The IL Believe trial, sponsored by Ascendis Pharma, is a first-in-human Phase 1/2 dose-escalation and expansion study assessing the safety and tolerability of TransCon IL-2 β/γ—a novel investigational IL-2 prodrug—as monotherapy and in combination with pembrolizumab, TransCon TLR7/8 agonist, trastuzumab, T-DM1, or chemotherapy in adults with locally advanced or metastatic solid tumors. The trial is currently active but no longer enrolling.
Ascendis Pharma Oncology Division has completed enrollment in the IL Believe study (NCT05081609), a first-in-human, open-label Phase 1/2 trial investigating TransCon IL-2 β/γ across a broad range of locally advanced and metastatic solid tumor indications. The study employs a dose-escalation design followed by expansion cohorts, evaluating the agent both as a single agent and in multi-drug combinations.
TransCon IL-2 β/γ is engineered using the TransCon prodrug platform, which is designed to selectively engage the IL-2 receptor β/γ subunits while minimizing binding to the α subunit (CD25) expressed on regulatory T cells. This receptor selectivity is intended to preferentially expand cytotoxic CD8+ T cells and NK cells without the preferential stimulation of immunosuppressive Tregs—a key limitation of conventional high-dose IL-2 therapy. The modified pharmacokinetic profile enabled by the TransCon linker technology is hypothesized to widen the therapeutic index compared to recombinant IL-2.
The trial encompasses a clinically diverse set of tumor types and treatment contexts, including platinum-resistant ovarian cancer (3L+), post anti-PD-1/PD-L1 non-small cell and small cell lung cancers, post anti-PD-1 melanoma, neoadjuvant melanoma and NSCLC settings, HER2-positive breast cancer in the third line or beyond, and second- or third-line cervical cancer. Combination arms incorporate pembrolizumab, TransCon TLR7/8 agonist, trastuzumab, trastuzumab emtansine (T-DM1), and cytotoxic chemotherapy, reflecting an intent to explore synergistic immunostimulatory and antitumor mechanisms across distinct tumor microenvironments.
As the trial is active but no longer recruiting, safety, tolerability, and preliminary efficacy data from dose-escalation and expansion cohorts are anticipated. Full characterization of the dose-limiting toxicity profile, recommended Phase 2 dose, and early signals of antitumor activity across the enrolled indications remain pending public disclosure.
Key points
- TransCon IL-2 β/γ is a first-in-human investigational IL-2 β/γ-selective prodrug designed to expand effector T cells and NK cells while limiting Treg stimulation.
- The IL Believe Phase 1/2 trial evaluates monotherapy and combination regimens across platinum-resistant ovarian cancer, post-checkpoint NSCLC and SCLC, melanoma, HER2+ breast cancer, and cervical cancer.
- Combination partners include pembrolizumab, TransCon TLR7/8 agonist, trastuzumab, T-DM1, and chemotherapy.
- The TransCon prodrug platform is intended to optimize the pharmacokinetic profile of IL-2 to improve the therapeutic index over conventional recombinant IL-2.
- The trial is active but no longer recruiting; safety and preliminary efficacy results are pending.
Why it matters
Conventional IL-2 therapy has been limited by systemic toxicity and Treg-mediated immunosuppression; TransCon IL-2 β/γ represents a mechanistically refined approach that, if validated, could expand the utility of IL-2-based immunotherapy across multiple refractory solid tumor settings. Clinicians managing checkpoint-refractory or heavily pretreated malignancies should monitor emerging data from this trial.