Melanoma: A model for scientific innovation

When Ravi K. Amaravadi, MD, started as a medical oncologist 20 years ago, there were no treatments for metastatic melanoma. Today, there are 17 FDA-approved therapies for this deadliest form of skin cancer.

“Melanoma is a model disease for scientific breakthroughs,” says Dr. Amaravadi, who is the Associate Director of Translational Research and Scientific Director at the Tara Miller Melanoma Center at the Abramson Cancer Center at Penn Medicine.

Dr. Amaravadi recently visited the Penn Medicine Physician Interviews Podcast to discuss those breakthroughs and how Penn Medicine clinician-scientists are advancing melanoma research and treatment.

Melanoma treatment innovations

Melanoma has seen rapid treatment advances over the last two decades, establishing a model for what cancer innovation can look like, Dr. Amaravadi says. “In cancer, melanoma was the proving ground for paradigm shifts,” he notes. These advances are especially important given the rising incidence of melanoma in the US, particularly in the Mid-Atlantic region.

Melanoma was the first solid tumor to be treated with molecular targeted immunotherapy in the form of PD-1-based checkpoint inhibitors, and, most recently, with cellular therapy in the form of tumor-infiltrating lymphocytes (TILs).

“Penn has played a major role in each of these paradigm shifts,” Dr Amaravadi says. “In fact, we were the first to launch a targeted therapy trial in melanoma in the early 2000s.”

In his interview, Dr. Amaravadi provided a comprehensive review of the recent innovations driving melanoma care, including:

Precision immunotherapy

Immunotherapy has been a significant advance in melanoma, but it’s not effective in all patients. Researchers at Penn Medicine are developing advanced tools using single-cell sequencing and new PET imaging probes to monitor how patients respond to immunotherapy treatments. “Immune monitoring is moving us towards what we call precision immunotherapy, where we give the right treatment to the right patient and switch treatments very early in the process when the treatment is not working,” Dr. Amaravadi says.

Dr. Amaravadi is also excited about advances in neoadjuvant therapy, including approaches that use immunotherapy before surgery. “This allows us to see how the immunotherapy is impacting the tumor, the lymphocytes, the lymph nodes, and the blood, and helps us devise ways to change the treatment if it's not working,” he says.

mRNA vaccines

Another important development in melanoma was the advent of mRNA vaccines. The initial work that made this possible, Dr. Amaravadi says, came from Penn Medicine researchers Drew Weissman, MD, PhD, and Katalin Karikó, PhD, who jointly won the 2023 Nobel Prize in Physiology or Medicine for their work on mRNA therapy.

Now, Dr. Amaravadi and his colleagues are exploring mRNA therapies for melanoma. Excitement has been mounting over a positive randomized phase II study of a personalized mRNA cancer vaccine that uses the patient’s tumor mutations to create a specific neoantigen-targeted vaccine for that individual. “A recent update from this trial showed sustained relapse-free survival in patients who received the mRNA vaccine with a PD-1 inhibitor after surgery for stage III melanoma compared to patients who received only the PD-1 inhibitor,” he says. Dr. Amaravadi’s team at the Abramson Cancer Center enrolled patients onto the phase III trial that could lead to FDA approval.

Tumor-infiltrating lymphocyte (TIL) therapy

The first-ever tumor-infiltrating lymphocyte therapy for solid tumors was approved to treat advanced melanoma. TIL therapy is similar to CAR T cell therapy, but instead of collecting T cells from the blood, lymphocytes are extracted from the patient’s tumor. The cells are grown in the lab for several weeks before being infused back into the patient following chemotherapy. It’s a complicated procedure that can be difficult for patients and can only be done at centers with advanced cell therapy capabilities, Dr. Amaravadi says. But for good candidates who don’t respond to other immunotherapy treatments, TIL therapy offers an encouraging path forward.

“Our Penn TIL Therapy Program is really robust, and that's because we have a strong, multidisciplinary culture of collaboration between surgical oncology, the Center for Cell Therapy and Transplant, and the Tara Miller Melanoma Center,” Dr. Amaravadi notes.

Melanoma research and treatment at Penn Medicine

Despite significant advances, 50 percent of patients with stage IV melanoma die from the disease. Researchers at the Tara Miller Melanoma Center aim to improve that statistic, developing novel therapies for treatment-resistant patients with advanced disease and extending those insights to early-stage disease.

“Our mission is pretty simple. We deliver world-class multidisciplinary care while pushing scientific boundaries to improve outcomes for our patients,” says Dr. Amaravadi.

In addition to offering patients access to a wide range of clinical trials and innovative therapies, Penn Medicine provides the most advanced practical melanoma care. The Penn Medicine team includes pathologists who are world experts in assessing tumors to guide treatment decisions, including neoadjuvant immunotherapy strategies. Penn Medicine’s Oncology Evaluation Center offers 24-hour oncology urgent care for patients experiencing hard-to-manage toxicities from immunotherapy.

Dr. Amaravadi and his colleagues apply their specialized expertise to each patient. “We have a multidisciplinary tumor board that really ensures the best possible care for the most complicated cases. We're always open to hear a case from the community and see how we can make a difference,” he says. “We see community oncologists, dermatologists, and surgeons as essential partners in melanoma care, and we're here to support you and your patients.”

Referrals and consultations

For a provider-to-provider consultation with Dr. Amaravadi, please call 877-937-7366, or refer a patient online.