A first-in-human study of the fibroblast activation protein–targeted, 4-1BB agonist RO7122290 in patients with advanced solid tumors

Abstract

This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent ( n = 65) or in combination with a 1200-milligram fixed dose of the anti–programmed death-ligand 1 (anti–PD-L1) antibody atezolizumab given every 3 weeks ( n = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8 + and Ki67 + CD8 + T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.

CB307: A Dual Targeting Costimulatory Humabody VH Therapeutic for Treating PSMA-Positive Tumors

“…By this means, we hope to avoid the toxicities found with first-generation CD137 agonists resulting from CD137 expression broadly on immune cells in the periphery, liver, and other on-target off-tumor organs ( 37 ). Although CB307 is, to our knowledge, the first-in-class clinical asset for using PSMA expression to restrict drug-mediated CD137 agonism, this type of tumor-antigen conditional CD137 agonism is a contemporary therapeutic approach with encouraging data reported by targeting CD137 agonism to other tumor-associated antigens including HER2 ( 38 ), FAP ( 39 ), and PD-L1 ( 40, 41 ).…”

Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-β antagonists

“…In our case, we intend to keep TGF-β at bay precisely in the tumor tissue area to which we are providing immunostimulation with IL-12 and anti-CD137 agonists. Our target choice for a 4-1BB agonist rather than other costimulatory members of the TNFR family was based on evidence for clinical activity 30 , 75 , 76 in contrast to reported failures using anti-OX40 mAbs. 77 , 78 , 79 However, other options are possible including engineering CD28, ICOS (inducible T cell costimulator), or CD27 costimulation.…”

Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy

“… I NCT03089203 14 [ 170 ] FAK Pancreatic ductal adenocarcinoma ICB PD-L1 Defactinib, Pembrolizumab, Gemcitabine PR (5%) SD (75%) I NCT02546531 20 [ 171 ] CAF FAP Solid tumors ICB PD-L1 RO7122290, Atezolizumab CR (1.7%) PR (7.8%) I N.A. 115 [ 172 ] FAP Pleural mesothelioma ACT CAR-T Anti-FAP-Δ-CD28/CD3ζ CAR T cells SD (100%) I NCT01722149 1 [ 130 ] FGFR4 Hepatocellular carcinoma ICB PD-L1 BLU-554, CS1001 CR (25%) PR (25%) SD (50%) Ib/II NCT04194801 4 [ 173 ] FGFR1–4 Urothelial carcinoma ICB N.A. Erdafitinib ORR (59.1%) II NCT02365597 22 [ 174 ] ACT adoptive cell therapy, CAF cancer-associated fibroblasts, CR complete response, FAK focal adhesion kinase, FGFR fibroblast growth factor receptor, ICB immune checkpoint blockade, HNSCC head and neck squamous cell carcinoma, HPV human papillomavirus, N.A.…”