Kirkwood Helped Chart Course of Adjuvant Immunotherapy in Melanoma

John M. Kirkwood, MD

For a time, John M. Kirkwood, MD, thought he might become a professional musician.

His mother, 2 sisters, and 2 brothers have worked as professional musicians, and he was as fascinated with music as he was with science. Kirkwood wanted to pursue both his passions in college, which is how a New York City kid wound up going to college in rural Ohio.

“I was intrigued by the possibility that a place would mix music and science and allow me to pursue the music that I thought might be an option to give serious consideration,” he says of his time at Oberlin College in the late 1960s. “It served me well because I could really get deeply into music and then decide the science was even more driving.”

Kirkwood, 70, still pulls out the viola from time to time, although less frequently lately, since he’s become busier. He used to play in 5 orchestras, and groups of musicians would join him at his wooded 40-acre property outside Pittsburgh to play the orchestral and baroque music he loves so much.

Someone heading past the property at the right time in the morning and evening might find him riding a strange contraption, a bicycle specially adapted to train the German shepherds his wife breeds and trains to compete in a sport called Schutzhund, a German word meaning “protection dog.” The sport focuses on 3 areas: tracking, obedience, and protection work.

A Groove that Used to be a Rut

“That’s how every day starts and every day ends,” he says, adding that he finds the routine invigorating.Kirkwood entered Oberlin College’s Senior Scholar program before his junior year and left the school to study immunology with a pioneer in cancer immunotherapy who became one of his mentors, Lloyd J. Old, MD, at what was then the Sloan-Kettering Cancer Institute. Kirkwood never made it back to Ohio, and the idea of a career in music took a back seat to his growing interest in oncology.

Instead, he stayed in New York and eventually matriculated at Yale School of Medicine, where he went to work in the laboratory of Richard K. Gershon, MD, professor of pathology, immunology, and biology and another giant in the field of immunotherapy.

Kirkwood received his medical degree from Yale in 1973 and founded the Yale Melanoma Unit alongside Aaron B. Lerner, MD, PhD, and Stephan Ariyan, MD, MBA, 5 years later. He led that unit until 1986, when the University of Pittsburgh Cancer Institute (UPCI) recruited him as professor and chief of the Division of Medical Oncology. He was named the school’s vice chairman for clinical research 10 years later.

Today, Kirkwood is the Thomas and Sandra Usher Professor of Medicine, Dermatology and Translational Science at the University of Pittsburgh School of Medicine and codirector of the UPMC Hillman Cancer Center Melanoma and Skin Cancer Program. In the 44 years since he began his career, he has seen melanoma become a growing field of research.

“This is a groove now. It once was a rut,” he says. “Melanoma, for many people, was a rut some wanted to get out of and people avoided.”

Kirkwood played no small part in changing the field’s reputation. He was the lead author on the pivotal ECOG EST 1684 trial published in 1996 that led to the approval of high-dose interferon alfa-2b for adjuvant treatment of deep primary (T4) or regionally metastatic (N1) melanoma.¹

ECOG EST 1684 was the first randomized, controlled trial of interferon alpha-2b to show a significant benefit for overall survival (OS) and relapse-free survival in patients with high-risk melanoma. Results from that study showed that interferon alpha-2b increased median disease-free survival from 1 to 1.7 years and OS from 2.8 to 3.8 years. Compared with observation, a median follow-up of 6.9 years, interferon alpha-2b treatment induced a 42% improve-ment in the percentage of patients who were continuously disease-free compared with observation (37% vs 26%).

Kirkwood also serves as the principal investigator of the National Cancer Institute’s Specialized Program of Research Excellence in skin cancer at UPMC. The program’s goal is to improve the understanding of molecular and immunologic mechanisms of cancer progression and to validate prognostic and predictive biomarkers for personalized treatment of advanced melanoma and cutaneous T-cell lymphoma (CTCL).

The program will evaluate (1) the prognostic and predictive value of the proinflammatory response and markers of immune suppression in relation to ipilimumab and interferon alpha adjuvant therapy (leveraging an ECOG-led adjuvant trial); (2) an engineered, 3-antigen dendritic cell vaccine and interferon alpha boost in patients with metastatic melanoma; (3) a phase I study of anti—PD-1 antibody MK-3475 and peginterferon alfa-2b for advanced melanoma; and (4) a new personalized microneedle vaccination technology for patients with melanoma and CTCL.

He has also been chair of the ECOG-ACRIN Melanoma Group since 1989. That group summarized results from 70 trial arms covering thousands of patients in 2008 and reached a disheartening conclusion.

“We humbly had to admit that not one of the treatments we had brought forward in phase II trials really had significantly improved either the time to progression or the overall survival of our patients,” he says. “The only immunotherapy approved for melanoma in the prior 25 years was interleukin-2 for metastatic melanoma, and that was approved not on phase III trials but on phase II trials [and] had response rates in the range of 15% to 20%. Maybe one-third of those were durable and high-quality responses, but that’s all we really had.

“Interleukin-2 for metastatic disease and interferon alfa for adjuvant therapy were, really, until 2011, the only therapies that we really thought had any meaningful, durable impact on melanoma,” he recalls.

Kirkwood was part of the research team that investigated the next step in melanoma treatment: the CTLA-4—blocking antibodies, ipilimumab (Yervoy) and tremelimumab. Ipilimumab won FDA approval for metastatic disease in 2011. The response rate wasn’t spectacular (10.6%), but Kirkwood says it was the first FDA-approved treatment for metastatic melanoma shown to offer any survival benefit.

That approval was expanded in 2015 to include adjuvant therapy for patients with stage III melanoma to reduce the risk for relapse and again in July 2017 to include treatment of unresectable or metastatic melanoma in pediatric patients 12 years and older.

Since the initial approval of ipilimumab, the armamentarium for treating patients with the malignancy has expanded dramatically to include the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and combination therapies that target BRAF V600E or V600K mutations. These include approvals in the adjuvant setting with lymph node involvement for nivolumab and the combination of dabrafenib (Tafinlar) and trametinib (Mekinist). Meanwhile, an application is pending for the use of pembrolizumab as an adjuvant treatment in patients with resected, high-risk stage III melanoma.

After going from 1996 to 2015 with no new adjuvant treatments, oncologists treating patients with melanoma now find themselves with an embarrassment of riches. It’s the kind of moment Kirkwood has been waiting for since the 1960s.

A Passion for the Work

“That would be truly stunning to have several adjuvant trials break positive and change the face of what we do,” Kirkwood says. “The experience with serology in Lloyd Old’s laboratory and with cellular immunology with Richard Gershon, and then with Harvey Cantor at Harvard in my fellowship days, has finally been brought to bear on the tumor. In oncology, there’s probably nothing more important than tenacity in attacking a problem to assure that if you just stick at it long enough, you will succeed. It’s been gratifying for all of us, and it’s a cast of thousands who’ve been involved in the assault on mela-noma with immunology.”Kirkwood isn’t sure what he’d be doing if he hadn’t pursued medicine. Certainly, something would have captured his imagination by now; maybe he’d be a first-chair violist. Both his sons are engineers—one working in Houston, Texas, the other at Stanford Research Institute—so it’s likely he would have brought passion and intellectual rigor to another scientific discipline.

But for as much as he loves research, it’s the practice of treating patients that truly motivates him. Kirkwood makes a point to work in the clinic at least twice, sometimes 3 days, every week. "Clinic is what keeps us honest. It's the place where our mission is both initiated and ultimately fulfilled," he says. The patients I see every Monday, every Wednesday, and some Fridays are the motivation to do all the work.

Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14(1):7-17. doi: 10.1200/JCO.1996.14.1.7.