Rosenberg's Many Breakthroughs Fueled by Passion and Hard Work

Steven A. Rosenberg, MD, PhD

Steven Rosenberg always knew that he wanted to become a physician scientist, and he quickly advanced to become the chief of surgery at the National Cancer Institute (NCI) at just 34 years of age.

Throughout his years at the NCI, he has pioneered cell transfer therapies in patients with a variety of widespread metastatic cancers and saved countless lives in the process.

Rosenberg credits his success in cancer therapies to the hard work and focus instilled in him at a very young age.

Early Influences

Rosenberg notes, “There are two properties that I think are associated with ability to succeed in science, and especially in the kind of translational science that I’m doing—trying to apply modern science to improve the care of cancer patients, which is what I’ve spent my entire career trying to do. You have to be passionate about what you do and you have to be highly focused in what you do.” He is certainly both of these things.Rosenberg was introduced to the importance of hard work early on. As a young boy, his father owned a string of luncheonettes. Rosenberg wrote in his biographical work The Transformed Cell, “My parents’ influence on me was profound but subtle."

"No matter how early I got up in the morning, my father had already left for work. And my own experience in the luncheonette taught me an enormous amount about life, about how difficult it could be—not only my father’s but those of his more Runyonesque customers—and about how hard one must work to accomplish anything.”

From an early age, Rosenberg dreamed of becoming a doctor. He writes, “I recall my first ambition, aside from becoming a cowboy, was to become a doctor and a scientist.

They were heroes to me. I often cut out newspaper articles about the exploits of a scientist or a doctor, kept them in a scrapbook, and daydreamed about them.”

A Scientific Goal

Rosenberg credits his older brother, who is a surgeon and scientist, with mentoring him when he was a young boy. “My brother…gave me books, usually about science. He was then studying medicine and was my role model. He believed that if he gave me enough stimulation, something would excite me, something would click. He was right,” Rosenberg recalled.Rosenberg excelled in academics throughout his early years. While still in high school, he laid out his plan to become a physician-scientist. Rosenberg attended a 6-year program from 1957 to 1964 at Johns Hopkins University, during which he earned both his bachelor’s degree and his MD, and completed a surgical internship at Peter Bent Brigham Hospital, which later became part of Brigham and Women’s Hospital.

However, he did not stop there. He still required training to become the scientist he dreamed about.

Rosenberg writes, “From my very first interest in medicine as a boy, I wanted to combine research and clinical work. I intended to master medicine and probe deeply into the nature of disease. The goal never varied.” To achieve this goal, Rosenberg worked on his PhD in biophysics after his medical training, from 1964 to 1968, at Harvard University.

Following his graduate research at Harvard, Rosenberg returned to Peter Bent Brigham Hospital as a surgical resident from 1968 to 1969.

Rise to Chief of Surgery

However, he soon grew restless and took a leave of absence to return to Harvard to perform immunological research from 1969 to 1970.After a year at Harvard as a research fellow, Rosenberg left for his first position at the NCI as a clinical associate in the Immunology Branch.

He recalls that it was exciting to be with the NCI, where he was able to work with some of the most talented scientists in the country. However, he missed medicine and taking part in the clinical care of patients. To fulfill this desire, he completed a surgical residency at Peter Bent Brigham Hospital, during which he was able to continue performing his research.

After two years spent completing his surgical residency, Rosenberg turned down the offer of the chief of surgery position at the Dana-Farber Cancer Institute to return to the NCI. Rather, he decided to accept a position as the chief of surgery at the NCI in order to continue both his research and his patient care in a fast-paced, fostering environment.

Rosenberg writes of his decision that the “NCI had a mixture of laboratory and clinical resources that could not be duplicated anywhere else in the world.”

Fighting a Natural Enemy

Thus, in 1974 at just 34 years of age, Rosenberg become the chief of surgery at the prestigious NCI, an impressive feat for anyone, but even more so for a young man who only recently had completed his medical training. Rosenberg has remained in this position for nearly 40 years, and still works from 7:00 am to 7:00 pm every day, spending about half of his time guiding laboratory research, about 40% of his time on the clinical care of patients, and the remaining 10% of time performing his administrative responsibilities.Rosenberg’s research had always focused on cancer—from studying how cells differentiate self from non-self during his PhD research, to identifying tumor antigens during his first stint at the NCI. Rosenberg writes, “In the lab and in my residency, my focus was on cancer. …It was my enemy, and I wanted to know my enemy and grow intimate with it.”

Rosenberg recalls what drove him to work so intricately with cancer. “To me, [cancer] resembles a holocaust. It is a disease you can hate. Other diseases, including heart disease, tend to attack older people, but cancer kills randomly, and it kills young.”

Rosenberg was intrigued after examining a patient who was cured of cancer without any treatment.

After trying—and failing—to cure others with cancer using blood from the cured patient, Rosenberg was determined to use the innate ability of the body’s own cells to destroy cancer cells. The experiments, observations, and successful (and some not so successful) treatments that followed resulted in his becoming a clear leader in the cancer immunotherapy field.

In 1985, Rosenberg showed for the first time that the administration of interleukin-2 (IL-2) to patients could aid in the regression of established invasive human cancers, which led to the FDA approval of this therapy in patients with metastatic renal carcinoma in 1992 and metastatic melanoma in 1998. Rosenberg also found that IL-2 can support the growth of cancer-fighting human lymphocytes in the laboratory, and this work led to the characterization of multiple human cancer antigens.

Adoptive cell therapy (ACT)—a technique pioneered by Rosenberg that involves the transfusion of T lymphocytes—has been touted as the best direct evidence that the immune system is capable of curing patients with cancer. Indeed, growing large numbers of these tumor- infiltrating lymphocytes (TILs) in vitro and activating them ex vivo before infusion has proved successful in some patients with metastatic melanoma, even those with extensive tumor burdens who have been heavily pretreated.

Rosenberg also pioneered the groundbreaking yet controversial technique involving the administration of genetically modified lymphocytes to treat metastatic melanoma. In his biographical book, Rosenberg recalls his excitement prior to administering the first treatment with genetically modified cells: “Infusing gene-modified TIL into [the patient] would open a door in medicine. The possibilities of gene therapy are extraordinary.

Manipulating genes creates an entirely new and almost unlimited way to deal with disease that could change the way medicine is practiced in the 21st century.”

Exciting Developments

In this technique, lymphocytes are genetically engineered to express T-cell receptors (TCRs) that recognize tumor antigens or to express other molecules that increase antitumor activity. Using genes encoding TCRs that recognized the melanoma-melanocyte differentiating antigens MART1 and gp1000, Rosenberg and his colleagues provided the first example of the successful treatment of patients with genetically modified lymphocytes; up to 30% of patients who received cells containing these TCRs had regressions of their cancers.Rosenberg has tremendously advanced the area of ACT, opening the door for several new and exciting cancer treatments. He notes, “When I came to the NCI, I started a whole new area of research trying to develop these cell transfer therapies, which are now becoming a very significant part of modern oncology…. This whole area of cell transfer therapy is going to be a very important part of cancer treatment in the future.”

“Now that we can genetically modify lymphocytes and give them new properties that they haven’t normally had or that lymphocytes haven’t had in the course of the evolution of the immune system, we have enormous flexibility in terms of manipulating these immune reactions. So we’re working daily on ways to genetically modify lymphocytes to have better and more effective antitumor properties.”

Rosenberg notes, “I have over the door of one of my labs a modification of a saying, I think it was originally by Louis Pasteur who said, ‘Chance favors the prepared mind.’ But I modified that to be, ‘Chance favors the prepared mind, but only when the mind is at work.’”

And based on Rosenberg’s impressive list of accomplishments and the numerous lives he has helped to save, we can safely assume that Rosenberg’s mind has been hard at work.

Lauding Rosenberg’s Milestones: “Bedside to Bench and Back Again”

James N. Kochenderfer, MD

Investigator Experimental Transplantation and Immunology Branch Center for Cancer Research National Cancer Institute Bethesda, MD

“Over the past 40 years, Steven Rosenberg has been the leading investigator in the field of translational research on cellular therapies for cancer. His contributions are notable in many areas including isolation of tumor infiltrating lymphocytes, application of gene therapy to cancer immunotherapy, and most recently, elucidation of the importance of mutated proteins as tumor-associated antigens. Dr Rosenberg is also notable for his ability to focus scientific work that ends up having beneficial effects in patients and for his superb ability at mentoring younger investigators.”

Christopher A. Klebanoff, MD

Assistant Clinical Investigator Surgery Branch Center for Cancer Research National Cancer Institute Bethesda, MD

“Dr Rosenberg’s work has had an unbelievably positive impact on the treatment of advanced melanoma. In a true tour de force of ‘bedside to bench and back again’ research beginning first with the development of interleukin-2 (IL-2), he and his team at the National Cancer Institute (NCI) were the first to demonstrate that the immune system could be used to cure a subset of patients with previously incurable disease. The principles and techniques first learned with IL-2 have been built upon and extended to help develop other potent immunotherapies. These have included immune checkpoint blockade, adoptive T-cell therapy of tumor infiltrating lymphocytes (TIL), and most recently, adoptive transfer of genetically redirected T cells. “For melanoma and renal cell carcinoma, the work of Dr Rosenberg and the NCI Surgery Branch changed the standard of care for patients with a good performance status. The group has seen remarkable and durable complete responses in response to IL-2 and anti-CTLA4— based immunotherapies lasting, in some cases, decades. These findings have now been confirmed and replicated in institutions around the United States and world.

“Dr Rosenberg’s work with the adoptive transfer of tumor-reactive T cells has demonstrated that this mode of immunotherapy is the most consistent means of delivering complete responses in melanoma patients. Depending on the clinical trial, up to 40% of patients with melanoma have obtained complete responses following adoptive transfer of TILs. This high response rate is true even if patients had failed other forms of immunotherapy, including IL-2, anti-CTLA4, and even anti-PD1/anti-PDL1.

“More recently, his groundbreaking work with genetically engineering peripheral blood T cells to express a chimeric antigen receptor (CAR) targeting CD19 have also demonstrated impressively high complete response rates in lymphoma and leukemia patients who had previously failed standard therapies. Although still experimental, it is highly likely that anti-CD19 CAR therapies will enter mainstream clinical practice in the coming years. Perhaps most exciting is his recent work demonstrating that adoptive transfer of TIL cells that recognize patient-specific mutations can cause disease regression in common epithelial cancers, including the notoriously recalcitrant cholangiocarcinoma. These findings open the possibility that highly effective immunotherapies might be successfully applied to patients with more common tumor types in the near future.

“I’ve learned a great deal from Dr Rosenberg. I know he feels a deep and personal sense of urgency to make progress that can hopefully benefit our patients. That feeling of urgency and focus becomes shared by those who work with him. Through personal example, he has taught that the best means of making progress is to be rigorous, self-critical, and to ask the most important and impactful questions possible. This advice has inspired and influenced myself and several generations of researchers and clinicians throughout the world.”

DR ROSENBERG’S SELECTED PAPERS

• Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial [published online October 10, 2014]. Lancet. doi:10.1016/S0140-6736(14)61403-3.
• Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor [published online August 25, 2014]. J Clin Oncol. pii:JCO.2014.56.2025.
• Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 364:2119-2127, 2011.
• Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19 [published online July 28, 2010]. Blood. 2010;116(20):4099-4102.
• Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):5233-5239.
• Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;314(5796):126-129.
• Dudley ME, Wunderlich JR, Robbins PY, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298(5594):850-854.
• Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(2):2105-2116.
• Fraker DL, Alexander HR, Andrich M, Rosenberg SA. Treatment of patients with metastatic melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Oncol. 1996;14(2):479-489.
• Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumorinfiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma: a preliminary report. N Engl J Med. 1988;319(25):1676-1680.
• Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986;233(4770):1318-1321.
• Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313(23):1485-1492.