CTLA-4 blockade, the story is not yet over

In this video, Prof Dr Lore Decoster summarised the session titled “CTLA-4 blockade: the story is not over yet,” reviewing the history, mechanisms, clinical relevance, and future directions of CTLA-4 inhibition in oncology. She noted that CTLA-4 was first described in 1987, and its role as an immune checkpoint was identified in 1995. The development of anti–CTLA–4 antibodies followed, revealing a triple mechanism of action: classical checkpoint inhibition through B7 binding, reduction of regulatory T cells in both tumours and peripheral tissues, and remodelling of myeloid cells.

The first clinical study of the anti–CTLA–4 antibody ipilimumab was published in 2003 for the treatment of melanoma. It showed, for the first time, durable tumour responses but also introduced new immune-related toxicities, with grade 3–4 events observed in 43% of patients. These results led to a successful phase III trial and regulatory approval of ipilimumab monotherapy in melanoma. However, ipilimumab alone demonstrated limited activity in most other solid tumours. Importantly, early CTLA-4 trials taught the field key concepts such as immune-related adverse events, pseudo-progression, and the presence of long-term responders reflected in the “tail of the survival curve.”

Because monotherapy was insufficient in other cancers, combination strategies emerged. Dual checkpoint blockade with anti–CTLA-4 plus anti–PD-1 (such as ipilimumab and nivolumab) has improved outcomes in melanoma and shown encouraging results in NSCLC, although many patients still progress early. This led to triplet regimens such as ipilimumab–nivolumab plus chemotherapy, exemplified by the 9LA study, which showed particular benefit for PD-L1–negative tumours. Additional combination approaches include pairing CTLA-4 blockade with anti-VEGF therapies in renal cell carcinoma and exploring triplet immunotherapy involving anti-CTLA-4, anti–PD-1, and anti–LAG-3 agents.

Looking ahead, current efforts focus on increasing the activity of CTLA-4–directed treatments while reducing their toxicity. Several strategies are being developed, including Fc-optimised anti–CTLA-4 antibodies, designed to lessen side effects, and conditionally activated antibodies that become active only within the tumour environment through mechanisms such as tumour-specific proteases or pH-dependent activation. Another promising approach involves bispecific antibodies that target both CTLA-4 and PD-1 simultaneously, producing a stronger and more focused immune response.

A major barrier to optimising treatment remains the absence of validated biomarkers for CTLA-4 blockade. Unlike PD-L1 for anti-PD-1/PD-L1 therapies, though imperfect, no predictive biomarker has been established for CTLA-4 inhibitors. Research is ongoing into potential indicators such as soluble CTLA-4 and tumour T-reg infiltration, but further validation is needed.

Prof Decoster concluded that the development of CTLA-4 therapies is far from complete. Continued innovation in drug design, biomarker discovery, and combination strategies suggests that CTLA-4 blockade will continue to play a crucial role in future cancer therapies.