Cibisatamab and FAP-4-1BBL Show Activity in Refractory Colorectal Cancer

Overcoming Immune Exclusion in Microsatellite-Stable Colorectal Cancer

Metastatic colorectal cancer remains a leading cause of oncology-related mortality, with five-year survival rates for advanced disease stagnating between 10% and 25% [1]. While immune checkpoint inhibitors have transformed outcomes for patients with high microsatellite instability, these benefits are largely absent in the 90% of patients with microsatellite-stable disease [2]. This resistance is primarily driven by an immunosuppressive tumor microenvironment and a lack of effector T cell infiltration, often referred to as a cold tumor phenotype [3, 4]. Bispecific T cell engagers designed to bridge CD3-positive T cells with tumor-associated antigens like carcinoembryonic antigen represent a strategy to force immune recognition, yet their efficacy as monotherapy has been limited by incomplete T cell activation and the absence of necessary co-stimulatory signals [5, 6]. A new study now evaluates whether adding a localized co-stimulatory agonist can bridge this therapeutic gap and sensitize these recalcitrant tumors to T cell-mediated destruction.

Dual-Targeting Strategy and Trial Design

The researchers investigated a dual-targeting immunotherapy regimen consisting of cibisatamab and FAP-4-1BBL. Cibisatamab is a bispecific antibody designed to engage T cells by simultaneously binding to the carcinoembryonic antigen (CEA) on tumor cells and the CD3 receptor on T cells. To enhance this immune response, the study added FAP-4-1BBL, a molecule that targets fibroblast activation protein (FAP), a protein highly expressed in the connective tissue of tumors, to provide localized co-stimulation through the 4-1BB (CD137) pathway. This approach aims to activate T cells specifically within the tumor microenvironment, potentially avoiding the systemic toxicity often associated with non-targeted co-stimulatory agonists. By focusing the 4-1BB signal on the tumor stroma, clinicians may be able to drive potent T cell activity without the hepatotoxicity that has historically plagued systemic 4-1BB agonists.

This open-label phase 1b dose-escalation trial (NCT04826003) enrolled 52 patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC). All participants had experienced disease progression after receiving at least two prior lines of systemic therapy, representing a population with limited remaining treatment options. The study utilized a dose-escalation framework to evaluate the safety and activity of combining these two agents in a clinical setting where traditional checkpoint inhibitors have historically failed to produce significant responses. For the practicing oncologist, this represents a critical attempt to convert immunologically silent tumors into targets for the patient's own immune system.

Participants received cibisatamab in combination with escalating doses of FAP-4-1BBL, which was administered either on a weekly schedule or every three weeks. To address the risk of immunogenicity, the protocol included pretreatment with obinutuzumab, an anti-CD20 antibody used here to deplete B cells and mitigate the formation of anti-drug antibodies (immune proteins produced by the patient that can neutralize the medication). This structured dosing approach allowed the investigators to monitor for dose-limiting toxicities while assessing the pharmacodynamics (the biochemical and physiological effects of the drug on the body) of the combined T cell engagement and co-stimulation.

Safety Profile and Management of Cytokine Release

The primary endpoint of this phase 1b trial was safety, and the investigators reported that the combination of cibisatamab and FAP-4-1BBL demonstrated a manageable safety profile in this heavily pretreated population. Dose-limiting toxicities occurred in only 2 out of 52 patients (3.8%), and the researchers did not establish a maximum tolerated dose for FAP-4-1BBL, the co-stimulatory ligand. This suggests that the localized delivery of 4-1BB stimulation via fibroblast activation protein targeting may avoid the systemic dose-limiting toxicities often encountered with non-targeted agonists. However, systemic immune activation was still evident through the incidence of cytokine release syndrome (CRS), a systemic inflammatory response characterized by the rapid release of cytokines into the blood. Cytokine release syndrome occurred in 30 out of 52 patients (57.7%), though the majority of these cases were low-grade.

To improve the safety of the regimen, the researchers implemented a dose reduction of cibisatamab to 60 mg during the first treatment cycle. This adjustment significantly impacted the severity of inflammatory events. While grade 3 or higher cytokine release syndrome occurred in 2 out of 52 patients (3.8%) across the entire study, no patients (0 out of 27) experienced grade 3 or higher CRS following the cycle 1 dose reduction to 60 mg. Among these 27 patients treated with the reduced starting dose, serious CRS (events requiring hospitalization or resulting in significant disability) occurred in 4 individuals (14.8%). These data indicate that early-cycle dose titration is a viable strategy for mitigating the risk of severe systemic immune reactions while maintaining the therapeutic window for T cell engagement, a finding that may guide future administration protocols in the outpatient or inpatient setting.

Gastrointestinal adverse events were also observed, which the authors attributed to the expression of carcinoembryonic antigen (CEA) in normal intestinal tissue, leading to off-tumor but on-target T cell engagement. Colitis occurred in 7 out of 52 patients (13.5%), a group that included cases of immune-mediated enterocolitis, an inflammatory condition of the digestive tract. The study also recorded one fatal case of cytomegalovirus colitis, a severe viral infection of the colon that can occur in the setting of therapeutic immunosuppression or intense immune dysregulation. These findings underscore the necessity of rigorous monitoring for gastrointestinal symptoms when utilizing CEA-directed T cell engagers, as the localized immune activation can occasionally lead to significant mucosal injury, requiring prompt clinical intervention.

Antitumor Activity and Intratumoral T Cell Recruitment

The secondary endpoints of the study focused on evaluating antitumor activity, pharmacokinetics (the movement of the drug through the body), and biomarker analyses to determine the biological impact of the combination therapy. In this cohort of 52 patients with heavily pretreated microsatellite-stable metastatic colorectal cancer, confirmed partial responses were observed in 7 out of 52 patients (13.5%). While these objective responses occurred in a minority of the study population, they represent a notable signal in a disease state that is typically resistant to single-agent immunotherapy. The researchers utilized pharmacodynamic analyses to track systemic immune responses following administration, providing a window into how the combination alters the host immune environment.

These pharmacodynamic assessments revealed significant systemic immune activation, characterized by increased systemic levels of interferon gamma (IFNγ), soluble CD25, and soluble 4-1BB (CD137). Interferon gamma serves as a critical cytokine for innate and adaptive immunity, while soluble CD25 and 4-1BB act as markers of T cell activation and costimulation. This systemic response was further evidenced by an increase in activated, proliferating CD8+ T cells in the peripheral blood. These findings suggest that the combination of cibisatamab and FAP-4-1BBL successfully engages the immune system beyond the immediate site of infusion, potentially overcoming the immune-excluded nature of these tumors by generating a pool of circulating effector cells.

The clinical relevance of these systemic changes was confirmed through the analysis of paired tumor biopsies, which allowed the researchers to compare the tumor microenvironment before and during treatment. These biopsies demonstrated increased intratumoral CD8+ T cell infiltration, suggesting that the therapy successfully recruited cytotoxic T cells into the tumor mass. Furthermore, the researchers identified increased intratumoral CD8+Ki67+ T cell infiltration, a specific finding that indicates active proliferation of these immune cells within the tumor itself. By demonstrating that T cells are not only entering the tumor but also actively dividing, these data provide a mechanistic basis for the observed antitumor activity and support the continued clinical development of localized co-stimulation strategies for non-inflamed malignancies, offering a potential path forward for patients who have exhausted standard-of-care options.

References

1. Steup C, Kennel KB, Neurath MF, Fichtner‐Feigl S, Greten FR. Current and emerging concepts for systemic treatment of metastatic colorectal cancer. Gut. 2025. doi:10.1136/gutjnl-2025-335412

2. Ashouri K, Wong AC, Mittal P, et al. Exploring Predictive and Prognostic Biomarkers in Colorectal Cancer: A Comprehensive Review. Cancers. 2024. doi:10.3390/cancers16162796

3. Shebbo S, Binothman N, Darwaish M, et al. Redefining the battle against colorectal cancer: a comprehensive review of emerging immunotherapies and their clinical efficacy. Frontiers in Immunology. 2024. doi:10.3389/fimmu.2024.1350208

4. Pu J, Liu T, Zhou Y, et al. T cells in cancer: mechanistic insights and therapeutic advances. Biomarker Research. 2025. doi:10.1186/s40364-025-00807-w

5. Segal NH, Melero I, Moreno V, et al. CEA-CD3 bispecific antibody cibisatamab with or without atezolizumab in patients with CEA-positive solid tumours: results of two multi-institutional Phase 1 trials. Nature Communications. 2024. doi:10.1038/s41467-024-48479-8

6. Anbari S, Wang H, Zhang Y, et al. Using quantitative systems pharmacology modeling to optimize combination therapy of anti-PD-L1 checkpoint inhibitor and T cell engager. Frontiers in Pharmacology. 2023. doi:10.3389/fphar.2023.1163432