Nature | Safety and Efficacy of Intratumoural Anti-CTLA4 Combined with Intravenous Anti-PD1 in Advanced Melanoma

This study provides critical evidence for melanoma immunotherapy strategies, demonstrating that intratumoural administration of anti-CTLA4 significantly reduces systemic toxicity while preserving antitumor activity, highlighting the clinical value of optimizing delivery routes for immune checkpoint inhibitors.

 

Literature Overview

The article 'Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1', published in Nature, systematically investigates a treatment strategy in patients with advanced melanoma involving intratumoural injection of the anti-CTLA4 antibody ipilimumab combined with intravenous administration of the anti-PD1 antibody nivolumab. Through a randomized multicenter phase Ib NIVIPIT trial, the study evaluates the safety, efficacy, and biomarker profiles of this combination regimen, revealing profound impacts of administration route on toxicity and immune responses.

Background Knowledge

Although current immunotherapies have significantly improved survival in melanoma, combination therapy with anti-CTLA4 and anti-PD1 is often associated with up to 60% grade 3–4 treatment-related adverse events (TRAEs), limiting its broad application. While intravenous ipilimumab is effective, its IgG1 subtype mediates FcγR-dependent immune cell activation, leading to significant systemic toxicity. In contrast, anti-PD1 monotherapy offers limited efficacy, necessitating new strategies that balance effectiveness and safety. This study’s innovation lies in using intratumoural injection to achieve high local concentrations of anti-CTLA4, enhancing intratumoral immune activation while reducing systemic drug exposure and thus minimizing toxicity. This approach relies on a deep understanding of Treg cells, M2 macrophages, and FcγR expression within the tumor microenvironment, offering new biomarker clues for precision immunotherapy.

 

 

Research Methods and Experiments

The study employed a multicenter randomized phase Ib NIVIPIT trial design, enrolling 61 treatment-naïve metastatic melanoma patients who were randomized in a 2:1 ratio to receive either intratumoural ipilimumab (0.3 mg/kg) plus intravenous nivolumab (1 mg/kg) (IT group) or intravenous ipilimumab (3 mg/kg) plus nivolumab (IV group). The primary endpoint was the incidence of grade 3–4 TRAEs at 6 months. The study systematically collected blood and fresh tumor tissue samples at baseline and during treatment for pharmacokinetic, pharmacodynamic, and multi-omics analyses, including WES, RNA-seq, flow cytometry, and IHC, to dissect dynamic changes in the immune microenvironment.

Key Conclusions and Perspectives

• Intratumoural anti-CTLA4 significantly reduced the incidence of grade 3–4 TRAEs (22.6% vs 57.1%), indicating that local administration effectively mitigates systemic toxicity, offering a safer option for patients at high risk of immune-related adverse events (irAEs).
• Objective response rates in injected lesions reached 65.7%, substantially higher than in non-injected lesions (50%), demonstrating that intratumoural anti-CTLA4 exerts potent local antitumor effects and induces systemic immune responses, supporting the presence of an in situ vaccine effect.
• Patients with high baseline expression of activated Treg cells and M2 macrophages in tumors were more likely to achieve durable clinical benefit (DCB), suggesting these immunosuppressive cell populations are prerequisites—not resistance factors—for anti-CTLA4 efficacy.
• A reduction in intratumoural Treg cell proportion was observed only in DCB patients and correlated with high FcγR expression, indicating that FcγR-mediated antibody-dependent cellular cytotoxicity (ADCC) is a key mechanism for anti-CTLA4–mediated Treg cell depletion.
• Systemic immune activation markers such as sCD25 and ICOS increased in both groups, but only DCB patients showed significant increases in cytokines like IFNγ and IL-2, underscoring the predictive value of early immune response dynamics for long-term outcomes.

Research Significance and Prospects

This study redefines the mechanism of action of anti-CTLA4, showing that its efficacy depends on the depletion of intratumoural Treg cells and requires effector cells with high FcγR expression, providing a theoretical foundation for developing next-generation Fc-optimized antibodies. From a drug development perspective, it supports local administration strategies to enhance tumor microenvironment reprogramming while reducing systemic toxicity. In clinical monitoring, baseline abundance of Tregs and M2 macrophages can serve as predictive biomarkers for patient stratification. Additionally, this strategy offers new insights for local control in oligometastatic or neoadjuvant settings, with potential for future exploration in other solid tumors.

 

 

Conclusion

This study establishes the safety and efficacy of combining intratumoural anti-CTLA4 with intravenous anti-PD1 in advanced melanoma, revealing the dual role of Treg cells and M2 macrophages in the tumor immune microenvironment—as both immunosuppressive elements and necessary prerequisites for anti-CTLA4 efficacy. By reducing systemic exposure, this strategy significantly decreases severe adverse events while maintaining antitumor activity, providing a practical optimization pathway for clinical translation. From bench to bedside, the study emphasizes the impact of administration route on the immunotherapy landscape, suggesting future efforts should more precisely regulate drug distribution and immune cell interactions. For melanoma care systems, this finding offers a safer combination immunotherapy option for high-risk patients and lays a biomarker foundation for personalized immunotherapy strategies, potentially driving a paradigm shift from 'one-size-fits-all' to 'precision delivery'.

 

Lambros Tselikas, Sandrine Susini, Matthieu Texier, Caroline Robert, and Aurélien Marabelle. Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1. Nature.