Tumor-Infiltrating Lymphocyte

Sophia Paxos, Pharm.D. Candidate of 2025

Reviewed by Dr. Lauren Eng, Pharm.D., RPh

Melanoma is a particularly problematic malignancy. Not only does it quickly metastasize, but it also frequently mutates. Mutations manifest as neoantigens on the cell surface, preventing our immune system from detecting the malignancy. Certain mutations, such as BRAF V600, demonstrate high rates of resistance to first-line immune-checkpoint inhibitors (ICIs), such as PD-1 inhibitors. For unresectable or metastatic melanoma patients that have failed a PD-1 inhibitor, and BRAF V600 positive patients that have failed a BRAF inhibitor with or without a MEK inhibitor, tumor infiltrating lymphocyte (TIL) therapy Amtagvi (lifileucel) is an emerging cellular therapy approved in February 2024.

Similarly to how we all know ourselves best, the tumor recognizes itself best. TIL therapy is a form of adoptive cell therapy utilizing polyclonal T-cells with diverse antigen activity. The first step is excising a piece of a fresh tumor and sending it to a lab. There, they will select T-cells within the tumor. Despite mutations, these lymphocytes are able to recognize the malignancy. They are simply outnumbered and unable to surmount an effective response. The answer to this issue is simple- just clone the lymphocytes a ton. By that, I mean billions of times.

To further encourage a strong response, the product contains interleukin-2 (IL-2), a pro-inflammatory protein the body naturally creates. Once the product is ready, the patient will undergo lymphodepletion chemotherapy to make room for the incoming TIL army. About 24 hours after the final dose of fludarabine, one of the agents used in lymphodepletion chemotherapy, the patient will be infused with the TIL therapy. In order to best assist the lymphocytes, additional IL-2 doses will be directly administered to the patient 3-24 hours post-TILs. Ideally, the patients should receive six doses of 600,000 units/kg of IL-2 every 8-12 hours as tolerated. The issue with creating an inflammatory response is that while it helps the immune response, you end up…well, inflamed.

Cellular therapies are often associated with Cytokine Release Syndrome (CRS), manifesting as fever, hypotension, and hypoxia. The incidence is much lower with TILs as they are non-modified patient- derived T-cells. However, due to the IL-2 administration, there may be some signs of CRS. While steroids are generally the go-to for controlling inflammation, in the case of TILs, they should be reserved as last- line as steroids will diminish the TILs response. That’s just time and money down the drain. Oftentimes, supportive care and discontinuing the IL-2 infusions will control the symptoms. IL-2 has a short half-life, as well, so symptoms subside within a day of the last infusion.

During my bone marrow transplant rotation at Weill-Cornell Medical Center, I was able to witness the first two TILs patients post-FDA approval in New York. It was incredible seeing how quickly TILs worked. Within two days after infusion, one of our patient’s nodules began to shrink. I’m eager to see more centers across the country begin using TIL therapy to continue to see their impact on response rates.

This article has been submitted in collaboration with the Rho Chi Honor Society.