Nanrilkefusp Alfa: A Promising Subcutaneous IL-15Rβγ Superagonist

An emerging treatment is drawing attention in the immuno-oncology domain. Nanrilkefusp alfa (nanril; SOT101), is an interleukin (IL)-15 receptor βγ (IL-15Rβγ) superagonist engineered to stimulate natural killer (NK) and CD8+ T cells. In a field working to overcome immune resistance and deepen responses to checkpoint inhibitors, IL-15 therapeutics show potential because of their compelling preclinical activity and encouraging early clinical outcomes. Here’s an overview of nanril’s mechanisms, efficacy, and safety.

Nanril’s Mechanisms

As a fusion protein, nanril is mechanistically distinct, covalently combining a domain of IL-15Rα with IL-15 itself and enhancing selective binding to IL-2/IL-15Rβγ complexes. Unlike high-dose IL-2 therapies, IL-15 and IL-2/IL-15R agonists avoid regulatory T cell (Treg) expansion and activation-induced cell death, maintaining a desirable safety profile while driving cytotoxic lymphocyte proliferation.

Preclinical Research

Taking a look at the preclinical research done on this treatment, mouse models showed that nanril alone or with anti-PD-1 therapy triggered potent anti-tumor responses—markedly dependent on both NK and CD8+ T cells—while simultaneously reshaping the tumor microenvironment toward a more inflammatory, effector cell-rich state.

Pharmacodynamics, pharmacokinetics, and safety profile studies were evaluated in cynomolgus monkeys, finding NK and CD8+ T cell proliferation was stronger with subcutaneous (s.c.) administration compared to intravenous (i.v.). The optimal s.c. administration schedule on days one, two, eight, and nine of each 21-day cycle maximized effector cell activation while preserving proliferative potential over time. With a solid translational rationale, nanril advanced into the first-in-human phase 1/1b trial.

AURELIO-03 Phase 1/1b Trial

The trial nanril advanced into, called AURELIO-03, was a multicenter, open-label, dose-escalation study including 51 patients with advanced/metastatic solid tumors. Nanril monotherapy was delivered subcutaneously as a monotherapy or in combination with i.v. administration of the PD-1 immunotherapy pembrolizumab.

Peripheral blood analyses demonstrated robust, dose-dependent proliferation of NK and CD8+ T cells. In tumor biopsies, nanril increased densities of tumor-infiltrating lymphocytes, especially CD8+ cells, and elevated expression of Th1 and cytotoxicity-related gene signatures. Nanril also enhanced checkpoint blockade by increasing PD1+CD8+ T cells.

As a combination therapy, Nanril’s efficacy was promising, showing the following results:

• Monotherapy (n=26): one partial response (3.8%), five stable disease (19.2%)
• Combination (n=19): one complete response (5.3%), three partial responses (15.8%), 10 stable disease (52.6%)

Disease control rate rose to 85 percent in the combination arm. Notably, a patient with PD-1-refractory cutaneous squamous cell carcinoma achieved a partial response with nanril alone and again upon crossover to combination therapy.

Nanril’s safety profile also proved reassuring. The most common treatment-emergent adverse events were pyrexia at 74.5 percent, injection site reactions at 68.6 percent, and chills at 58.8 percent—mostly low grade. Lymphopenia was the most frequent event greater than or equal to grade three at 52.9 percent, likely reflective of lymphocyte trafficking rather than cytotoxicity. Dose-limiting toxicities were infrequent, and a recommended phase 2 dose of 12 mg/kg was established for both treatment arms.

Nanril’s Future as a Treatment Option

Overall, Nanril’s biologic precision, manageable safety profile, and capacity to synergize with checkpoint inhibition position it as a compelling agent for further development as an immune modulator, not just an additive. By amplifying innate and adaptive arms without triggering Treg dominance or exhaustion, it opens a therapeutic avenue for patients with limited responsiveness to anti-PD-1 therapy alone. Phase 2 trials combining nanril with pembrolizumab and cetuximab are already underway.

Reference:
Champiat S, Garralda E, Galvao V, et al. Nanrilkefusp alfa (SOT101), an IL-15 receptor βγ superagonist, as a single agent or with anti-PD-1 in patients with advanced cancers. Cell Rep Med. 2025;6(2):101967. doi:10.1016/j.xcrm.2025.101967