The advent of immune checkpoint inhibitors, such as PD-1/PD-L1 antibodies, has been a revolution in oncology, providing hope for long-term survival to countless patients with advanced cancer. However, a harsh reality remains: only about 20% to 30% of patients benefit significantly, while more than half either show no initial response or develop resistance after a period of treatment. Overcoming this resistance to extend the benefits of immunotherapy to more patients is currently one of the most urgent challenges in oncology.
Scientists have been searching for the "culprit" behind this resistance. In recent years, the protein Transforming Growth Factor-beta 1 (TGF-β1) has come into focus. It is often described as the "master of immunosuppression" in the tumor microenvironment. TGF-β1 helps tumor cells "disguise" themselves to evade immune attacks and can also "subvert" immune cells, causing them to lose their fighting capacity. This makes it a key mechanism behind the failure of immunotherapy. However, targeting TGF-β has been difficult; previous drugs targeting this protein often failed due to severe toxic side effects. Now, a breakthrough Phase I clinical study has brought a turning point.
Recently, a research report titled "Linavonkibart and pembrolizumab in immune checkpoint blockade-resistant advanced solid tumors: a phase 1 trial" was published in the international journal Nature Medicine. Results from the Phase I DRAGON trial, conducted by scientists from the University of Texas MD Anderson Cancer Center and other institutions, introduced a novel monoclonal antibody called linavonkibart. This drug is poised to become the "key" to unlocking the puzzle of immunotherapy resistance.
Why is targeting TGF-β1 so difficult?
The TGF-β family consists of several members (β1, β2, and β3). While TGF-β1 is a "bad actor" that promotes tumor growth and immune escape, TGF-β2 and β3 are "good citizens" essential for maintaining normal physiological functions in the heart and blood vessels. Previous drugs acted like "carpet bombing," indiscriminately inhibiting all three isoforms. Consequently, while attacking the tumor, they also severely damaged normal tissues, leading to intolerable toxicities such as uncontrollable cardiovascular events and bleeding. This has long been an insurmountable obstacle in the field.
The highlights of Linavonkibart: Precision and Intelligence
1. First-in-class Selectivity: It is the world's first fully human, selective antibody targeting latent TGF-β1. Acting like a "smart lock," it precisely binds to and locks TGF-β1 in its "off" state, preventing activation, while remaining "blind" to TGF-β2 and β3. In theory, this selectivity significantly reduces toxicity.
2. Fully Human Design: The antibody is composed entirely of human antibody structures. This greatly reduces the risk of the human immune system recognizing the drug as "foreign" and producing anti-drug antibodies, thereby enhancing safety and potential long-term efficacy.
Safe and Effective, Opening a New Window for Resistant Patients
The DRAGON trial was divided into three parts: A1 (monotherapy dose escalation), A2 (combination with pembrolizumab dose escalation), and B (combination dose expansion).
1. Manageable Safety: Among a total of 112 patients, the combination of linavonkibart and pembrolizumab demonstrated a good overall safety profile. The side effect profile was largely consistent with pembrolizumab monotherapy, with only skin reactions identified as a new risk. No dose-limiting toxicities or Grade 4/5 treatment-related serious adverse events were observed, and there were no instances of cytokine release syndrome or infusion interruptions. This provides preliminary validation of the safety advantages of its selective design.
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2. Encouraging Efficacy: Among 78 patients with advanced tumors resistant to prior anti-PD-1 therapy, the combination treatment showed exciting anti-tumor activity:
- Clear Cell Renal Cell Carcinoma (ccRCC): The objective response rate (ORR) reached 20.0%, a significant figure for patients who have failed multiple lines of therapy.
- Melanoma, Head and Neck Squamous Cell Carcinoma, and Urothelial Carcinoma: The ORRs were 18.2%, 9.1%, and 9.1%, respectively.
Exploratory biomarker analysis also identified potential efficacy predictors for ccRCC patients, which will help in the precision screening of populations most likely to benefit in the future.
Figure 1. Clinical efficacy in the part B dose expansion. (Yap T A, et al., 2026)
Professor Timothy Yap stated that this is a very exciting trial because the field has long attempted to effectively target this protein. This could be an important step in helping patients overcome resistance and further benefit from immunotherapy.
While the Phase I results are positive, it is important to recognize that this is still an early-stage study. The long-term safety of the drug and confirmation of its efficacy in larger populations will require validation in subsequent Phase II/III clinical trials. The journey from target confirmation to drug marketing usually takes years or even a decade. However, the DRAGON trial undoubtedly shines a light on this difficult path, proving that ingenious drug design can "tame" once-daunting targets, providing new weapons and tactical ideas for conquering the fortress of cancer immunotherapy resistance.
Reference
Yap T A, et al. Linavonkibart and pembrolizumab in immune checkpoint blockade-resistant advanced solid tumors: a phase 1 trial. Nature Medicine, 2026: 1-10.