Your research focuses on cancer immunotherapy. Can you explain what this is and why it holds so much promise for the treatment of the disease?
Cancer immunotherapy aims to recruit a patient’s immune system to recognize cancer as foreign and dangerous and to remove it from the body, as it would an infection.
Treatments are designed to help activate the immune system by blocking the ‘stop signs’ or ‘brakes’ that prevent immune cells from destroying cancer cells. The goal of immunotherapy is to get the patient’s immune system activated so cancer is recognized, and it gets controlled as an infection would be by the body.
With immunotherapy, we’ve entered a new era of cancer therapy. It’s helped us turn advanced cancer into a chronic rather than an acutely deadly disease by enabling the immune system to continuously monitor against the reappearance of ‘foreign’ cancer cells.
Your research yielded positive results on a new immunotherapy combination ― ipilimumab (Yervoy) and the investigational, PD-1 targeted drug nivolumab. Can you explain why this is so exciting?
This combination treatment for metastatic melanoma is an important advancement in the treatment of this deadly skin cancer because it demonstrated our ability to safely block two different inhibitory pathways that keep the immune system from becoming fully engaged in responding to cancer.
We know that cancers use multiple mechanisms to evade detection by the immune system, so it is likewise important to attempt to use multiple means to circumvent this immune evasion.
The combination of nivolumab with ipilimumab – the first approved drug shown to extend survival of people with metastatic melanoma – has the potential to be a major step forward not only for the thousands of people fighting this disease, but also for the entire field of oncology.
What were the results of the Phase I trial, and were you surprised by these findings?
Our trial results revealed that 40% (or 21) of the 52 evaluated patients who received the combined ipilimumab and nivolumab therapies showed objective responses in measurable tumors.
In fact, 31% (or 16) of the evaluated patients had tumor regressions greater than 80% compared with baseline. And in five of those patients, detectable tumors regressed completely.
About 90% of responding patients continued to respond to the therapy as of February 13, after a median 13 months of follow-up.
We were pleasantly surprised by both the speed and depth of the response to this combination of antibody therapies.
These results buttress a growing conviction among researchers that the immune system can be effectively harnessed to control cancer and that such treatments can induce durable regressions. That said, this is a modest-sized Phase I trial, and results need to be confirmed in larger studies.
Have any attempts been made to confirm these results in larger studies?
Based on our successful results, a randomized Phase III trial has recently been initiated and is actively accruing patients, comparing the ipilimumab/nivolumab combination to single agent nivolumab or ipilimumab in advanced melanoma.
What do you think could be the reason behind the increased effectiveness of the two drugs when given in combination?
These drugs are effective in combination because the two antibodies have similar but distinct mechanisms of action. Ipilimumab blocks a ‘braking’ mechanism, which is important early in T cell activation, while nivolumab disrupts a cellular interaction that allows tumors to evade that attack.
By blocking these braking pathways, although in different ways, the two treatments each result in effective immune activation. It is also possible that ipilimumab could induce inflammation in the tumor, which may allow nivolumab to be more effective.
Why do you think that patients responded to the concurrent therapy even when they did not have biomarkers that correspond to positive responses to each of the therapies?
It is possible that ipilimumab could induce inflammation in the tumor which may allow nivolumab to be more effective.
Do you have plans to test other drug combinations against metastatic melanoma?
Yes, we are currently evaluating combinations of therapies that target aberrant signaling pathways inside melanoma cells with immunotherapies, as well as combining immunotherapies with other immunotherapies, vaccines and radiation therapy.
What inspires you most about your research today?
It’s the ability to bring new treatments to people who need them. Once a week, I have the extraordinary privilege of trying to help people who are facing a devastating illness. And what more motivation could a person want than to be face-to-face with someone who desperately needs a better answer?
Over the past 17 years, I’ve been able to change the tenor of the conversation I have with patients. It’s gone from, “I’m sorry there’s nothing we have that works well,” to “We have several options that will extend your survival but we’re trying to do better than that and that’s why you should consider a clinical trial.”
The advances accrued over the past decade have fundamentally changed the conversations that doctors can have with their patients.
With all the research coming out now, what excites you the most?
What excites me the most is the ability to construct combination therapies that help people with cancer live better and longer.
In the history of medicine, we have seen the most challenging problems successfully countered with combination therapies. Two examples are HIV and tuberculosis, on which triple drug therapy made the biggest impact.
I spent the first years of my career treating HIV when many young people were dying from AIDS. It was very demoralizing for everyone – patients, health care providers, physicians and family members alike.
At the time, we used the drug AZT to treat AIDS, but it didn’t work very well. It was not saving people’s lives. However, once AZT was combined with other medicines like protease inhibitors, all of a sudden people started talking about living out their normal life expectancy. It transformed the way that people considered their initial diagnosis.
In my lifetime, that was the most graphic example of combination therapy. Cancer requires the same type of approach.
Where can readers find more information?
The paper has been published in the June 2 issue of the New England Journal of Medicine.
Nivolumab plus Ipilimumab in Advanced Melanoma
Jedd D. Wolchok, M.D., Ph.D., Harriet Kluger, M.D., Margaret K. Callahan, M.D., Ph.D., Michael A. Postow, M.D., Naiyer A. Rizvi, M.D., Alexander M. Lesokhin, M.D., Neil H. Segal, M.D., Ph.D., Charlotte E. Ariyan, M.D., Ph.D., Ruth-Ann Gordon, B.S.N., Kathleen Reed, M.S., Matthew M. Burke, M.B.A., M.S.N., Anne Caldwell, B.S.N., Stephanie A. Kronenberg, B.A., Blessing U. Agunwamba, B.A., Xiaoling Zhang, Ph.D., Israel Lowy, M.D., Ph.D., Hector David Inzunza, M.D., William Feely, M.S., Christine E. Horak, Ph.D., Quan Hong, Ph.D., Alan J. Korman, Ph.D., Jon M. Wigginton, M.D., Ashok Gupta, M.D., Ph.D., and Mario Sznol, M.D. NEJM. 2013 June 2.
About Dr. Jedd Wolchok
Dr. Jedd Wolchok is a medical oncologist who serves as Director of the Ludwig Institute’s Collaborative Laboratory at Memorial Sloan-Kettering Cancer Center (MSKCC), Director of Immunotherapy at the Ludwig Center at MSKCC, Director of the CRI/Ludwig CVC Trials Network and Director of Immunotherapy Clinical Trials at MSKCC.
Wolchok is a leader in promoting the advent of combination immunotherapeutic treatment for patients with metastatic melanoma. His career in science began in 1984, when, as an undergraduate at Princeton University, he worked in Dr. Alan Houghton’s laboratory as part of the Summer Research Program. Then, after receiving both his MD and PhD from New York University, Dr. Wolchok returned to Memorial Sloan-Kettering, entering the Medical Oncology Fellowship Program in 1996. Four years later, after serving as Chief Fellow, Dr. Wolchok was appointed to the Memorial Sloan-Kettering faculty.
The overall goals of his laboratory efforts are to develop and implement new ways to use the immune system to treat cancer. His current research focus includes investigation of the GITR pathway as it relates to regulatory and effector T cells, use of OX40 agonists alone and in combination with chemotherapy and exploration of the role of myeloid derived suppressor cells in tumor immunity.
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