So Dr. Bethoff, can you describe the impact of TIL therapy in melanoma and why this approach is important within the current melanoma treatment paradigm?

Yeah, what a game changer.

You know, when Lifelucil was approved in February of 2024, at that time, we really actually did not have an FDA approval for an agent for patients who were progressing on standard of care checkpoint inhibitor, right? BRAF targeted therapy for the appropriate BRAF mutated patients, which we know has limited durability.

And that was it, right? And patients were either going on clinical trials sometimes getting really refractory chemotherapy or going on hospice.

And to have a true standard of care option with a durable response rate in these patients was truly a game changer.

It has taken some time and some effort to really implement as a true standard of care in clinics across the country.

And I think some key things that we've learned, right? This is not a treatment for every patient.

So, Dr. Bethoff, can you discuss the importance of IL-2 and maybe some of the real-world data that are coming up regarding the number of IL-2 doses during till therapy and then how this might affect tolerability and efficacy?

Can you first tell us how TCR therapy contrasts with TIL therapy? And then can you tell us your thoughts on early returns in this pan-cancer frame-directed therapy?

Yeah.

So I think we actually have three entities that we're sort of talking about here.

So we have TIL therapy where we resect a patient's tumor, identify tumor-infiltrating lymphocytes.

Those are polyclonal against multiple tumor targets.

There are TCR T-cells, and we've seen an IMMA two oh three, which is a actual engineered TCR T-cell.

And these are naive lymphocytes that are obtained via leukapheresis and then engineered to target an intracellular antigen presented by MHC.

So based on these data, is this enough data to finally get personalized vaccines approved for cancer? Do you see this supplanting current options for adjuvant therapy in melanoma?

And so if we look at the biggest differences between how TIL was delivered historically in a mostly research setting versus how it's being delivered in broader practice today, what do you think the biggest differences are realistically for what patients experience or what we should expect in working them up?

Yeah.

So, I mean, I think if we take this all the way back to, you know, the NCI days and the amazing pioneering work that Dr. Rosenberg and his group have done, right? At that point, patients had to fly to Bethesda and have their procedure done there.

And cells were manufactured on site, first only at the NIH and then at very few other sites around the country.

And that completely changed with the ability to centrally manufacture.

Patients can have surgery closer to home, ship tumor, and then central manufacturing cells are then frozen and cryopreserved and shipped back.

And that is a game changer, both from a patient perspective of being closer to home with their own care team, but also from a quality control perspective and a scaling perspective, right? This is very, very hard to do on a large scale if you're a single center.

So what has been your experience around some of these factors? Which ones can we control for versus is just sort of part of the process?