Phase I Study of GS-3583, an FMS-like Tyrosine Kinase 3 Agonist Fc Fusion Protein, in Patients with Advanced Solid Tumors

Abstract

Purpose: GS-3583, a FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDCs) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell–mediated antitumor activity in cancer patients. This phase Ib open-label study assessed GS-3583 in adults with advanced solid tumors. Patients and Methods: Multiple escalating doses of GS-3583 (standard 3+3 design) were administered intravenously on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle for up to 52 weeks. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 at each dose level. Results: Thirteen participants enrolled in 4 dose-escalation cohorts, after which the study was terminated following safety review. Median (range) age was 71 (44–79), and 7 (54%) participants were male. There were no DLTs. Seven participants had grade ≥3 AEs; 2 participants had grade 5 AEs, including a second primary malignancy (acute myeloid leukemia) considered treatment-related. Dose-dependent increase in GS-3583 serum exposure was observed in the dose range of 2–20 mg with GS-3583 accumulation at higher dose levels. Expansions of cDCs occurred at all 4 doses with a dose-dependent trend in the durability of the cDC expansion. Conclusions: GS-3583 was relatively well tolerated and induced dose-dependent expansion of cDCs in the periphery of patients with advanced solid tumors. However, development of a second primary malignancy provides a cautionary tale for the FLT3 agonist mechanism.

Multi-Cohort Transcriptomic Profiling of Medical Gas Plasma-Treated Cancers Reveals the Role of Immunogenic Cell Death

“…For example, the enrichment of multiple NFkB activation pathways in plasma-treated prostate cancer cells may denote that the therapeutic regulation of NFkB activation could possibly augment the therapeutic efficacy of plasma treatment in prostate cancer cases [ 69 ]. On the other hand, in cancer cell lines where plasma treatment achieved poor immune activation, further induction of the involved immune pathways, such as the use of an FLT3 agonist in the case of SK-MEL-147, would have a synergistic effect in inducing immunogenic cell death in cancer cells [ 70 , 71 ]. These hypotheses should be evaluated in in vitro studies to further examine the role of medical gas plasma in eliciting potential ICD-enhancers in distinct cancer types [ 72 ].…”