Expert perspectives on the mechanism of action behind tumor-infiltrating lymphocyte (TIL) therapy and how it might address existing unmet needs in the treatment of solid tumors, including melanoma and non–small cell lung cancer.
Amod Sarnaik, MD: Welcome to this OncLive® session titled “Updates on TIL Therapy for Solid Tumors, Including Melanoma and Non–small Cell Lung Cancer.” My name is Dr Amod Sarnaik. I’m a senior member at the H. Lee Moffitt Cancer Center and Research Institute and a professor at the University of South Florida in Tampa, Florida. I have appointments in cutaneous oncology and immunology. I’d like to welcome my colleague, Dr Krishna Komanduri, who’s the chief of hematology-oncology and the clinical director and physician-in-chief at the University of California San Francisco. Welcome, Krishna.
Krishna Komanduri, MD: Thanks so much. It’s a pleasure to be here with you.
Amod Sarnaik, MD: I’d like to start with an introduction for those who are not familiar with TIL, which stands for tumor-infiltrating lymphocyte. This therapy is relatively complex. It’s a cellular therapy that’s gained a lot of attention of late. The treatment involves surgical resection of a portion of a patient’s disease burden. The tumor is explanted into a lab, where the conditions can be artificially manipulated to encourage the proliferation of these immune cells, the T cells that are infiltrating the tumor. These are what we’re going to refer to as TIL. In the patient’s body, TIL tends to be suppressed by the immunoinhibitory microenvironment of the tumor. But in laboratory conditions, usually exposed to high doses of interleukin-2, the TIL mass proliferating can be used as a cellular therapy. The TIL is amplified to tens of billions in number and then infused into the patient.
The treatment itself requires a preparative lymphodepleting chemotherapy, typically cyclophosphamide and fludarabine. That’s immediately followed by the TIL transfer intravenously. The patients receive an abbreviated course of IV [intravenous] bolus interleukin-2. This treatment has been generated to effectively treat patients with advanced melanoma, typically those who are treatment refractory to frontline PD-1 antibody therapy. This treatment has also been used for non–small cell lung cancer. Similar to melanoma, patients tend to be those who have progressed on frontline PD-1 antibody-based therapy. Krishna, do you have anything to add?
Krishna Komanduri, MD: There are a few things, just broadly. We’re all excited about T-cell therapy because we’ve seen dramatic results with T cells, typically chimeric antigen receptor CAR T cells in the context of hematologic malignancies expressing antigens including CD19 in lymphoma and BCMA in the setting of myeloma.
There are a couple of things to highlight. First, those are engineered T cells, so they aren’t pulled out of the patient’s body in a natural setting. We have to use a natural T-cell receptor on those cells, or we have to replace it with something that looks like an antibody, which is the case in the setting of CAR T cells. There are a few important therapeutic distinctions. There’s lymphodepletion that happens in the setting of TIL therapy. Typically, the doses of chemotherapy that we give in CAR T-cell therapy are significantly lower, so the cyclophosphamide doses are a bit higher in the setting of TIL therapy. There’s this need to administer IL-2. That IL-2 is not the IL-2 that some of the older individuals in the audience will remember in the setting of melanoma or especially renal cell cancer. When that was utilized, it often resulted in very high fevers and even vital sign instability and ICU [intensive care unit] transfers. This is a much lower dose of in vivo IL-2, which helps expand the T cells once its infused into the patient but without severe toxicity associated with IL-2 therapy that we used to use.
There are some definite differences. As this program highlights—with 2 of us who come at this from different modalities—it’s something that requires coordination. There’s a surgeon involved who harvests the TILs from the tumor. They are sent away for manufacturing, as they are with CAR T-cell therapy but in this case, the starting product is a tumor and not an apheresis product for CAR T cells. There are some important lessons that we can learn from CAR T-cell therapy, but also some significant differences. It’s great to have our varying perspectives because we’re going to have to come together when it comes to the approval of T-cell therapies to coordinate our own efforts to make this happen in our centers and broadly.
Amod Sarnaik, MD: You raised a couple of important points that help us get a picture of where TIL might fit in in the treatment landscape. When I started doing TIL in our cancer center, I used to say that this form of immunotherapy resulted in some significant adverse effects and treatment-management issues. Soon thereafter, we started treating patients with CAR T. There’s no question that CAR T patients got a lot more sick compared with TIL patients, despite TIL having a bit higher dosing or higher intensity of lymphodepletion.
Having said that, TIL isn’t for everyone. It fits an unmet need, especially for patients who progressed on frontline PD-1 antibody-based therapy. However, you still do have to be judicious in selecting your patients. We typically don’t treat patients over the age of 75 years old, for example. Although the IL-2 is attenuated in dose and number of doses infused, there are still significant hypotension and fluid requirements for those who have COPD [chronic obstructive pulmonary disease] or coronary artery disease. They would have to undergo rigorous testing, such as pulmonary function testing, an echocardiogram, and probably cardiac stress testing in those with a cardiac history, before committing to the treatment. But with the appropriate patient selection, this is an exciting treatment modality that we’re going to hear more about. It has a niche in terms of meeting an unmet need for patients with melanoma, non–small cell lung cancer, and hopefully other solid tumor histologies.
Transcript edited for clarity.