TIL Therapy: Lessons Learned and Potential Future Directions in Care
Experts Amod Sarnaik, MD, and Krishna Komanduri, MD, consider lessons learned about TILs and CAR T-cell therapy in hematologic cancers, and how they anticipate TILs fitting into treatment paradigms for solid tumors.
Transcript:
Amod Sarnaik, MD: Well, that’s a great segue into our final topic, and that involves future directions. Are there any interesting ongoing either trials or data or concepts that you look forward to seeing with regards to the TIL [tumor-infiltrating lymphocyte] space?
Krishna Komanduri, MD: I would say the first thing is that we shouldn’t underestimate the importance of this moment. I mean, it’s been a long time coming. We’ve been talking about cell therapies and gene therapies for a long time, axi-cel [axicabtagene ciloleucel], tisagenlecleucel, and ide-cel [idecabtagene vicleucel] have been absolutely transformative in the setting of CD19 diseases. And lately, we have really remarkable successes in the context of BCMA [B-cell maturation antigen] approaches and now we have TIL therapies. I do think one of the things that we’re going to have to look for is how therapies that require bespoke manufacturing like CAR [chimeric antigen receptor] T-cells and TIL therapy are going to compete with therapies that can quite easily be manufactured at scale like bispecific antibodies that may not have quite the success that TIL therapies or CAR T-cell therapies have, but are a lot easier to manufacture and might not have or won't have, I think, the downside associated with treatment delays.
I think that we’re in a setting and we’re starting to see this in areas like myeloma where we’ve just had a number of dramatic advances. We went from immunomodulatory therapies to proteasome inhibition therapies. Now, we have bispecifics and CARs all competing with other pharmacologic agents. In melanoma, of course, we still have targeted agents that can interfere with MAP [mitogen-activated protein] kinase and MEK [mitogen-activated protein] signaling, for example. I think one of the curious things that we’re going to have to see is how do we as a field come together, sequence therapies, use combination therapies generally as immunologists.
I think that we’re going to be moving further toward combination therapies. And yet those trials are hard to do. These agents are expensive individually, and they’re even more expensive together. So how do we do that and appropriately ask questions as a field in ways that we’re not stepping on each other’s toes and competing with each other as we do these trials? I think that’s going to be a real challenge. I know that that’s not a direct answer to where are we going but I think in a way we have amazing successes and new approved therapies coming and that’s going to create challenges for us as academicians to figure out how to do that. I’m curious if you have any thoughts on that topic or if you can see other obvious directions that we’re going to go in.
Amod Sarnaik, MD: I think one of the interesting points you raised is that there’s going to be a lot of competition between agents and how to sequence. I think also how to attribute biological response to the actual agent in question and what I mean by that is it’s good news that our patients are now living much longer with advanced melanoma than 10 years ago. But what you notice is that some of the efficacy may be additive. Somebody gets a PD-1 antibody, and they progress, there still may be a lingering biological effect of that PD-1 antibody because it’s not the PD-1 antibody that’s exerting the response, it’s the effect of the PD-1 antibody on the immune cell. So unlike chemotherapy, where it’s a nonspecific poison and it only works for as long as the drugs in the patient system, immunotherapy is not like that at all.
And I think one of the things that we do need to develop are surrogates for response, readout assays that are beyond just scanning the patient or functional path, or immunologic assays to detect and track a specific antitumor immunologic response from your treatment. And I think if we’re able to do that, we should be able to logically sequence our patient treatment. And we may be able to do that in a patient-specific way. I think we’re still a bit primitive in our clinical trial design where we take a group of 100 patients and treat them not really understanding that well maybe some portion of that patient population would respond to one treatment better than another. If we’re able to build better readout assays to predict which treatment modality would give the best biological effect, that’ll come a long way for us.
The last thing I wanted to mention, tying it back into some of these preclinical abstracts that we’ve discussed, I do think that improving the efficacy of cell therapy on a per cell basis may have a couple of advantages. Number 1, we may not need to treat patients with such large number of TILs that we’re doing now. I think that is one distinction between CAR T and TIL is that CAR T uses a much smaller number of cells and TIL does and in part it could be the target of your CAR T is a lot more amenable than it is for melanoma or non-small cell lung cancer because you need the TIL to traffic outside of the blood supply which you don’t need for CAR T-cell therapy.
And secondly, the need for such intensive lymphodepletion. If we have more potent T cells, we may be able to attenuate or even do away with the lymphodepletion and that would result in our being able to treat more patients and possibly also give repeated cycles of therapy. Right now, we’re limited in our cycles of therapy because the lymphodepletion can cause some permanent bone marrow fibrosis and bone marrow failure. But if we get tumor-specific TIL, we won’t get the on-target off-tumor effect and then we’ll also get the ability for improved efficacy. What are your thoughts about that?
Krishna Komanduri, MD: Well, first I’d say, no I consider myself card-carrying immunologist. I don’t think I could do much better than you just did, so I won’t try and riff on what you just said. I think all those things are really critical.
Transcript edited for clarity.
