Immunotherapy Innovator Jedd Wolchok Honored

Jedd D. Wolchok, MD, PhD

Before the Internet and global interconnectedness, advancements in science and medicine were usually slow and incremental, with research and findings conducted by solo researchers and shared over time.

“The idea of team science is something that evolved quite a lot in the past few years. It used to be that this idea of large groups was more uncommon than it is now. It has become quite the norm to assemble large groups to solve problems more quickly, and I’m all for it,” said Jedd D. Wolchok, MD, PhD, the recipient of the 2014 Melanoma Giants of Cancer Care® award. Wolchok is chief, Melanoma and Immunotherapeutics Service, and Lloyd J. Old Chair for Clinical Investigation at the Memorial Sloan Kettering Cancer Center in New York City.

The collaborative effort, in which all the researchers involved play a role to accomplish a common goal, can only succeed with a keen understanding of interpersonal dynamics. For Wolchok, this kind of group dynamic is well demonstrated in a favorite book, American Prometheus, the classic biography of J. Robert Oppenheimer written by Martin J. Sherwin and Kai Bird. The coming together of colleagues from multiple disciplines toward a vital and common goal was evident in the Manhattan Project and subsequently in the efforts to find more peaceful and controlled applications of the atomic science.

Once a group comes together, good decisions can be made based on logic, reasoning, and instinct, with the good of a group sharply in focus. Approaching problems analytically, logically, and with calmness has gotten Wolchok this far—and for patients with melanoma that is quite far indeed.

Wolchok is among the team of scientists who are developing anticancer strategies aimed at manipulating the body’s immune checkpoints, thus promoting a more robust activation of T cell responses to cancerous cells. He served as the principal investigator on the pivotal clinical trial that led to the FDA’s 2011 approval of ipilimumab (Yervoy), an anti-CTLA-4 monoclonal antibody that is the first agent to employ the immune checkpoint blockade strategy in any tumor type.

Summers at Memorial Sloan Kettering

The death of a loved one is often the inspiration for a budding scientist to pursue a career in cancer research. In Wolchok’s case, the death was his grandmother’s—she had pancreatic cancer—but his passion for research was gradual, fueled by the summers away from Princeton University, where he completed his undergraduate studies.

“By the time I finished college, the research experiences I had during summer breaks while working at Memorial Sloan Kettering in the translational laboratories fueled my interest,” said Wolchok. “I saw incredible possibilities that existed in terms of moving research from the laboratory to the clinic, and taking those successes and failures back to the laboratory for refinement. That was a very inspiring set of experiences for me.”

Wolchok was mentored by Lloyd J. Old, MD, considered the father of modern tumor immunology, and Alan N. Houghton, MD. The Houghton Laboratory brings together a mix of molecular biologists, immunologists, medical oncologists, and surgeons. The participants understand that this type of environment encourages cross-fertilization of scientists and clinical investigators. The laboratory, which Wolchok now heads, is interested in two fundamental questions: “How does the immune system recognize cancer, particularly mutations?” and, “How does the immune system reject cancer?”

Unraveling the Response Puzzle

Wolchok considers it an incredible honor to continue his mentors’ work, although he would much rather have Houghton actively engaged in the ongoing research. Houghton suffers from amyotrophic lateral sclerosis and Lloyd Old died from prostate cancer in 2011.

Persistence in Immunotherapy Research

Until about three years ago, there were no medications that improved survival in patients with metastatic melanoma. Immunotherapies were considered complicated and marginal. They were only administered at a few cancer centers. In addition, immunotherapy’s low success rate and low tolerability, with only otherwise healthy patients as candidates, made it a difficult clinical treatment to pursue.

“I think one had to be persistent in both immunotherapy and in melanoma treatment because there was so much failure until recently,” said Wolchok. “There were so many trials that did not meet expectations. There was so much questioning of the validity of the underlying science because of that.” But he pointed out that persistence in this field has paid off. Researchers stuck with it until agents were developed that could modulate the immune system in a potent enough manner to impact tumor growth.

“In my mind, the science was never in question. Because many ideas were explored in the clinic, but failed to meet expectations, there was a characterization of the field as being speculative in nature. That was a challenge,” said Wolchok.

He recalled that much of the focus of discussions with patients was about the hope and promise of clinical trials. Following advances in the understanding of melanoma biology and tumor immunology, there have been seven new therapies approved for the treatment of melanoma since 2011, including ipilimumab, two anti-PD-1 antibodies, and three targeted agents. “The tenor of those patient conversations now has some concrete source of hope,” Wolchok said.

The deployment of immunotherapy agents in clinical trials and in practice has prompted a new way of looking at how patients respond to therapy. Wolchok discussed one patient who participated in a phase II trial involving ipilimumab in which an initial set of imaging scans suggested that the disease had grown markedly worse since treatment began.

“Yet the patient told me that he felt better. It caused my colleagues to rethink the way we judge the clinical efficacy of this kind of cancer therapy,” said Wolchok. It also gave him a newfound respect for the complex biology that exists between the patient and the tumor, and the fact that when treating the immune system, the patient’s condition might not improve on schedule.

“That patient had another set of imaging scans performed 2 months later with no further therapy and showed that almost all the disease had regressed,” Wolchok said. In the official documents filed for the trial with the FDA, that patient was scored as a drug failure. “In that instance, I realized that we need to rethink the way we judge the clinical activity of novel anticancer therapies.

“My lab research is very linked to clinical care, either in forming new clinical trials or helping to understand current clinical trials.There is nothing that can possibly be more thrilling than to help a patient improve the state of his or her health. That is the number one thing that buoys me but there is a lot of laboratory science that feeds forward and feeds back from that,” said Wolchok.

The Collaborative Effort

Wolchok values the collaborative effort— whether it’s working on a vexing problem in the laboratory with many team members or mastering a challenging musical piece in the Brooklyn Wind Symphony where he plays tuba. He pointed out that “there aren’t many career opportunities for professional tuba players,” but even if there were, he still would not consider a change in career paths.

The Giants of Cancer Care award is given for individual accomplishments, but Wolchok understands that success stems from a team effort and from others who have come before. When accepting the award during a reception last year in Chicago, he noted that some people in attendance were “mentors and role models to me,” such as James P. Allison, PhD, who won the 2014 Giants award for scientific advances in recognition of his work in elucidating the checkpoint blockade strategy. “Having a former fellow from Memorial Sloan Kettering, Dr Jason Luke, present me with the award—I felt acknowledged in a 360-degree way,” said Wolchok. “That was very meaningful to me.”

As Humble as He is Accomplished

David F. McDermott, MDAssociate ProfessorDepartment of Medicine Harvard Medical SchoolBoston, MA

“There are some people (eg, Oprah, Michael) who make such large contributions to their field that they can be recognized by only their first name. An immunotherapy pioneer, Dr Wolchok and his team are identifying new targets, developing predictive bio- markers, and uncovering mechanisms of resistance.

“His team’s work will ensure the rational application of an approach that can dramatically improve patient outcomes. He is an investigator who is as humble as he is accomplished. We all want to be more ‘like Jedd.’”

Michael A. Postow, MDAssistant Attending PhysicianMelanoma-Sarcoma Oncology ServiceMemorial Sloan Kettering Cancer CenterNew York, NY

“I met Dr Wolchok when I was a first-year medical student. At that impressionable early stage of medical training, Dr Wolchok’s compassionate patient care and enthusiasm for his research in immunotherapy profoundly affected my decision to become an oncologist.

“Dr Wolchok has taught the world how to treat patients with new immunotherapies, particularly antibodies that block CTLA-4 (ipilimumab) and PD-1 (nivolumab and pembrolizumab). The observations he has made in his clinic have led to remarkable advances in our understanding of how these therapies can benefit patients. He has been a leader in developing the immune-related response criteria; finding the best strategies to treat immunotherapy-related side effects; and conducting translational studies in his laboratory that inspire the next major treatment advances. Cancer immunotherapy would not be where it is today without his leadership of this field.

“I feel so fortunate to be mentored by Dr Wolchok. He repeatedly advocates for my career development, often selflessly promoting me and other junior mentees with major opportunities that he otherwise could have had for himself. Beyond career growth, Dr Wolchok has welcomed me to New York City and provided a ‘home away from home.’”

Dr Wolchok's Selected Papers

• Kiess AP, Wolchok JD, Barker CA, et al. Stereotactic radiosurgery for melanoma brain metastases in patients receiving ipilimumab: safety profile and efficacy of combined treatment [published online March 5, 2015]. Int J Radiat Oncol Biol Phys. pii:S0360-3016(15)00010-3. doi:10.1016/j.ijrobp.2015.01.004.
• Maio M, Grob JJ, Aamdal S, et al. Five-year survival rates for treatment-naïve patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial [published online February 23, 2015]. J Clin Oncol. pii:JCO.2014.56.6018.
• Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. [published online February 9, 2015]. J Clin Oncol. pii:JCO.2014.56.2736.
• Hannani D, Vétizou M, Enot D, et al. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25 [published online January 13, 2015]. Cell Res. 2015;25(2):208-224.
• Gerber NK, Young RJ, Barker CA, et al. Ipilimumab and whole brain radiation therapy for melanoma brain metastases [published online October 2, 2014]. J Neurooncol. 2015;121(1):159-165.
• Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial [published online July 15, 2014]. Lancet. 2014;384(9948):1109-1117.
• Carvajal RD, Wong MK, Thompson JA, et al. A phase 2 randomised study of ramucirumab (IMC-1121B) with or without dacarbazine in patients with metastatic melanoma [published online June 12, 2014]. Eur J Cancer. 2014;50(12):2099-2107.
• Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma [published online June 2, 2103]. N Engl J Med. 2013;369(2):122-133.
• Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma [published online June 2, 2013]. N Engl J Med. 2013;369(2):134-144.
• Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925-931.
• Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma [published online June 5, 2011]. N Engl J Med. 2011;364(26):2517-2526
• Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials [published online September 8, 2010]. J Natl Cancer Inst. 2010;102(18):1388-1397.