Adaptive NK Cell Platform Shows Safety for Hematological 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.

TRANSCRIPTION:

0:08 |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.

1:08 | 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.

1:26 | 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.