Precision Skin Cancer Treatment with Dr. Amanda Kirane

In this episode, Dr. Amanda Kirane, an assistant professor and specialist in complex general surgical oncology, shares her unconventional journey into melanoma research. Discover the latest advancements in immunotherapy for skin cancer, including Tumor Infiltrating Lymphocytes (TIL) therapy, and the science behind creating patient avatars with organoid models. Dr. Kirane also shares her admiration for influential surgeons in her life and offers insightful advice.

Rachel Baker: [00:00:00] Welcome to Scrubcast, where we take a closer look at the research happening at Stanford University's Department of Surgery. I'm your host, Rachel Baker. Today, we're speaking with Dr. Amanda Karani. Welcome to the show. Hi, how are you? I'm good, how are you? I'm very good. Excellent. Dr. Khurrani is an assistant professor in our division of general surgery and a board- certified specialist in complex general surgical oncology with a clinical practice that focuses on the diagnosis and treatment of skin cancers.

So tell me, how did you get interested in melanoma?

Amanda Kirane: Very circuitously is the short version. I did not know that I wanted to be a surgeon for most of my life, basically, until it was time to apply to residency. It was my last rotation. I always thought I was headed for adolescent psychiatry. [00:01:00] Very different.

Yes. Although very applicable, I find sometimes, um, but I did cancer research at MD Anderson in undergrad as part of my pre-med exposure. And I was always very fascinated. And so, when I realized that psychiatry was not for me in my third year, I, uh, I thought a lot about oncology and pediatric oncology and I always wanted to be back in the lab.

But as I said, surgery was my last rotation and I loved it and fell into the, there's nothing else I could do with my life category. And then for melanoma, um, I was always a soft tissue person. I loved oncoplastics. I loved sarcoma. And I was, uh, the sarcoma fellow at Memorial Sloan Kettering, but by virtue of that, I spent a lot of time on melanoma, gastric mixed tumor, with just wonderful people, and it was a lot of, a lot of which was the people that, that led me to the field, but at the same time, that was the [00:02:00] year that immunotherapy really exploded, and in most of my cancer research training, we had never And Talked as much about immunology.

A lot of our mouse models were immunodeficient. And so all of that was just very fascinating to me scientifically, but then seeing the impact in the clinic Going from being a resident and thinking melanoma is, you know Terminal prognosis with most people having six months to live at advanced stages To then seeing them cured like truly cured was just fascinating.

Um, and so I followed that route towards Immunotherapy. Amazing.

Rachel Baker: So I feel like half the people I know have a weird- looking mole or freckle and they go to the derm and they punch it out, uh, and that's the end of it. I'm guessing this is not the kind of melanoma that you work on.

Amanda Kirane: No, so I mean, skin cancer is one of the most prevalent diseases, especially as our [00:03:00] population lives, uh, to much older ages.

We see it develop in a lot of immunodeficient populations, so, uh, you know, at UC Davis, for example, there's a very large transplant center, so treating skin cancers was a very big part of the adjunct. field. And so there is a lot of early- stage melanoma, which as long as it is caught early, it is absolutely surgically treatable and it's curable.

But there, beyond that, melanoma is something that spreads very quickly, very early in the disease process. And so most of the patients then that I see are already at risk for having a metastasis to their lymph node, at least a 5 percent risk. And so that's how they get filtered to us.

Rachel Baker: Wow. All right. So everybody, if you see that, Abnormal-looking molar freckle.

Go to your dermatologist immediately in the hopes that you don't end up with Dr. Amanda Karani, even though she's a lovely human. Uh, so let's get back to immunology. Back in February, I learned that TIL doesn't just stand for Today I Learned. It is also the [00:04:00] acronym for Tumor Infiltrating Lymphocytes, which is a newly FDA-approved science.

Cell therapy for solid tumors. And you were on the team that performed the first case in the country. Tell me, how does this treatment work and where does the surgeon come in?

Amanda Kirane: Yes. Well, actually a surgeon was involved from the beginning. Dr. Steve Rosenberg at the NIH is the pioneer of this type of therapy.

And so there's incredible data going all the way back to the nineties on how well this approach can work. Um, and many of those patients, Dr. Rosenberg treated were effectively cured. The challenges were in the manufacturing of the final product and, you know, maybe. Not even 20 percent of patients actually made it from surgery date to the receipt of cell therapy.

So over the last few decades, there's been a lot of focus on how do we improve this to make it more accessible, make it more rapid, and the way it works is that a tumor is harvested from a patient [00:05:00] and then it is processed. There's some initial processing that happens in the operating room and then further processing by the cell therapies team before sending it off to the manufacturing plant based on the industry partner that you're working with.

So in this case, you know, Iovance was the first approved TIL therapy for the clinic. And then it comes back from quality control checks. And once it's ready to administer to the patient, the patient's admitted to the hospital for lymphodepleting chemotherapy, meaning it's very similar to what a lot of people may know more conventionally for like a bone marrow transplant.

Plant or other kinds of therapies like that, right? Where, so a patient will have basically their own immune system significantly depleted so that they can then receive the immune cells from the tumor and have that replaced in their body. And then that gets expanded by using high-dose drugs that increase your T cell proliferation.

Uh, and then hopefully they have a good response to the therapy. How long does this process take? [00:06:00] So the minimum time now to get from a. Tumor procurement to a cell therapy product is about 22 days, but in clinical practice, it's a little bit closer to about five weeks from the day of surgery to the day of receiving cells back.

Rachel Baker: And so you're just seeing people really respond to this new type of therapy?

Amanda Kirane: So, across the data, it does depend on what stage of treatment you are in, and so there is a push to now move this therapy into an earlier line of therapy where it works potentially better. But in the current application, which is after a patient has failed standard therapies to include checkpoint therapies and targeted therapies, they become eligible, um, in that space it's about a 31 to 35 percent response rate.

Okay,

Rachel Baker: that's great.

Amanda Kirane: I mean, that's pretty, still pretty good.

Rachel Baker: Um, and so you were, uh, saying that you're looking at immunotherapy for earlier stages of the disease. You, Dr. Calvin [00:07:00] Kuo and Dr. Alison Betthoff Warner were awarded a team grant from the Melanoma Research Alliance for your translational therapy predictive program.

Organoid model. Um, so I was reading this project description and not going to lie, it sounds a little Frankensteinian. Um, so are you really growing tumors in like little lab incubators? Am I going to come over to your building and find little tiny. Tumors hooked up to oxygen and no one supply and

Amanda Kirane: yeah, not not exactly.

I mean essentially yes Um, that is the idea but in a dish they look similar to most cell cultures Although some of them I have to tell you behave so aggressively that I do I do have nightmares that will walk into a situation Like that one day. Um, but For, no, for the most part, we are taking patient samples from their tumors before they start therapy.

And then again, after therapy, if they don't respond to look at how the tumors drift over time, but we essentially dissolve the tumor into single-cell suspensions. And then what's [00:08:00] really, really fascinating is that then when you put them back in a dish, they self assemble and, you know, re aggregate and then they become mini patient avatars, if you will, that retain a lot of the same properties of the original tumor.

And then they can be tested for drug therapy. manipulate them a number of ways as we do in the lab to see what could be best second-line therapy, et cetera. So, um, it's a really cool technology that has evolved to replace. Our animal models, which have not really served us as well as we want over the years.

Rachel Baker: Okay. Yeah. I'm definitely having nightmares about this later. There's just a ton of really cool science happening in your lab. I was watching the virtual Holman poster sessions, and one of them was from your research, Dr. Usman Ahmad and the science. Is a little confusing, but after watching it about 12 times, I think you have discovered a new type of immune cell.

Is that correct?

Amanda Kirane: It's possible. Um, it's very hard in using single-cell studies like [00:09:00] this that sort of opened a completely new gateway and the way that project started is that we had decided to interrogate all available databases for macrophage profiles. Macrophages are my cell of interest and most of my training we held a dogma of two types of macrophages, one that is essentially good for tumors and one that is bad.

And with the evolution of single-cell genomic studies, it became very clear that The line between those two is very blurry, and that there's many, many types of macrophages that have various features. And so, what Usman did was use machine learning to do a top-down approach on the cells and have the algorithm tell us how many types of macrophages we really had amongst our samples that were distinctly different macrophages.

And from that, the cell that we identified as being apparently critical for survival response to therapies looks to be like a hybrid cell, somewhere in between a macrophage [00:10:00] cell. It's controversial to some people because we're finding more and more of these hybrid-type cells. And so the question becomes, is that a data error or is that truly a cell that we didn't identify?

Appreciate before and a number of mechanisms of how that cell could have come to be, but it's been very reproducible amongst the data sets. We've tested it on and so we will keep looking at it now prospectively in our new studies.

Rachel Baker: Awesome. I mean, so once you find a new cell type, what do you do with that?

Um, I mean, do you. Do you go tell somebody I or I don't even know who you tell?

Amanda Kirane: Yeah. So the question will become, is it something that was native to that patient's immune function or is this something that evolved and therefore is it something that we can encourage as a therapy? Is there a way that we could make this cell as an engineered cell therapy in the future?

Or is there a drug mechanism that makes a cell perform this way? Very

Rachel Baker: cool, and I can't wait to learn how it all turns [00:11:00] out, but we are at the point in every episode of Scrubcast where we ask each of our guests the same two questions. The first of which is, Who is a surgeon you

Amanda Kirane: admire and why? I find this question, uh, very high pressure Because there are so many and you would of course never want to leave anyone out and At baseline, I admire anyone who is trying To where the surgeon plus at, I mean, being a surgeon alone and taking care of patients and doing that well is hard enough, you know, emotionally, physically, but then to also straddle worlds to try to have a lab or to try to perform clinical research or to try to be in leadership.

I admire so many people in our field and here at Stanford. In my training, I probably have to identify. Probably the first surgeon to leave a real impact on me, which was Patricia Bergen from UT Southwestern. She was a trauma surgeon. She was the CMO [00:12:00] of the University Hospital when I was a resident. She was the student clerkship director when I was a student.

And to be honest, as embarrassing as it sounds, since it was 2000 and She was the first woman surgeon I ever met. And it just wasn't even a field that occurred to me. And that representation really mattered. And then beyond that, she was just an incredibly tough person, smart, kind, a good mentor, very human, and very approachable, despite being a woman.

Being this giant of surgery. And so she meant a lot to me and she looked out for me as a student when we went through difficult things in my family around the time I was applying to residency. And so without her involvement, I don't know that I would have made it through. So I really, really respect all that she did for students and residents outside the clinic.

Rachel Baker: That is such a moving story. That is such a moving [00:13:00] story. Thank you for sharing it with us. The second question we ask each of our guests is what is the best advice you have received in 10 words or less?

Amanda Kirane: Fall down seven, get up eight.

Rachel Baker: What does that mean?

Amanda Kirane: It's from a Japanese proverb, and it's meant to be taken quite literally, but the idea is that perfectionism does not help us, that failure is often part of the journey, and it's all about how you choose to receive it, and what matters is how you decide to get back up.

And in some ways, it's very literal for Those of us who submit grants, because that's about the success rate on grants is one in seven. And so if you don't expect to keep getting back up, you will not get funded. But yeah, it's a reminder that we all experience setbacks and you can either take them as opportunities to learn and feedback and just part of the process, or you can let them discourage you.[00:14:00]

Great

Rachel Baker: advice. Well, it has been such a pleasure chatting with you. Is there anything you wanted to add before we sign off other than wear sunscreen?

Amanda Kirane: Definitely wear your sunscreen, it's about to be summer now. Especially out here in California. I encourage everyone to remember, I guess another great piece of advice uh, from a former mentor was um, that this was all supposed to be fun.

And so, that is possible. And that, let that be your

Rachel Baker: guide. In every job that must be done, there is an element of fun. As Mary Poppins would say. And that brings us to the end of another episode. If you like Scrubcast, we hope you'll tell your friends and subscribe wherever you get your podcasts. Scrubcast is a production of Stanford University's Department of Surgery.

Today's episode was produced by Rachel Baker. The music is by Midnight Rounds. And our chair is Dr. Mary [00:15:00] Hawn.