In 2012, I embarked on a career to harness our body's own immune response to treat and to cure cancer. In the guidance of mentor Ron Levy, I had initiated a foundation in the field of immuno-oncology, initially demonstrating that breast cancers can prevent themselves from being attacked by the immune system due to the hijacking of our normal, immune inhibitory pathways which prevent auto-immune disease. My desired contribution to the field has been clear since that time, as I realized the potential exists to re-engage the immune system, correct altered immune profiles, and to re-educate the immune response so that it could become an effective force against cancer.
It has been a personal dream to carry an idea from inception and preclinical studies to clinical trials. I presented at the ASCO Annual Meeting in 2010 (Kohrt first author) the first findings of a novel immunotherapy observed under the mentorship of Ron Levy during my doctoral work. This observation became the focus of my graduate degree both in the preclinical modeling, however also in the degree in clinical trial design and biostatistics. This led to a Phase 1 trial, first in human study, with a therapeutic developed by Pfizer. Today there are over half a dozen clinical trials I have contributed to the design of and which investigate the activity of this novel therapy. During the trial, and given my continued exposure to clinical care, and the value which this practice provides as a physician-scientist, I observed an advanced patient obtain a durable complete response which has now lasted approximately 3 y. Completely overwhelmed by this experience, and its impact on my lab's focus, my clinical practice, and a perpetual fuel to the fire of my career, during ASCO Annual Meeting, 2015, I have the pleasure of being senior author on our Phase 1 results which report an impressive 38% response rate across the cohort of refractory patients. This series of events, from concept discovery, preclinical validation, first-in-human investigation, and further clinical testing toward registration represents the paradigm and concrete evidence from which I have gained insights to providing teaching and mentorship on, impacts the population I see and referrals I obtain in clinical care, scholarship for continued research and novel target discovery, and finally, my reputation along with the duties it brings, are based on this opportunity and provided recognition in the field above my expectations at this stage in my career.
The concept for this work is improvement of the effectiveness of the monoclonal antibodies currently used to treat cancer, such as rituximab, trastuzumab, and cetuximab, which target lymphoma, breast cancer, and colon cancer and head-and-neck cancer, respectively. These monoclonal antibodies work by recruiting natural killer (NK) cells that are part of the innate immune system. These antibodies seek out and bind to their respective tumor targets, and the NK cells then kill the cancer cells that are coated by the antibodies. I have found that a second antibody against a target called CD137 can enhance the killing of tumor cells by stimulating the NK cells. In regards to my scholarly accomplishments, this work has been presented in oral form at our society's annual meetings, provided the support for numerous filed and issued patents with Stanford University, and over a dozen publications including the results in lymphoma were published in Blood, and subsequently in the Journal of Clinical Investigation for breast cancer, and Journal of Clinical Investigation for EGFR-expressing tumors. These results have been recognized by the Department of Defense Breast Cancer Research Program, Damon Runyon Foundation, American Society of Hematology and Leukemia and Lymphoma Society. The field has recognized these results in my selection to provide the “Hot Topics” Lecture at our annual meeting, numerous guest-lectures around the world, election to the co-Director position of the Cancer Immunotherapy Trials Network, editorial board of 2 high-quality journals, study section positions at the National Institutes of Health and Department of Defense, scientific committee positions for the American Society of Hematology, American Society of Clinical Oncology, American Association of Cancer Research, and Society for Immunotherapy of Cancer.
Translating such basic observations into treatments for patients with cancer requires a thorough knowledge of clinical trial design and biostatistics – areas in which I focus my teaching and mentorship – and provides an outlet for my desire to have continued clinical involvement. Given my tailored PhD training to include coursework and practical experience in clinical research under the mentorship of Dr. Phillip Lavori, Chair of Health Research and Policy and the Director of Biostatistics for the Stanford Cancer Center, I continue to mentor and teach at the Stanford Center for Clinical and Translational Education and Research Course which I began in 2009 and have continued through 2015, as well as annually lecturing in Health Research and Policy (HRP). My teaching and mentoring efforts in HRP bring a unique and practical experience to the students as the prior conceptual therapeutic approach, today is a part of numerous clinical trials, all either investigator-initiated or designed with my guidance and the financial support from foundations or pharmaceuticals. As a part of my responsibility as a physician-scientist, I am committed to providing teaching and mentorship also to the younger generation. This has included hosting approximately a dozen high school students in the laboratory over 3 y in order to provide exposure to the career lifestyle of a physician-scientist. This provides me with personal reward as I am able to follow their careers unfold, and although my lab is too young to see where their aspirations will take my mentees, I continue to believe that this opportunity is a gift and a privilege as Stanford faculty.
About Holbrook Kohrt. Dr. Kohrt investigated novel therapeutic strategies to enhance anti-tumor immunity, including the discovery of checkpoint inhibitors and cancer vaccine strategies. Dr. Kohrt was the co-director of the Cancer Immunotherapy Trials Network. As a faculty member at Stanford, Dr. Kohrt was developing novel vaccine strategies which induce tumor antigen-specific immunity and improve graft-versus-tumor reactions without exacerbation of graft-vs.-host disease. His studies included efforts to identify and develop immunomodulatory antibodies targeting immune effector cells subsets, such as natural killer cells, which enhance the anti-tumor activity of tumor-targeting antibodies. Dr. Kohrt was a leader in the clinical development of agents including IL-15, IL-7, anti-CTLA-4, anti- CD137, anti-PD-1, anti-PD-L1, BTK inhibitors, and HPV-targeted and WT1-targeted vaccines. He attended Stanford University Medical School, where he trained in Internal Medicine through the Clinical Investigator Pathway and completed a fellowship in Hematology and Oncology at Stanford with a research focus on preclinical models for novel immunomodulatory antibodies. During this time, he developed, validated, and nationally implemented a nomogram for risk prediction in early stage breast cancer. Dr. Kohrt received his PhD in clinical trial design, biostatistics, and tumor immunology from Stanford under mentor Ron Levy with a thesis including the first report of an agonistic monoclonal antibody capable of enhancing the efficacy of tumor-targeting therapeutics. This antibody is now in five Phase 1/2 clinical trials. Dr. Kohrt passed away on 24 February 2016 from complications of hemophilia.
As I follow a physician-scientist path, I am constantly battling the balance push-pull between the clinic and laboratory. Though discovery of novel immune modulators, my laboratory is currently investigating its fourth novel immune checkpoint, has potential clinical impact well beyond my own practice, it is in the moments that I can offer a patient whom I have been providing her oncology care, a new treatment option that has no risk of nausea, vomiting, numbness or tingling, infection or hair loss – in those moments, and when such a patient responds to the trial therapy – that the greatest impact is made on my clinical career. This effort has rapidly matured and these observations provide the needed insight into clinical trial design. Based on my efforts designing and implementing the first series of clinical trials testing of CD137, I have been offered opportunities to guide the drug development of colleagues in the field and both small and large biopharma. As a major contributor to this, I have been selected to co-Direct the Cancer Immunotherapy Trials Network (CITN), and as such I have written and implemented 6 multi-center clinical trials. Fortunately, this leadership role has fostered sample acquisition for biomarker analysis in my laboratory that would not otherwise be possible. The numerous hours of paperwork and administrative tasks associated with this role, are justified by the weekly conference calls during which I can hear if patients are benefiting from the discoveries made in my laboratory.
To allow critical assessment of my contribution to the Stanford community, I have outlined 4 goals of my career as a translational researcher in cancer immunotherapy. This highlights my future plans in research, the foreseeable clinical translation of such, and the arears on which I will focus my teaching and mentorship.