Unlocking the Mysteries of the Immune System

Ever since he was struck with an autoimmune disease at 8 years of age, physician-scientist William Grossman has been driven to understand disorders in the immune system. Now, at Genentech, he is working to develop the next generation of drugs to use immunotherapy to target cancer cells.

I became interested in medicine and immune diseases early on, unfortunately as a patient. When I was eight years old, I was hospitalized for months because of an undiagnosed immune disease that caused me severe arthritis, difficulties walking, fevers, headaches, and weight loss. I spent endless hours being poked, prodded, and stuck with IV needles. Fortunately, I got better, but was left with the certain and lasting knowledge that medicine was filled with unknowns waiting to be discovered, and that we needed new ways of diagnosing and compassionately treating patients. I wrote a paper in second grade where I said I wanted to become a physician scientist—a paper my mom gave me when I set off for medical school.

I went into the field of immunology because I wanted to bridge the sciences of virology, immunology, and cancer biology. I quickly learned that there was still relatively little known about what genetic defects resulted in human immunological disorders, many of which predisposed individuals to cancer. I did a fellowship in hematology/oncology/bone marrow transplantation, where I started concentrating on clinical immunological deficiencies at St. Louis Children’s Hospital and found my calling. During my time there, two patients grabbed my attention, which led me down my academic scientific pathway. One child had developed multiple, severe, life-threatening autoimmune disorders from birth, ultimately requiring a Bone Marrow Transplant. The second child also had problems with clearing essentially all viruses he encountered. The first child became one of the first patients described to have a deficiency of the FOXP3 gene, which has since become known as the master regulatory gene required for T regulatory cell development. The second child had a deficiency in in a subunit of the IL-2 receptor, CD25, which was subsequently found to be a marker and essential receptor for human T regulatory cell function and development.

At the time, it was somewhat taboo to work on this new field of T regulatory cells, which were essentially a rediscovery of an older known subset of immune cells called “suppressor cells.” But observing these human defects and their evolution firsthand led my colleagues (Dr. Talal Chatilla and Dr. James Verbsky) and me to understand more about how this very small subset of T cells functioned and ultimately controlled both good (viral responses) and bad (autoimmune) immune responses.

My colleagues and I wanted to know how human T regulatory cells actually function to regulate not just autoimmune responses but also other regulatory diseases, such as cancer. To that end, we were developing various mouse models to confirm our human observations and going back to mouse models again to understand the pathways. Then we wanted to find ways to monitor those pathways to address them clinically–either enhancing T regulatory cells for patients who have autoimmune problems or targeting T regulatory cells for patients who had cancer.

After spending a few more years in academics, I wanted to apply what I had been learning at a larger scale, and started evaluating how to manipulate the immune system into attacking cancer cells. Now, 20 years of research are finally paying off in concrete drug development.

After spending a few more years in academics, I wanted to apply what I had been learning at a larger scale, and started evaluating how to manipulate the immune system into attacking cancer cells. Now, 20 years of research are finally paying off in concrete drug development.

We are on the brink of a lot of advances in treating cancers, with the first wave of immunotherapy agents impacting patients across many cancer types, some offering more time, and some looking at long-term potentials for remission. We’ve seen an incredible leap, but it’s still just a small fraction of people—10 to 30%--who have really incredible responses to immunotherapy. I’ve come to Genentech to work on developing the next generation of cancer immunotherapy drugs and combinations. With Genentech and Roche’s commitment to science, we are well positioned to drive the next generation of therapies, potentially optimizing our response rate and potential cure rate for patients across many different locations.

Having been in academics and other companies, one of the aspects of Genentech that is important to me is the culture, where the larger team has the science and patient at heart. This environment where everyone is collaborating across all functions is unique with respect to other places I’ve worked. There’s a mindset that minimizes barriers between various disciplines so that people are working in a cross-functional, very collaborative way. At every meeting, it comes out loud and clear that everyone is working toward the same common goal of “Doing now what patients need next.”

I continue to be humbled every day about the complexities of the immune system and understanding how to find better therapies and approaches to treating cancer patients. Even so, I’m optimistic that we will unlock and embrace true personalized medicine approaches in the future, and shift the paradigm of how we develop oncology drugs for the benefit and compassionate care of our patients.