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NIH grant 1P50CA298941-01A1: Targeting B7-H3 using tri-specific killer engagers (TriKE) to treat metastatic castration-resistant prostate cancer.
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Jeffrey S. Miller. Award: $410012.
Start: 2026-09-18T00:00:00.
PROJECT SUMMARY/ABSTRACT – Project 3
Prostate cancer (PCa) is the most common non-cutaneous malignancy in US men and second most-common
cause of cancer deaths in men. The backbone of treatment consists of androgen-deprivation therapy, using
gonadotropin-releasing hormone agonists or antagonists. Immunotherapeutic approaches exploiting T cells or
dendritic cells have produced modest results in metastatic castration resistant prostate cancer (mCRPC). Over
the past 25 years, our team has focused on natural killer (NK) cell therapeutics and has treated over 500 cancer
patients with NK cell products under 18 INDs. Our best data shows the efficacy of NK cell immunotherapy in the
treatment of acute myeloid leukemia. We have learned that the biggest limitation of NK cell immunotherapy is
the lack of specificity to enable treatment beyond hematologic malignancies. We have also discovered that IL-
15 can activate NK cells without the unwanted effects of IL-2 stimulating suppressive regulatory T cells. We have
performed 3 first-in-human trials using IL-15 agents from the NCI or developed by industry. We have developed
a therapeutic platform that binds and agonistically ligates the most potent single activating receptor on NK cells,
CD16, along with co-stimulation by IL-15 and directed tumor antigen targeting. These Trispecific Killer Engagers
(TriKEs) have been tested in AML without toxicity and show a clinical signal (NCT03214666). To treat prostate
cancer, we modified our TriKE to target B7-H3 because it is expressed on a majority of mCRPC (including those
negative for PSMA), its expression increases with advanced disease, and expression is maintained after
androgen receptor signaling pathway inhibition (ARSI) therapies, such as enzalutamide. Our camelid nanobody
anti-B7-H3 Trispecific Killer Engager (camB7-H3 TriKE) contains three components: an arm that engages and
activates CD16 with high affinity on NK cells; an arm that engages B7-H3 to target mCRPC; and an IL-15 linker
to drive NK cell proliferation and survival. We aim to conduct a multi-center, first-in-human phase Ia clinical trial
to investigate the safety of camB7-H3 TriKE and then a phase Ib study for the treatment of mCRPC patients with
progression on novel ARSIs, to be initiated in early 2026. We will seek to identify the maximum tolerated dose
using the BOIN method. Once a recommended phase Ib dose is established, we will perform a phase Ib trial in
mCRPC progressing on novel ARSIs with a “composite response endpoint” using both PSA and radiographic
criteria. We will then evaluate peripheral blood and the tumor microenvironment immune signatures and tumor
characteristics before and after camB7-H3 TriKE therapy. Finally, we will evaluate pre-clinical formulations to
develop dual antigen targeting of both B7-H3 and PSMA using our TriKE Poly-Antigen Cytokine Complex
(PACC) to potentially reduce tumor antigen escape. We have assembled an experienced team that integrates
the complementary expertise co-led by Drs. Miller (leader in NK cell therapies), Felices and Zorko (NK cell
engager therapies) with Co-I’s Drs. Antonarakis (leader in PCa trial design) and Kennedy (spatial omics) to
complete the studies in this proposal. This study would be the first to target mCRPC with an NK cell engager.document fetched 2026-09-27 02:45