When Kim Margolin, M.D., talks about her work, the words are packed with information and pour out with energy and passion. She’s a dynamo, and it’s easy to see what makes her an internationally recognized leader in the fight against melanoma.
Margolin is a medical oncologist and clinical professor in the Department of Medical Oncology & Therapeutics Research at City of Hope. She was recently named a fellow of the American Society of Clinical Oncology, a rare honor reserved for the most outstanding in this field.
Kim Margolin, M.D.
What fuels her are the advances she’s seen over the course of her career.
“Melanoma is really the poster child for all immunotherapy, not only in skin cancers but in all types of cancer,” she said. “It’s beyond my ability even to describe how much progress has been made, and it never stops being exciting.”
For more than 30 years, she has played a key role of the evolution of melanoma treatments and was instrumental in the development of ipilimumab, approved in 2011, the first of a new generation of highly effective immunotherapy drugs.
The City of Hope melanoma team, led by Margolin, conducts an impressive number of clinical trials — a dozen now open or recently closed — for targeted and immune system therapies. She filled us in on some of the most noteworthy.
Viruses — surprising allies against cancer
A promising new type of melanoma therapy involves directly injecting a tumor with a virus.
Yes, that’s right, a virus.
Margolin is City of Hope’s principal investigator on two open melanoma trials involving this type of therapy — one with coxsackievirus A21, a cause of the common cold, and another with CMP-001, a virus-like immune stimulant. A third trial with talimogene laherparepvec (T-VEC), a genetically engineered form of the herpes virus, has recently completed its accrual and should be analyzed soon.
The direct injections cause inflammation, and the immune system — supported in these trials by the immunotherapy drugs ipilimumab or pembrolizumab — responds by attacking and killing the tumor. And that’s not all.
“One of the most exciting things about this type of treatment is that sometimes the immune system becomes so activated that the response can travel to other parts of the body and kill tumors that were not injected.”
Curing metastatic melanoma to the brain
“My own particular interest and passion is the treatment of melanoma when it's metastatic to the brain, which has a very high incidence,” said Margolin.
Until recently, even with the standard treatment of radiation, it was often incurable.
“If radiation didn’t work or if you had a recurrence, you pretty much had to tell people to get their affairs in order, because there was little more that you could do.”
That is no longer the case. “We now have both targeted therapies and immunotherapies that can actually reach the brain and effectively treat metastatic melanoma,” she said.
A recently closed trial led by Margolin combined the immune system stimulant ipilimumab with the checkpoint inhibitor nivolumab — a drug that blocks signals instructing the immune system to shut down — followed by nivolumab alone. The results of are encouraging. While a smaller, simultaneous study from Australia has just been published in The Lancet Oncology, a paper by Margolin and her colleagues will soon appear in the New England Journal of Medicine.
This type of therapy is not only a way to treat patients for whom radiation doesn’t succeed — it may also prevent the disease from recurring in areas of the brain that have not been treated.
New hope for advanced squamous cell cancer
When caught early, squamous cell carcinoma can be taken care of in a dermatologist’s office, but in its advanced stages, it becomes life-threatening. This is particularly dangerous for people whose immune system has been weakened, whether from AIDS, underlying lymphomas, drugs given for a transplant or other immunosuppressant conditions.
Margolin was recently involved in a trial whose principal investigator was City of Hope dermatologist Badri Modi, M.D. This study, which has just closed, tested the effectiveness of the immune checkpoint inhibitor REGN2810, which is now known by its generic name “cemiplimab” and is soon likely to have a trade name, as it is expected to gain prompt approval by the Food and Drug Administration.
“The data are still being analyzed,” Margolin said, “but early reports suggest that at least half the patients were responding, and that’s really quite dramatic for advanced squamous cell cancer.”
What the future holds
Margolin is also interested in interdisciplinary collaboration and high-tech genomics, and she’ll be involved in some state-of-the-art trials in the near future.
She has just teamed up with City of Hope researcher Hua Yu, Ph.D., the Billy and Audrey L. Wilder Professor in Tumor Immunotherapy, who has devoted her career to studying the role of the “transcription factor” STAT3 in cancer. Transcription factors are proteins that read our DNA codes and transcribe them into RNA, the genetic messengers that tell our cells what to do.
“If you have transcription factors that are important for tumors, they can have a major influence on how a tumor will behave and how the immune system responds against them,” Margolin explained.
She’ll also be joining forces with Peter Lee, M.D., the Billy and Audrey L. Wilder Professor in Cancer Immunotherapeutics and chair of City of Hope’s Department of Immuno-Oncology. His next-generation genomics work with other types of cancer, including breast and bone, may have significant applications for melanoma.
And Margolin will soon be collaborating with Anna Wu, who is coming to City of Hope from UCLA. Wu genetically engineers antibodies and has developed a highly sophisticated imaging system with which to study them — another powerful tool in the search for more effective ways to fight melanoma and other malignancies.
For Margolin, clinical trials are an indispensable for treating cancer patients.
“I don’t see any reason ever to treat patients just with standard of care. Nobody’s standard of care is good enough to help all melanoma patients, so treating patients on trial is just the right thing to do.”
What about the risks?
“To quote my esteemed colleagues, the worst toxicity of cancer therapy is failure to control cancer.”