Shared insight from Amod Sarnaik, MD, and Krishna Komanduri, MD, on the halted DELTA-1 clinical trial of ITIL-168 in melanoma, followed by a focused discussion of SITC 2022 data on emerging TIL design and manufacturing strategies.
Krishna Komanduri, MD: I think the field also had a bit of a setback in the last few weeks. Another abstract that was reported on was about the design of the DELTA-1 trial, which was another TIL [tumor-infiltrating lymphocyte] trial, in patients who had failed primary therapy with checkpoint inhibitors, and MEK inhibition if BRAF associated. Unfortunately, we got the news just a couple of weeks ago that Instil Bio, the sponsor of that trial, is suspending its lead product, ITIL-168, and has had a significant commercial setback. We don’t know to what extent that will affect the development of other products that are competing. I certainly think it’s always good from my perspective, from an academic perspective, to have healthy competition driving success and providing more options for patients. I think we’re all not yet cognizant of what the factors were, but that’s a bit sad.
We do think the trial you did, and the work that’s happening should lead to an approval sometime. Again, being optimistic and having no idea of what the FDA is exactly thinking, but we’re hopeful that there will be an approved TIL therapy in 2023 for patients who have failed prior melanoma therapies.
Amod Sarnaik, MD: Excellent. I think time permits a couple more abstracts to be discussed, and you as an immunologist should be uniquely poised to answer them. There was an abstract at SITC [Society for Immunotherapy of Cancer annual meeting] by Carmela Passaro, PhD, et al, involving TILs expressing IL-15 [interleukin-15] along with other cytokines. Please comment.
Krishna Komanduri, MD: So a couple of things. I think one of the other abstracts we were going to talk about is the interaction between natural TIL expansion and things like checkpoint inhibitors that regulate how T cells respond. We know that checkpoint inhibitors obviously have a role broadly in human cancers across the solid tumor spectrum. Some pioneering work by Arlene Sharpe, MD, PhD, looked at the role of PD-1 signaling in the TILs, which was also reported at the SITC meeting, and the idea that perhaps if we modulated PD-1 signaling in TILs as they’re being expanded, that could lead to optimized expansion approaches. So this abstract by and colleagues; we talked about the role of IL-2 administered in patients to lead to the survival and expansion of the TILs following an infusion of the patient. But it’s also important to note that IL-2 is used to expand almost all categories of T cells that are in commercial therapies. IL-2 is used in CAR [chimeric antigen receptor] T cell manufacture, it’s used in antivirus-specific T-cell manufacturing. And it is one of the things that is used to expand T cells outside the body in the TIL manufacturing process.
What this group did was use some genetic transduction methods to express other molecules that are also important in T-cell expansion, and that included IL-15 and IL-18, and they had an undisclosed member of the TNF [tumor necrosis factor] receptors family that was also used. All these approaches in conjunction with interferon alpha were used to basically optimize the expansion of the TIL product.
Now, I would say none of this from my perspective is quite ready for prime time, but it tells us, and you thoughtfully mentioned earlier, that the TIL is not common from person to person. The T cells that are around my tumor might be different from the T cells around your tumor. They might have different ratios of CD4 to CD8 cells, regulatory T cells, or other cells. By optimizing the manufacturing environment, it’s very likely that we’ll over time improve the speed of manufacturing, the reliability of manufacturing, and I think the subsets of T cells. You mentioned, for example, in the preclinical analysis that you had done, that if you had more TILs at the end of the product manufacturing time, that was likely something that should theoretically affect clinical responses in vivo.
I think this is an interesting look forward into ways we could use better engineering approaches to generate a better TIL product. I think associated with that, there were a couple of other interesting abstracts where, again, we’ve talked about the interplay between checkpoint inhibitors, not only in patients that relate to their prior responses, but the notion that checkpoint inhibitors on the TILs themselves might be modulated in vitro to get better expansion. Another abstract by Colin Thalhofer, PhD, looked at silencing using an RNA [ribonucleic acid] interference approach of PD-1, which again led to better expansion and potentially the function of those T cells in a more rich and functional product that can be infused.
I think these are some exciting approaches. For all of us who are both clinically and scientifically oriented in this field, as you and I both are, we want to see an approved product go to patients, and we want to see that effectively manufactured and reach patients, and provide a treatment alternative. But I think it’s clear once we have that, there are a number of things that are iterative that can be done in the pipeline to manufacture better products. To more reliably manufacture products, it could be that some patients won’t have a product that’s manufactured, and some of these theoretical approaches might lead to more reliable or successful product manufacturing in a shorter period of time. All of the factors that you talked about are going to be critical for us as we move forward.
Transcript edited for clarity.