Refractory cancers exhibit profound tumor-induced immune suppression. IL-15, the homeostatic factor stimulating NK cells and T-cells, has shown little antitumor activity as a monotherapy and exhibits dose limiting toxicities. We hypothesized that simultaneous targeted delivery of IL-15 and cancer antigen directed NK cell killing would restore a patient’s endogenous NK cells from tumor induced immune suppression. We developed a novel Tri-Specific Killer Engager protein therapeutic, GTB-3550 TriKE™, comprised of two engagers targeting CD16 on NK cells, CD33 on myeloid malignancies, and an IL-15 linker.
Relapsed/refractory CD33+ malignancies were treated with three consecutive weeks of GTB-3550 (5-150 mcg/kg/day) by continuous infusion (CI x 4 days) in a phase I study (NCT03214666). Immune monitoring was assessed. Preclinically, a second generation TriKE using a single domain camelid (cam) anti-CD16, IL-15 and targeting Her2 or B7H3 was tested.
GTB-3550 administered at >10 times the molar equivalent MTD of rhIL-15 was found to be safe. All lymphocytes decreased from blood during CI egressing into tissues with a dose-dependent proliferative rebound after 3 days of rest. After week 2 and 3 of CI, almost all NK cells were proliferating (Ki-67+) with little proliferation of CD4 or CD8 T-cells. GTB-3550 rescued patientʼs NK cells from immune suppression resulting in cells that were highly functional, predominantly CD16+, and retained enhanced killing for weeks after CI was discontinued. Preclinically, second generation TriKEs against Her2 and B7H3 showed the same targeted delivery of IL-15 to NK cells, in vitro activity to relevant antigen expressing targets, rescue of tumor-induced immune suppression from blood of advanced cancer patients and in vivo activity in xenogeneic models of human tumor.
GTB-3550 TriKE given as a monotherapy safely induced a sustained functional expansion of endogenous NK cells with anti-tumor activity in advanced AML and MDS patients treated with at least 25 mcg/kg/day. Second generation solid tumor TriKE therapeutics against HER2 and B7H3 will be tested clinically next year.
Clinical trial identification
Legal entity responsible for the study
NIH, GT Biopharma.
J.S. Miller: Financial Interests, Personal and Institutional, Advisory Board, Consulting and reserach support: GT Biopharma. D.A. Vallera: Financial Interests, Personal and Institutional, Funding: GT Biopharma. M. Felices: Financial Interests, Personal and Institutional, Research Grant: GT Biopharma. All other authors have declared no conflicts of interest.