in helping patients survive and thrive.

Most immunotherapies for cancer — e.g., checkpoint inhibitors, chimeric-antigen receptor T (CAR-T) cell therapies, and vaccines — target only one half of the immune system: the adaptive immune system. This approach completely ignores the critical role that the innate immune system plays. The innate immune system is our first line of defense against both infection and cancer. In the past, it was believed simply to keep bacteria, parasites, viruses, and other microbes at bay. The major function of the innate immune system was thought to be identifying and removing foreign substances, recruiting immune cells to the sites of infection, and activating the adaptive immune system. Until recently, we believed that the role of the innate immune system was to provide responses to simple problems through short-term means of protection.

The Other Side
The adaptive immune system is an immunologist’s dream, offering a durable pathogen-specific immune response. The adaptive immune system is responsible for killing pathogens and developing an immunological “memory” against future invasion. And although both sides of the immune system have the ability to distinguish friend from foe (self from nonself), they do so in different ways: The innate immune system makes a snap decision and goes on the attack in minutes. The adaptive immune system is slower to respond — and arguably, more precise in its actions — but such a response is not always without problems. Although the innate immune system never attacks the wrong thing, the adaptive immune system can err and attack the patient’s own cells, which leads to autoimmune diseases.

As our understanding of the immune system continues to evolve, immunotherapeutic strategies to treat cancer can advance along with it. Today, we understand better that both arms of the immune system work together to keep a human body healthy — and more important, how we need to harness the power of both sides of the immune system in treating cancer. By focusing immunotherapy treatments solely on the adaptive side of the immune system while ignoring the innate side, we are hindering a patient’s natural ability to fight disease. Against such a background, we should not be surprised to see that most immunotherapies developed so far are not effective in all patients. If we want to improve cancer patients’ responses to immunotherapy, we need to add treatment strategies that recruit the innate immune system to the fight.

Current immunotherapeutic strategies for cancer treat just half the problem in another way as well: The tumor microenvironment (TME) is filled with immunologically active cells that protect tumors from a patient’s immune system and, by extension, from immunotherapy. Those protector cells are identified by an alphabet soup of acronyms: MDSCs (myeloid-derived suppressor cells), Tregs (regulatory T cells), TAMs (tumor-associated macrophages), and CAFs (cancer-associated fibroblasts). Originally tasked with attacking tumors, these cells are subverted by cancer to protect it instead — and protect it they do.

Protector cells working in concert with a tumor, fill the TME with cytokines, chemokines, and growth factors that place an immunosuppressive shield around it, protecting it from immunologic attack, promoting tumor growth, de-differentiating and facilitating metastases. Thus the effector cells — the T and natural killer (NK) cells that are tasked with killing cancer — must run a gauntlet of protector cells committed to subverting their work. Because a majority of cancer patients have progressive disease that leads to morbidity, it appears that those protector cells win more often than not.

Pulling It All Together
Put simply, effective immunotherapy for cancer must deal with both sides of the cancer immunology equation: effector and protector. Targeting protector cells should enable effector cells to attack tumors more successfully. Most immunotherapies for cancer are designed to promote effector-cell function by making T and NK cells better at killing cancer. However, the most powerful T cell in the world will be ineffective against an immunologically competent TME. For T and NK cells to be effective, the immunosuppressive shield surrounding a tumor must be breached. And that requires immunotherapy targeting a whole new group of cells: MDSCs, TAMs, Tregs, and CAFs. Such therapies do not yet exist.

To be truly effective, immunotherapies must leverage the synergy of the adaptive and innate immune systems involved in the immune response to cancer. But no single immunotherapy can fill all of these roles. Consequently, the future of cancer therapy will be in combination immunotherapies — and very likely, in drug development companies working together to share their expertise. Today, when an oncologist discusses combination therapy for cancer, he or she is referring to combining different immunotherapeutic agents or combining chemotherapy with immunotherapy. Future combination therapies will include at least two immunotherapies targeting all sides of the immune response to cancer. Is it possible that those combination therapies will be able to exclude cytotoxic chemotherapy? We can only hope so.

Raymond J. Tesi, MD, is chief executive and chief marketing officer at INmune Bio, 1224 Prospect Street, Suite 150, La Jolla, CA 92037; 1-858-964-3720; [email protected]; www.inmunebio.com. Dr. Tesi received his medical degree from Washington University School of Medicine in 1982, and he has been an academic transplant surgeon and a fellow of the American College of Surgery.