Selective antibody shows promise in reversing immunotherapy resistance across several advanced cancer types

A Phase I trial led by researchers at The University of Texas MD Anderson Cancer Center has reported that the novel monoclonal antibody linavonkibart may help to overcome resistance to immune checkpoint inhibitors across several advanced cancer types

A Phase I clinical trial led by a team at The University of Texas MD Anderson Cancer Center, Houston, Texas, USA, has reported that the novel monoclonal antibody linavonkibart demonstrated potential to overcome resistance to anti programmed cell death protein 1 immune checkpoint inhibitors across multiple cancer types.

The study was led by Dr. Timothy Yap, professor of Investigational Cancer Therapeutics and vice president and head of clinical development within MD Anderson’s Therapeutics Discovery division.

“This is a very exciting trial because we have been trying to effectively target this protein, called transforming growth factor beta 1 for a long time,” Yap said.

“We have known that it helps tumours evade the immune system and develop resistance to immunotherapies but, until now, attempts to target it have failed.

“This is potentially a significant step to help patients to overcome resistance and to benefit further from immunotherapies,” he added.

Immune checkpoint inhibitors such as pembrolizumab have transformed the treatment landscape for several cancers, yet many tumours either fail to respond or acquire resistance after an initial period of benefit. Previous research has shown that this resistance frequently involves transforming growth factor beta 1, a cytokine that suppresses anti-tumour immune responses and promotes immune evasion within the tumour microenvironment.

Earlier therapeutic strategies attempted to block transforming growth factor beta signalling more broadly, which resulted in inhibition of transforming growth factor beta 2 and transforming growth factor beta 3 in addition to transforming growth factor beta 1. Subsequent studies demonstrated that transforming growth factor beta 2 and transforming growth factor beta 3 are essential for normal physiological function, which explained why these approaches were associated with substantial dose limiting toxicities.

Linavonkibart has been designed as a first-in-class selective immunotherapy to address this challenge. The antibody binds to transforming growth factor beta 1 in its inactive conformation, thereby preventing its activation while sparing the related isoforms required for normal tissue homeostasis. The agent is also a fully human monoclonal antibody, which means that it is constructed entirely from structures found naturally in the human body. This design aims to reduce immunogenicity and to improve tolerability, an expectation supported by the early clinical data.

The Phase I DRAGON trial was conducted in three parts. These included a single agent dose escalation arm involving 19 patients with a median age of 66 years and four prior lines of therapy, a combination dose escalation arm in which 15 patients with a median age of 65 years received linavonkibart together with pembrolizumab, and a combination dose expansion arm that enrolled 78 patients with a median age of 65 years and a median of three prior lines of therapy.

Across the study, the safety profile was reported as manageable. Combination treatment produced adverse effects consistent with those observed for pembrolizumab monotherapy, with dermatological reactions identified as the main additional risk. No grade four or grade five toxicities or dose limiting toxicities were observed in either dose escalation cohort. Within the dose expansion cohort, rash was the most common adverse event at grade three or higher severity and only four patients experienced any grade four adverse effects.

Clinical activity was observed in the dose expansion cohort, which comprised 78 heavily pre-treated patients whose disease had progressed despite prior immune checkpoint therapy. Investigators reported multiple objective responses, including an objective response rate of 20 per cent in patients with heavily pre-treated advanced clear cell renal cell carcinoma. Exploratory biomarker analyses also identified a potential strategy to select patients within this subgroup who may derive greater benefit from treatment. Responses were additionally recorded in melanoma, head and neck squamous cell carcinoma, and urothelial carcinoma.

“It is notable that our Phase I trial involved a very heavily pre-treated population with a prognosis of just more than three months,” Yap said.

“We believe that this linavonkibart combination will be even more effective when it is given in earlier treatment settings, before significant resistance to immunotherapy has developed,” Yap added.

Further clinical studies are planned to evaluate linavonkibart in earlier lines of therapy and to refine patient selection strategies that could maximise benefit from selective transforming growth factor beta 1 inhibition.

For further reading please visit: 10.1038/s41591-025-04157-w