Cibisatamab and FAP-4-1BBL in microsatellite-stable metastatic colorectal cancer

New data recently published on Nature Medicine showed the feasibility of combining tumor antigen-directed T cell engagement by cibisatamab with localized co-stimulation by FAP-4-1BB ligand, with evidence of immune activation and preliminary antitumor activity in microsatellite-stable metastatic colorectal cancer (mCRC).

In this phase 1b trial, a total of 52 patients with microsatellite-stable mCRC progressing after two or more prior therapies received cibisatamab with escalating doses of FAP-4-1BBL weekly or every 3 weeks, after obinutuzumab pretreatment to mitigate anti-drug antibody formation. The combination showed a manageable safety profile, with cytokine release syndrome occurring in 30 patients and gastrointestinal toxicities (colitis) in 7. The treatment resulted in demonstrated systemic immune activation and tumor biopsies showed increased intratumoral CD8+ cells infiltration; confirmed partial responses were observed in 7 patients (13.5%). Despite several limitations, as authors point out «The consistent clinical, pharmacodynamic and biomarker findings support the biological rationale for combining T cell-engaging bispecific antibodies with tumor-localized 4-1BB co-stimulation and warrant further investigation of this strategy in solid tumors. Cibisatamab plus FAP-4-1BBL demonstrates that spatially restricted co-stimulation can enhance intratumoral T cell activation and antitumor activity while maintaining an acceptable safety profile in microsatellite-stable mCRC». As authors conclude, «These findings provide proof of principle that localized co-stimulatory signaling can augment the efficacy of T cell engagers without recapitulating the systemic toxicities associated with untargeted agonists and support further development of T cell engager combinations incorporating tumor-restricted co-stimulation».