Immunomodulatory Activity of a Colony-stimulating Factor-1 Receptor Inhibitor in Patients with Advanced Refractory Breast or Prostate Cancer: A Phase I Study

Abstract

Therapeutics; and grants from Kite/Gilead outside the submitted work. D. Schaer was an employee of Eli Lilly and Company at the time of the study. J. Kauh is a former employee of Eli Lilly and Company. S.F. Slovin has nothing to declare. M. Adamow has nothing to declare. V.S. Blinder reports personal fees from Pfizer outside the submitted work. M. Brahmachary is a former employee of Eli Lilly and Company and may have Eli Lilly and Company stock. M. Carlsen is an employee of Eli Lilly and Company. E. Comen reports consultancy fees from Pfizer, Novartis, Bristol Myers Squibb, COTA, Genentech-Roche, outside the scope of the submitted work. D.C. Danila reports research support from

Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages

“…Radiographic response was assessed per Response Evaluation Criteria in Solid Tumors (RECIST1.1). Circulating CSF1 and IL-34 levels as well as nonclassical monocyte levels were used as biomarkers of CSF1R inhibition, all of which are known to be modulated by CSF1R inhibitors (10,12,14).…”

“…Small molecule inhibitors or antibodies targeting CSF1R (or one of its ligands, CSF1) have advanced into the clinic as direct antitumor treatments or potential immunotherapies (9)(10)(11)(12)(13)(14).…”

Clinical Development of Colony-Stimulating Factor 1 Receptor (CSF1R) Inhibitors

“…(IMC-CS4) [38,39] LVEF decrease, rhabdomyolysis þ AKI, pancreatitis None 100 mg None Durvalumab RG7155 [42] Emactuzumab None None 1000 mg 2 CRs þ 22 PRs in TGCT Avelumab SNDX6532 [45,46] Axatilimab None None 6 mg/kg None Durvalumab CSF1 MCS110 [47] Lacnotuzumab There was reduction in nonclassical (CD14 þ CD16high) monocytes and increase of PD-L1-expressing, CD4 or CD8-positive cells in on-treatment tumor biopsies. [35] FPA008 (cabiralizumab) FPA008 is a humanized immunoglobulin G4 (IgG4) MAB that blocks ligand binding, receptor signaling, and therefore depletes TAMs.…”

“…No response was observed. [39] RG7155 (emactuzumab) RG7155 (emactuzumab) is a MAB that inhibits CSF1R activation. High-affinity binding of dimeric CSF1 to CSF1R requires receptor dimerization, which is inhibited by RG7155's blocking the receptor dimerization interface.…”

Immunological barriers to immunotherapy in primary and metastatic breast cancer

“…Supporting this concept, a CSF1R‐targeting antibody considerably enhances the efficacy of focal RT given in five daily fractions of 2 Gy each in preclinical GBM models, further extending the survival of GBM‐bearing mice (Akkari et al , 2020 ). While CSF1R‐targeting strategies are currently being evaluated in patients with GBM (NCT02829723), CSF1R inhibition has also shown some promise in patients with advanced refractory BC bearing brain metastases (Autio et al , 2020 ), further underscoring the similarities between GBM and BC‐derived brain lesions.…”