Melanie Cole (Host): Welcome to AHN MedTalks, an informative resource for physicians across various specialties as we delve into the latest medical insights and best practices, ensuring you stay at the forefront of your field. I'm Melanie Cole and joining me today is Dr. Yazan Samhouri. He's a Hematologist and an AHN Cancer Institute physician. And he's here to highlight cell therapy for us today.

Dr. Samhouri, it's a pleasure to have you join us. I'd like you to start by giving us a brief overview of the link between the immune system and cancer. How do these tie together?

Yazan Samhouri, MD: Hi Melanie, and thank you for having me today. So the interaction between the immune system and cancer is important, because one of the several mechanisms where cancer develops and cancer cells continue to grow without control; is by evading the immune system. This has established the foundation of immunotherapies in oncology and this has established our interest for the last two or three decades of trying to understand how we can use this interaction between cancer cells and the immune system to use it in our patients' advantage and developing new immunotherapeutic approaches.

Host: It's a fascinating topic we're discussing here today, Dr. Samhouri, and it's one of the most fascinating cores of adaptive immunity. How have cell therapies such as CAR-T Cell Therapy changed the landscape of cancer treatments? I'd like you to speak about some exciting available immunotherapy approaches and how these approaches differ from other immunotherapy approaches that we've heard about.

Yazan Samhouri, MD: So the current immunotherapeutic approaches that are available other than CAR-T and we have been using them for many years in a variety of cancers, are checkpoints inhibitors and biospecifics. Those checkpoints inhibitors, for example, like pembrolizumab and nivolumab have changed how we think of many cancers, including metastatic lung cancer, renal cell cancer, and melanoma.

In addition, to a certain degree, to almost every cancer we are treating. The issue with checkpoints inhibitors and biospecific antibodies, they rely on the endogenous immune system. They rely on the patient's own T-cells. Although they help us a lot in a variety of cancers and really change the prognosis and how we think of these the endogenous immune system or the T-cells can get exhausted. And that's why cancers develop resistance to these immunotherapy approaches very quickly. What cell therapy offers, they offer is a memory T-cells. Those are adaptive immune cells that we transfer to the patients.

So the treatment is cellular therapy. We give the patient immune cells that have the characteristic of developing memory cells. Those T-cells, they are manipulated in the lab. So those are new to the cancer. Those are new to the patient. So they don't get exhausted very quickly as the endogenous T-cells and they develop Memory T-Cells or Memory Immune Cells that allow us to administer only this treatment once, but the idea for the cells is to work for a long time, which we are hoping forever to achieve the cure of many cancers we are treating. This has shown already to be an effective approach in many hematologic malignancies.

As an example, CAR-T Cell Therapy is approved by the FDA to treat multiple hematologic malignancies, including acute lymphoblastic leukemia and diffuse large B cell lymphoma and follicular lymphoma. And we are talking now about an opportunity to cure these lymphomas in patients where we never dreamt of such an approach or such a solution or treatment for these patients. So that's how cell therapy differs from current immunotherapeutic approaches.

Host: Speak about some of the challenges. You've mentioned a few and limitations associated with these types of therapies. How are you addressing them and what do you see as some of the ways to mitigate some of those limitations?

Yazan Samhouri, MD: So one limitation is that this therapy is logistically demanding. So Cellular Therapy in general, either is CAR-T or TIL Therapy. It needs for the patient in certain situation to undergo surgery first. That's specifically true for TIL Therapy. So that's an additional procedure that is needed specifically just so we are able to harvest those immune cells and send them to the lab and manufacture the immune therapy or the cell therapy product before we administrate back to the patient. The other limitation would be, the patients need to stay in the hospital for two to three weeks, and that will include administration of a lymphodepleting chemotherapy. The most common regimen we use is fludarabine and cyclophosphamide followed by the cellular therapy or the immunotherapy product administration.

And in TIL therapy, we also administer high dose interleukin 2 afterwards, which can be toxic for some patients. So it's logistically can be demanding. It can't be provided by every center. It has to be a center who has the foundation of cell processing lab and the ability and the expertise to administer cellular therapies.

And, also the patient need to travel to these centers. So it can't be done everywhere. How we address these limitations? Unfortunately, the way we administer this therapy, we cannot change that. That's how this therapy is administered and we have to just follow the protocol.

But we try to offer our patients help from traveling or having accommodations closer to the center where we administer it, which here at Allegheny Health Network we administer it in west Penn Hospital. Those are the limitation. The advantage, although it's logistically demanding, it's one and done treatment.

Patients don't have to repeat that treatment again. We just give it to them those two to three weeks when they get admitted to the hospital and we send them home and we hope the treatment will continue to work for a long, long time. And as I said before, hopefully forever.

Host: Dr. Samhouri, what an exciting time in the field of cell therapy. Are these used as addition to, and in some cases, as alternatives to traditional treatment modalities? Is there combination therapy? How does that work?

Yazan Samhouri, MD: No, it's not. It's a treatment that we give to the patient as a second line or third line of therapy after they relapse from their first line of treatment. We don't combine it with other therapies. In certain situations, I shouldn't say we don't combine it at all. In certain situation, we can combine it with checkpoint inhibitor, which is the traditional immunotherapies that we use like Keytruda and like pembrolizumab and nivolumab.

But some protocols, it's just only this is the treatment. What do they offer is, there are a lot of cancers, once patients fail first line of therapy, there is really no good standard of care, a subsequent line of therapy. And I'll give you an example. Let's say a metastatic lung cancer patient, in the last five to 10 years, we added a checkpoints inhibitors to chemotherapy in the first line. And that helped our patients a lot. It really changed how we think of metastatic lung cancer. But this is not a curative approach. Almost every patient would develop resistance to this chemo immunotherapy approach and they will need a second line of therapy during their journey.

The second line of therapies in metastatic lung cancer include more chemotherapies and immunotherapies like docetaxel and ramucirumab.Those treatments, once you reach a second line and third line therapy, still can be toxic for patients who received chemotherapy before. The response rates and cure rates is not great, and we're always in need of new therapies that can help our patients in that stage.

So that's where cellular therapy come into play; in difficult to treat patients, in lines of therapies where we don't have really a great option. And that's where it's been used. And it's only combined in certain situations with checkpoints inhibitors.

Host: What about the future of cell therapy and research? Why don't you give us a little bit of a blueprint? What do you see happening in the next decade or so? I mean, we're moving quickly.

Yazan Samhouri, MD: Correct. So in cell therapy, when we say cell therapy, we're talking about multiple technologies. One of them is CAR-T Cell Therapy. It's already approved, as I said, in several hematologic malignancies, but we don't have any CAR-T product that is approved for solid malignancies yet. That's because of the nature of solid malignancies.

It was more challenging for us to find a CAR-T product that works very well, that is effective and safe at the same time. The future would hold that we find a CAR-T product for solid malignancies for sure. That's what all the research is happening. When we talk about the other technology, which is TIL Therapy, TIL Therapy is more, I would say in research standpoint, in advanced phases in solid malignancies compared with hematologic malignancies, which is opposite to CAR-T Cell Therapy. We are expecting the first FDA approval soon, maybe in the first quarter of 2024 for the first TIL therapy product for melanoma specifically.

But there are multiple, ongoing research in almost every disease sites, including colon cancer, breast cancer, some of the gynecologic malignancies like ovarian cancer and cervical cancer. We also have clinical trials in newer technologies of cellular therapies in melanoma that we're hoping to improve the initial product that we already have.

So that's where are we? We're trying to improve the technologies. We're trying to expand the indication to include all disease sites.

Host: And now, as we get ready to wrap up, tell us a little bit about AHN's program and focus. Tell us about your team and the multidisciplinary approach for patients in the program, when you feel it's important that other providers refer.

Yazan Samhouri, MD: At Allegheny Health Network, we made it a mission to be a destination of such therapies because we believe cellular therapies in general, can change the future of how we treat cancer in general. So we have a dedicated team that includes surgeons, cellular therapist, disease site expert from medical oncology.

We have a dedicated research coordinators, and we have a dedicated inpatient unit that has expertise to administer these therapies. So that's the whole team for the multidisciplinary approach for these patients. The Allegheny Health Network, we have several clinical trials, and I can think of at least seven of them that include CAR-T Cell Therapies, TIL Therapy and also T-cell receptor, T-cell therapy.

Those are the three technologies of adaptive immune therapy that we are studying in cancers. That covers almost five to seven disease sites in solid oncology alone. We have also several clinical trials in the malignant team world. So we're hoping to expand this profile, so we have this therapy available for our patients locally in Pittsburgh, that they don't have to travel to get this kind of a promising and hopeful therapy. The earlier their referral, during the patient journey, to be considered for cell therapy, the better. That's because as I mentioned, Melanie, how challenging, or I would say logistically demanding. Early preparation for these patients to finish their screening test, to get an OR date for them to go for surgery, that's specifically true for TIL therapy.

And then there is a manufacturing time between surgery and between the product to come back. It can range from as early as three weeks to as long as eight weeks. So these therapies, preparation for it takes time. The earlier the referral, the earlier we see the patient, we can work with them, work with the surgeon, work with our research coordinators and everyone, to put them on the list and we're able to help them as soon as they need it. So that's our team at Allegheny Health Network that administer these therapies.

Host: Dr. Samhouri, thank you so much for joining us today. It was so informative and again, really such an interesting topic. Thank you again. To learn more or to refer a patient, please call 844 MD REFER. Or you can visit ahn. org. Thank you so much for listening to this edition of AHN MedTalks with the Allegheny Health Network.

Please remember to subscribe, rate, and review this podcast and all the other AHN MedTalks podcasts. I'm Melanie Cole.