NK Cell Destruction May Boost IL-15 Efficacy in Refractory Cancers

Jeffrey Miller, MD

IL-15, which is a homeostatic factor stimulating natural killer (NK) cells and T cells, has shown little anti-tumor activity as a monotherapy in patients with refractory cancers. Delivering IL-15 in combination with antigen directed NK cell killing may help to improve efficacy.

A phase 1/2 study (NCT03214666) evaluated the safety and efficacy of GTB-3550, a tri-specific killer engager, in high risk hematological malignancies. The non-randomized study has an estimated enrollment of 60 participants and an estimated completion date of August 2025. The primary end points of the study are maximum tolerated dose and the incidence of complete or partial remission due to the experimental treatment. Secondary end points include the incidence of adverse events and overall survival.

The study was split into 2 phases. Phase 1 was a dose finding phase and phase 2 was a dose expansion phase. During the study, all patients received GTB-3550. 

In an interview with Targeted Oncology™: Jeffrey Miller, MD, a professor of medicine in the Division of Hematology, Oncology, and Transplantation, deputy director of the Masonic Cancer Center, the Roger L. and Lynn C. Headrick Chari in Cancer Therapeutics, and associate scientific director of Molecular and Cellular Therapeutics at the University of Minnesota Medical School, discussed the use of NK cell destruction to boost IL-15 efficacy in refractory tumors.

TARGETED ONCOLOGY™: Can you discuss your analysis on GTB-3550?

MILLER: NKs are lymphocytes in the body, that have the capacity to kill cancer cells. I initially got involved in the NK field based on doing adoptive transfer. And one of the things that we realized after treating really hundreds of patients is that NK cells needed an additional specificity signal to be more active. So, this is when we really built this Tri-Specific Killer Engager (TRICK) platform. So, it's an immune engager, that binds to the FC receptor on the NK cell surface called CD16. The key piece to why we think that this is so interesting to us is it's actually a combination drug, and it has an IL-15 sequence between the NK cell engager and the target cell engager. 

So, we first did a number of preclinical studies using an in vitro assay, using acute myeloid leukemia targets of either cell lines or primary cells. And this is really the background work that led up to the current study. We then produced the GTB-3550 molecule, got it cleared by the FDA and started a clinical trial.

What were the results of this study?

The thing that's been the most interesting to me in the study, remember, as I explained in the introduction, we really have an IL-15 drug delivery, with specificity to the immune synapse between an NK cell and a tumor target. And we've done a lot of immune monitoring analysis on patients from the clinical trial. What I showed was an update of a couple of things. First of all, because we have targeted delivery of IL-15, we've been dosing now to levels of 150 microgram per kilogram. And this is a drug being given currently by continuous infusion. And we've not seen any dose limiting toxicity. We started at five micrograms per kilogram, we're now at 150 micrograms per kilogram. So by design, there seems to be something relatively special about this targeted delivery of IL-15 that is very, very much more specific to NK cells, but not does not have off target activity on T cells. The reason we think this might be important is when T cells get over activated, we know that that can lead to cytokine release syndrome and neurotoxicity. And we've not seen any of these safety events. And what was reported at the meeting is that we had no dose limiting toxicity. So again, this is the rationale for us to take this proof of concept that we have in this first clinical trial, and now change out the targeting domain, to really start attacking the more common solid tumors. And again, B7H3 is really, really interesting, because it's a pan solid tumor target. And I think that's one of the things that we hope to get into the clinic after IND enabling studies next year.

What can you tell community oncologists about the kind of patients that you're looking for as you continue this analysis?

Oftentimes it's a case in science, as we are doing clinical trials, we find out that there might be improvements that can be made to the drug. So, we're trying to make a decision with a company that we've been working in partnership with here on whether to continue to the actual target goal of the patients or whether to transition to what we call the second-generation TriKE. This second-generation trick nearly binds to NK cells a little bit different. Binding sequences have the capacity to be from whole antibodies, or single chain of fees, which is, what, GTB-3550 is. And we've discovered that if you use a single heavy chain antibody and take that binding sequence, that you can get a camelid binding domain that seems to be tighter, and gives us potency of a drug that is more than 10 to 24 fold better than the GTB-3550 that's currently in the clinic. So, I think the decision we're trying to make now is how far to go with GTB-3550. I think that at least from the academic perspective, one should go with where their data is. I've been advocating for a plan to continue on with these studies, but then go to the better druggable compound that has better binding activity. So I think we're in the process of going through those logistics, obviously talking to the FDA, and trying to weigh all those decisions before we figure if we're going to really go to the initial targeted dose, or whether we're going to try to keep that as proof of concept, and then move on with the better concept that we think will have a better clinical activity. 

What is the timeline?

At least we've been able to muster up the support with a company sponsor to start the commercially manufacture for that second-generation drug. The only downside is like everything, it takes a little bit of time. And I think that the goal is to have a clinical drug for human use some time by the middle of 2022 and we're almost to the end of 2021. So, this is part of the strategic decision making. We have good proof of concept. The other thing that I presented at the meeting is a drug really in the immune monitoring assay reacts exactly like we expected it to do in a preclinical study. So, it increased NK cells, had very little activity to T cells. And again, we saw no dose limiting toxicity. So that's been the motivation to say, maybe taking a pause, or with limited accrual on to the current trail to just explore the extended safety and move on to the second generation platform, I think in the long run is probably going to be a smarter way to go moving forward. And the only delay factor is really clinical quantities of commercially manufactured drug, which is what we're working on now.

_REFERENCE:

_{Miller J, Warlick E, Wangen R, et al. GTB-3550 tri-specific killer engager safely activates and delivers IL-15 to NK cells, but not T-cells, in immune suppressed patients with advanced myeloid malignancies, a novel paradigm exportable to solid tumors expressing Her2 or B7H3. Ann Oncol. 2021;32(5): S829-S866. doi: 10.1016/annonc/annonc705}