Walking Through the TIL Therapy Process in Advanced Melanoma

Patients with metastatic melanoma have limited options after progression on immunotherapy and targeted therapy, but tumor-infiltrating lymphocytes (TILs) offer a new therapy modality in this setting. During a Case-Based Roundtable event in California, Omid Hamid, MD, chief of Translational Research and Immuno-Oncology and the director of the Cutaneous Oncology and Phase 1 Programs at The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate in Los Angeles, presented on the use of lifileucel (Amtagvi) TIL therapy and focused on the patient journey and practice guidelines. Because of the need for a speedy referral to an authorized treatment center, understanding the logistics and multidisciplinary process of TILs is important to all oncologists involved in treating melanoma.

Targeted Oncology: What resources are available to learn about the use of TILs?

Omid Hamid, MD: The TIL working group did a position article and guidelines on TILs. These are the consensus guidelines on management and best practices for TILs. It's in the Journal for Immunotherapy of Cancer.¹ Of note, the senior author here, Adam Schoenfeld, MD, is a thoracic oncologist. There are trials in other solid tumors, most importantly clinical trials looking at lung cancer.

How do you identify an eligible patient for TILs?

[The requirements include] unresectable or metastatic melanoma, good performance status, and good cardiac and pulmonary reserve—older patients need pulmonary function testing. [There can be] no active brain metastases, and this is important: no active immune-related adverse events requiring greater than 10 mg of prednisone or equivalent. For me, if you've had colitis, I make sure that there is no active colitis [and give them] a sigmoidoscopy and biopsy. If they’re adrenally insufficient, you can’t give TIL. There must be at least 1 resectable lesion of minimum 1.5 cm [or] it could be an aggregate. You can have 3 nodes…you can have bunch of skin metastases, and have it sent to be made for TIL.

What are the requirements for removing and sending the tissue?

There is a specific way to clear that tissue, surgically and in a sterile fashion, and it is transferred into a receptacle that is then sent centrally. The majority of the centers that were part of the trial were centers that had never done TIL, or…you did not need a GCP [Good Clinical Practice] facility. Many years ago, when Mark Faries, MD, was at [Saint John’s Cancer Institute]…I assisted in putting a TIL program from the ground up, and what you needed was a sterile lab. You needed a GCP facility. You used to have it reviewed by the Foundation for the Accreditation of Cellular Therapy [FACT]. It had to be FACT accredited, and it was audited multiple times. This program obviates the need for you to have that. You need a surgeon, you need a hospital to give the TIL, and you need an oncologist…to follow during therapy. That's all you need.

What is the process for referring a patient for TILs?

If you have a patient you want to refer, let's say you refer them…. The patient gets seen and is considered an active patient for TIL. Then that consulting physician calls the referring physician and says, “Yes, we can do this.” There's a discussion about whether the patient needs bridging therapy. You ensure that there are no active brain metastases. You look at the scan; you call the surgeon. They look at it and find the area that is the least morbid that would give you the tissue.

You have to register them in the system with [the manufacturer], Iovance. We have a nurse who is responsible for doing that, and we have someone who is responsible to ensure that it is covered by insurance. When that's all done, a surgical time is placed. That patient has already screened for contraindications and goes into surgery. That surgery…is registered through a system with Iovance that says, “We would like to bring this person. I need a TIL procurement date that is set up with the ability to send it over and have TIL manufacturing done,” so it doesn't just go over and sit. It goes over and the process to make the TIL is done.

Once that's done, that starts the clock on how long it will take to make the TIL. The TIL therapy is taken through the process centrally at the Iovance facility. From time to time they report back to you [to say] the cells are growing well. They may report back the cells aren't growing, so you either have to consider another therapy or another tissue harvest. The majority of the time, they call you to say everything is fine. Then you know a time when that TIL should be arriving. A week before, you bring the patient in for induction chemotherapy. It's a lot of moving parts, but if it's a center that's done it, it becomes as rote as sending someone for CAR T or [stem cell] transplant, etc.

What are the contraindications for TILs?

[One is] rapidly progressive disease, because you have to have a surgical time. It takes 3 weeks after that to make the TIL, etc. Poor pulmonary reserve is why we do pulmonary function tests. [Others include] untreated brain metastases, poor renal reserve, patients who require a lot of growth factor or transfusions, and immune-related adverse events. [The guideline mentions] active uveitis that requires treatment, but I think it's [any] active grade 1, 2 or more immune-related adverse events. You cannot have systemic infections, [be] pregnant or breastfeeding, or have major illnesses, and if you have hemorrhage prior to enrollment, the concern there is you're taking someone to a major cytopenic situation. Like in the clinical trials, it’s not age but performance status and organ function that I use.

What are the concerns with active brain metastases and pulmonary function?

[Brain metastases] can be exacerbated with the therapy. They're doing trials with small brain metastases, etc, and there are some early data, but that's not the codex for the approval. If I had someone, I would rather treat and stabilize their brain before going to it. [For pulmonary function], it’s more that if they get into a situation of sepsis or bacteremia, they need to have the lung [function] because you can have pneumonitis.

I did high-dose IL-2 for 5 to 8 years. There was always the idea that the number of doses that you got into the patient [should be maximized]. That is not how the IL-2 is given here. At the incidence of early grade 1 or 2 toxicity, you stop it. It is not the major [therapeutic].

What resources are required for authorized treatment centers?

Authorized treatment centers are certified. They make sure that you have the resources. They make sure they have [staff]. They take you through it a couple of times. The procurement, surgery, treatment infusion, and post infusion care are carried out at the center, and supportive care and monitoring are conducted at the center until a patient is deemed appropriate for discharge. Then they go back to the referring physician.

How does the patient journey proceed from referral?

Preoperatively, there's a multidisciplinary evaluation and patient selection that is done with the surgical oncologist, the medical oncologist, patient representatives, etc, [to identify] the patient, their ECOG performance status, where we would get the TIL from, etc. Then they are given a surgical time and they are admitted. The procurement is done, there is prosection, which is trimming and fragmentation, so the surgeon trims out the unnecessary [tissue] and just sends the tumor. You need about 1.5 cm. That is done in the operating room. It is put into tumor tissue transport media and is shipped to the manufacturing facility. The final TIL cell product is put into infusion bags with 150 billion T cells. Then the call is made that it’s ready, and it is transported back in a cryoshipper from the manufacturing facility to the local medical center.

During that time, the patient is followed postoperatively [with] coordination of care. After this is brought in, the TIL converges with the patient. They get the preparative regiment, the nonmyeloablative lymphodepletion, which is fludarabine/cyclophosphamide. Then a week later, some [centers] admit the patient, and they watch them for 7 days. Some do this as an outpatient, and they admit the patient for the one-time TIL therapy infusion. This is done in the ICU for us because there are infusion reactions, hypotension, etc, and then anytime between 6 and 24 hours after the TIL you begin the IL-2 infusions. There are about 6 infusions, 6 to 8 hours apart. You can hold for symptomatology and give each dose 24 hours afterwards.

They are in the ICU for us during the IL-2. Then after that, if they're stable, they're taken back to the hematology ward. We looked at the adverse events, and capillary leak syndrome is very rare. Capillary leak and cytokine release are more associated with some of the other T-cell therapies.

What is the role of community oncology in TIL therapy?

[The role consists of] patient and physician education and timely referral. My clinic has shifted from all the patients needing to be seen and treated by me to patients coming in, and we collaborate on the care, and if at imaging time points or in forks in the road for therapy, they come back, or we do a video visit. We have second- or third-line or fourth-line options to discuss locally or not locally.

_{DISCLOSURES:Hamid previously reported honoraria from Bristol Myers Squibb, Novartis, Pfizer, Regeneron, and Immunocore; consulting or advisory role with Amgen, Novartis, Roche, Bristol Myers Squibb, Merck, BeiGene, Genentech, GlaxoSmithKline, Immunocore, Incyte, Janssen, Regeneron, Tempus, Zelluna, BioAtla, Idera, Pfizer, Iovance Biotherapeutics, Alkermes, Eisai, Bactonix, Georgiamune, GigaGen, Grit Biotechnology, Instil Bio, IO Biotech, KSQ Therapeutics, Moderna Therapeutics, Obsidian Therapeutics, Vial, and NGM Biopharmaceuticals; and speakers' bureau for Bristol Myers Squibb, Novartis, Pfizer, Regeneron, and Immunocore.}

REFERENCES

1. Betof Warner A, Hamid O, Komanduri K, et al. Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. J Immunother Cancer. 2024;12(2):e008735. doi:10.1136/jitc-2023-008735

2. Mullinax JE, Egger ME, McCarter M, et al. Surgical considerations for tumor tissue procurement to obtain tumor-infiltrating lymphocytes for adoptive cell therapy. Cancer J. 2022;28(4):285-293. doi:10.1097/PPO.0000000000000608