Melanie Cole, MS (Host): Welcome to the podcast series from the Specialists at Penn Medicine. I'm Melanie Cole. And today, we're highlighting innovations in skin cancer care.

Joining me is Dr. Ravi Amaravadi. He's the Associate Director of Translational Research at the Abramson Cancer Center at Penn Medicine. Dr. Amaravadi, thank you so much for joining us today. So as we begin, you're the Scientific Director of the Tara Miller Melanoma Center. Tell us a little bit about the center, its mission, and core values.

Ravi K. Amaravadi, MD: Well, first of all, Melanie, thank you for having me on this podcast. The Tara Miller Melanoma Center is Penn's hub for comprehensive melanoma care and research. The center was named for Tara Miller, a young woman who died of melanoma more than 10 years ago. And amazingly, while she was dying of cancer, she started this foundation, the Tara Miller Melanoma Foundation, which has collected donations from donors, spanning in the millions of dollars, and that has directly affected melanoma patient care to this day. And we take our inspiration from Tara's story. So, our mission is pretty simple. We deliver world-class multidisciplinary care while pushing the scientific boundaries to improve outcomes for our patients.

Host: That's so important. What a great comprehensive center, as you mentioned multidisciplinary. And when we think of melanoma specifically, Doctor, why is this such an important cancer to focus on?

Ravi K. Amaravadi, MD: Well, while some cancers are declining in incidence, melanoma is increasing in incidence, especially in our area, the Mid-Atlantic region. And this is primarily due to two reasons. Melanoma is caused mainly by UV exposure and also increasing age. And as our population ages, we see a lot more melanoma in our elderly, but also this burst of melanoma in young patients who're still seeking out tanning activities such as UV tanning beds.

The other major reason we're interested in melanoma is that it is a model disease for scientific breakthroughs. In cancer, melanoma was the proving ground for paradigm shifts, such as the first molecularly targeted therapy in solid tumors, the first immunotherapy in solid tumors in the form of PD-1-based checkpoint inhibitors and, most recently, cell therapy in the form of Tumor Infiltrating Lymphocytes (TILs).And Penn has played a major role in each of these paradigm shifts, each of these modalities. In fact, we were the first to launch the first targeted therapy trial in melanoma in the early 2000s, and I was fortunate enough to lead that trial. And so, the two reasons we are really focused on melanoma is the incidence is increasing and the innovation just doesn't stop in this field.

Host: Yeah. And it's a pretty exciting time in your field, Doctor. So much of the clinical research at the Tara Miller Melanoma Center is in metastatic melanoma. Explain a little bit about why this concentration. Are you working on stage II and III melanomas as well? Tell us a little bit about what you're doing.

Ravi K. Amaravadi, MD: Right. So, metastatic melanoma has historically been the deadliest form of skin cancer. When I started 20 years ago, we had no treatments for metastatic melanoma. And so, every patient joined a clinical trial back then, and that's the reason why we now have 17 FDA approvals. But still, 50% of our stage IV patients are dying of melanoma.

So now, we are focused on those treatment-resistant patients and developing new therapies for them. But we are focused on moving that benefit into earlier stages of disease. We have many clinical trials in stage III melanoma. But also, more recently, we presented at an international conference the first results of the first clinical trial of neoadjuvant therapy in stage II melanoma. So since there are 10 times more patients with stage II and III melanoma compared to stage IV, we now have more patients eligible for our clinical trials than ever before. We're reaching a larger proportion of the melanoma population to benefit them.

Host: That's so interesting. Now, much of the research you're involved in can't be simplified necessarily for the general discussion, but perhaps you can discuss it in more broader terms. Can you, for example, give us an idea of what immune monitoring is in melanoma therapy, what it brings to the field?

Ravi K. Amaravadi, MD: Absolutely. So, immune monitoring is an advanced way of measuring how a patient's immune system is responding to immunotherapy. We typically get blood tests in patients to look at your blood counts and your kidney function. But we don't have a really focused immune test and we want to change that.

So, our team is developing advanced tools using single cell sequencing, tetramer-based flow cytometry, TCR sequencing, and new PET scan imaging probes to understand how patients are responding to treatment and can we tailor treatment better to the patients that are not responding to the treatment.

So, immune monitoring is moving us towards what we call precision immunotherapy, where we give the right treatment to the right patient and switch treatments when the treatment is not working very early in the process.

Host: Yeah, that's certainly the way it's going towards that precision personalized medicine. And the last year has seen some significant advances in melanoma therapy. For example, there's now a vaccine based upon MRNA technology for which Penn was a pioneer, elaborate on this for us. Elaborate on the trial and how it could potentially impact melanoma care in the future, because this is pretty exciting.

Ravi K. Amaravadi, MD: I agree this mRNA vaccine space is incredibly exciting. This is all based on 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 just for that patient. And this vaccine hopefully will teach the immune system exactly what the melanoma in that patient looks like.

So, 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. Our group has participated in the FDA registration study, which is a randomized phase III study testing the same treatments, mRNA vaccine plus PD one versus PD one alone. But now in a broader population in stage II, III, and IV melanoma. We will learn next year if that trial is positive. And if that's the case, this neoantigen vaccine approach with mRNA technology will become the standard of care in melanoma and could be a game-changer in other cancers.

It's important to note, as you mentioned, that Penn has played a major role in this technology. Really, the primary work that has made this possible comes from Drew Weissman and Katalin Karikó, who won the Nobel Prize in 2023 for MRNA therapy, and they're working with us in the Tara Miller Melanoma Center on many different MRNA projects as well.

Host: So, Dr. Amaravadi, you mentioned this just a little bit before when you were talking about therapies and there's—for the  first-time—an approved cell therapy for advanced metastatic melanoma, and you mentioned it earlier, TIL therapy. Tell us a little bit about patient selection for this treatment, and the next steps for cell therapy in melanoma.

Ravi K. Amaravadi, MD: Right. So, TIL Therapy, it stands for tumor-infiltrating lymphocyte. And it is the first FDA-approved cell therapy for advanced melanoma, really for any solid tumor. It's a complicated procedure, and it can only be done in approved centers of excellence. It involves a surgery that removes one tumor. And the TILs in that tumor, the lymphocytes in that tumor, which may be 100 cells or so, are pulled out of that tumor and sent to a lab and expanded. And that takes about four to six weeks.

The goal is to get billions of cells out of those few hundreds. Then, the patient comes into the hospital for a week of chemotherapy that can be quite difficult. They then get the TIL infusion. And because of the chemotherapy, their blood counts are low, so the TILs can come in, and not get destroyed or not get crowded out. And then, they get a very harsh cytokine called IL-2 that supports the TILs, as they come into the body, but also can wreak havoc on the patient. So, we are really looking for specific patients that can withstand this complicated, multi-week procedure. And it's important to evaluate these patients early in their course of disease to say, "Yes, you are a TIL candidate." If things don't go right with your first-line treatment, the first kind of treatment you're getting, then we know that you'd be a good candidate for TIL. So, come back and we get you on the schedule to go through the process.

And I am happy to report that our Penn TIL therapy program is really robust, and that's because we have this strong, multidisciplinary culture of collaboration between surgical oncology, the Center for Cell Therapy, and the Tara Miller Melanoma Center. And we are treating maybe one to two TIL patients a week, which is quite a lot if you think about how complicated that procedure is.

Host: Yeah, that is. And it's so interesting. Now, what about then combination immunotherapy strategies and immune profiling? Tell us about some other bench to bedside insights that you're really excited about now.

Ravi K. Amaravadi, MD: Yeah, we're really excited, as I mentioned, about neoadjuvant therapy, there's a lot to do there where we give the immunotherapy before surgery. And this allows us to see how the immunotherapy is impacting the tumor, the lymphocytes, the lymph nodes next to the tumor and the blood all at the same time, and helps us devise ways to change the treatment if it's not working.

And one of those ways is to use a triplet immunotherapy, which has not been done in large scale in melanoma. And we're about to launch a trial with three drugs, immunotherapy drugs. We're also, as I mentioned, using novel biomarkers such as PET scans. We have a really interesting trial using CD-8 PET scans that's looking for T cells in the tumor, applying this to the TIL. Can we pick the best tumor to cut out and generate the TILs and ensure that the patient will respond? So, these are just some examples of how we're taking bench to bedside approaches to improve melanoma care for patients.

Host: Dr. Amaravadi. As we get ready to wrap up, how are community and academic oncologists partnering in melanoma care today, as you look at the broader picture? And if you were to offer guidance to community oncologists navigating an increasingly complex treatment landscape, as you've described here today, what would you like them to know? And what are some of the really important key takeaways that you would like us to learn from this podcast today?

Ravi K. Amaravadi, MD: Yeah, I think that we see the community clinicians as essential partners in melanoma care. And then, the key message to community oncologists, dermatologists, surgeons is, we're here to support you and your patients. And we have some specific things to offer and it's just important to know these are resources at your disposal.

One of those things is specialized pathology. Now, that we're in the neoadjuvant realm, interpreting how the tumor looks under the microscope is not that easy with these neoadjuvant immunotherapies. And our pathologists are really world experts on that.

We have access to 24-hour oncology specialized urgent care. It's called the Oncology Evaluation Center (OEC). And this is for patients experiencing hard-to-manage toxicities from immunotherapy, which can be very, very time-consuming and resource-consuming. Avoiding the ER by sending to the OEC has proven to be an incredible benefit for our patients and our hospital system, to be quite honest. I talked about clinical trials. That can't be overemphasized. This is the way we get to changing the clinical practice of melanoma. And we are excited to share patients and enroll them on our trials and co-manage them with the community oncologists.

And finally, we have a multidisciplinary tumor board that really ensures the best possible care for the most complicated cases. And I think that's where, as patients are getting older, there are more and more patients with multiple comorbidities, other problems. And we often use video Zoom technology to dial in doctors from around the region to present their cases in our tumor board. And I think that's a great starting point that we're always open to hear a case from the community and see how we can make a difference.

Host: Dr. Amaravadi. Thank you so much for joining us and telling us about all the treatment options and exciting research going on at Penn Medicine. And to refer your patient to Dr. Amaravadi at Penn Medicine, please call our 24/7 provider-only line at 877-937-PENN, or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/refer. That concludes this episode from the specialist at Penn Medicine. I'm Melanie Cole.