tumors, often due to the same immunosuppressive tumor microenvironment usually associated with the inability of checkpoint inhibitors to be efficacious. Most excitingly, killer CAR T cell therapies are now being tested in autoimmune diseases to eliminate a subset of autoreactive B cells and the production of pathogenic autoantibodies, for example, in lupus nephritis patients.
How are we going beyond a single-disease, single-treatment approach? The immune system is a fundamental platform organ in the body. It ’ s liquid, exists in all tissues and spends all its time surveilling. Many diseases are caused by inflammation and the inability to effectively and consistently recalibrate the immune imbalance, resulting in the manifestation of autoimmune diseases, cancer or inflammatory diseases like Alzheimer ’ s or amyotrophic lateral sclerosis ( ALS ) .
“ The immune system is a systemic and broad sentinel for tissue dysregulation. ”
The immune system has incredible plasticity and multifaceted activity. The same drug should work across multiple diseases if given to the right patients at the right time. We don ’ t need to recreate the wheel but tailor our therapies to a particular disease based on a common mechanism of action. It ’ s about tweaking the class of drugs to work specifically at disease sites while limiting off-target activity. With cancer, can we pinpoint which checkpoints the immune system is using to shut down anti-tumor immunity? Can we make the treatments work for prostate cancer versus melanoma, for instance, or will one drug work for all? Diseases won ’ t be defined by the tissue they target but by the biological pathways they use. In the future, we will likely develop drugs that target common pathways that affect multiple diseases and core activities throughout the immune system independent of the tissue affected. Autoimmune diabetes, rheumatoid arthritis and some neurological diseases, including multiple sclerosis, have common pathways. If we can develop a drug for those common pathways, the same drug should work in various settings.
What therapies or real-world solutions have emerged from your research that you ’ re most proud of or excited about? My career has followed a mantra with three philosophies, either by serendipity or intention.
“ Do kick-ass science, collaborate like hell and make a difference. ”
The first example I mentioned was the development of a monoclonal antibody to delay and, in some cases, prevent the development of T1D. It ’ s now given to people before they develop clinical disease and require insulin injections. Ten years out, some patients who received a single course of teplizumab still haven ’ t developed T1D. This effort started in the 1980s. The trials and tribulations were frustrating, but we finally got over the finish line in 2022. It would not have been possible without the early science and great collaborative efforts with Dr. Kevan Herold and others. Hopefully, teplizumab will have a significant impact on T1D and other autoimmune diseases. Another example of great science, collaboration and impact was our discovery of the first checkpoints and the development of the first antagonists to treat cancers. This work included efforts in both academia and industry. I was fortunate to be involved early and recently as CEO of the Parker Institute for Cancer Immunotherapy, a consortium of scientists who pioneered this field. The latest example is the work that led to the founding of Sonoma Bio and its novel strategy for developing Treg-based cell therapies. The discovery by our co-founders of the key molecular switch that turned a small subset of T cells into Tregs has led to a new class of drugs that might be useful for multiple diseases and may lead to cures as long-lived drugs. Decades from now, I hope people look at cell therapy and recognize how transformative it is.
What progress have we made with autoimmune disease? Immunotherapy in autoimmunity is further behind cancer because autoimmune diseases are generally not lethal. There is less focus on curing autoimmune diseases rather than dealing with their symptoms. In many conditions, while you are tackling an
unhealthy and unhappy lifestyle, you ’ ll be alive. Secondly, we have these sledgehammer-like drugs, including steroids, immunosuppressants and monoclonal antibodies like anti-TNF. Thirdly, the field has not been as organized, and there isn ’ t the same sense of commonality in disease processes. In the last five to ten years, we ’ ve realized we should treat autoimmunity like cancer. We need therapies that can profoundly change the patient ’ s biology, give durable cures and tackle the fundamental processes responsible for the disease, not just its symptoms. The field is changing, and different stakeholders are coming together and recognizing the possibilities. The science around autoimmunity has become more creative, and technology has helped us understand the core biology. We now have
Through his current venture, Sonoma Biotherapeutics, Dr. Bluestone has been at the forefront of developing new insights to control the immune response and create engineered regulatory T cell therapies to treat autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease
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