Jeffrey S. Miller, MD

Jeffrey Miller, MD, 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, discusses what is next to come following an analysis of GTB-3550.

phase 1/2 study (NCT03214666), the safety and efficacy of GTB-3550

 a tri-specific killer engager, in high risk hematological malignancies was being evaluated. However, the study was terminated due to the development of GTB-3650.

According to Miller, GTB-3650 is a second-generation TriKE which works by binding to NK cells. The novel molecule is based on camelid single-domain antibody technology and has shown significantly higher potency than GTB-3550 in preclinical models.

This second-generation trick nearly binds to NK cells a little bit differently. Binding sequences have the capacity to be from whole antibodies, or single chain of fees, which is, what, GTB-3550 is. 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 20 fold better than the GTB-3550 that's currently in the clinic.

 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. 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.

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Jeffrey Miller, MD, discusses what is next to come following an analysis of GTB-3550.


Future Directions for NK Cell Platforms in Hematologic Malignancies

Jeffrey S. Miller, MD, deputy director of the Masonic Comprehensive Cancer Center; professor of medicine in the division of hematology, oncology, and transplantation, the Roger L. and Lynn C. Headrick Chair in Cancer Therapeutics, and associate scientific director of Molecular and Cellular Therapeutics at the University of Minnesota, discusses the findings of a study of the Tri-Specific Killer Engager (TriKE) platform for the activation of natural killer (NK) cells for the treatment of refractory acute myeloid leukemia and other cancers.

Activating NK cells can boost their efficacy in attacking cancer cells to induce remission. The TriKE platform targets CD16 on NK cells and CD33 on myeloid malignancies while delivering interleukin-15 (IL-15), which stimulate NK cells without activating T cells. Miller says that over-activating T cells can lead to cytokine release syndrome (CRS) and neurotoxicity.

In a phase 1/2 trial (NCT03214666), patients with hematological malignancies received a continuous infusion of the protein therapeutic GTB-3550 TriKE starting at 5 μg/kg. According to Miller, the dose had been increased to 150 μg/kg with no dose-limiting toxicity (DLT) in addition to successful proliferation of NK cells.

Miller says that this trial is encouraging and could lead to clinical studies of patients with solid tumors as well. Based on preclinical data, TriKE can be modified to target B7H3, which is expressed in many solid tumor types.

We…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 μg/kg. This is a drug being given currently by continuous infusion and we've not seen any DLT. We started at 5 μg/kg, we're now at 150 μg/kg. 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 CRS and neurotoxicity. We've not seen any of these safety events and what was reported at the meeting is that we had no DLTs.

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. I think that's one of the things that we hope to get into the clinic after [investigational new drug]-enabling studies next year.

Jeffrey S. Miller, MD, discusses the findings of a study of the Tri-Specific Killer Engager platform for the activation of natural killer cells for the treatment of refractory acute myeloid leukemia and other cancers.

Jeffrey S. Miller, MD | Authors

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