Novel Immunotherapy Regime Shows Promise in Recurrent Glioblastoma

A novel, chemotherapy-free regimen combining nogapendekin alfa inbakicept-pmln (Anktiva, formerly N-803), an interleukin-15 (IL-15) agonist, with natural killer (NK) cell therapy and tumor treating fields (TTFields) has demonstrated encouraging early results in a pilot study of patients with recurrent glioblastoma (GBM).¹

Initial data from 5 patients with GBM who had progressed after standard of care showed a 100% disease control rate (DCR), with 3 patients achieving an objective response, including 2 with a near-complete response. Additionally, treatment increased absolute lymphocyte count (ALC) in all 5 patients who had experienced lymphopenia after standard of care radiation and chemotherapy.

The early findings are from a pilot study (NCT06061809) investigating the safety and efficacy of nogapendekin alfa in combination with PD-L1 t-haNK cell therapy and Optune Gio TTFields. This trial marks the first time this specific chemotherapy-free, immune-boosting combination has been used in patients with GBM, a notoriously difficult-to-treat and aggressive form of brain cancer.

“GBM is a devastating type of brain cancer for which there are currently no durable treatment options, which is why this study has such important potential,” said Simon Khagi, MD, medical director of neuro-oncology at the Hoag Family Cancer Institute and the principal investigator for this study, in a press release. “In my years of treating patients with glioblastoma, I have never experienced these near-complete responses as well as the rapidity of the response as seen in these patients to date. There has been little advance in therapy for decades for glioblastoma. This chemotherapy-free, immune-stimulating combination approach with [nogapendekin alfa] is highly promising and may represent a fundamental advance in therapy in patients with tumors of the brain.”

About the Phase 2 Study

The phase 2, open-label study of nogapendekin alfa in GBM is recruiting patients at 2 sites in California.² The study treatment consists of nogapendekin alfa at 1 mg subcutaneously, PD-L1 t-haNK at ~2 x 10⁹ cells intravenously (IV), and bevacizumab at 10 mg/kg IV during 28-day cycles on days 1 and 15 for a maximum treatment period of 76 weeks/19 cycles.

The study’s primary end points are incidences of treatment-emergent adverse events (AEs) and serious AEs and clinically significant changes in comprehensive metabolic panel, hematology blood panel, urinalysis, temperature, heart rate, respiratory rate, blood pressure, and oxygen saturation. Secondary end points include pharmacokinetics.

Patients are required to have progressive or recurrent disease, received previous first-line treatment of at least radiotherapy and temozolomide, recovered from prior treatment-related toxicities to grade 2 or less, a life expectancy of at least 12 weeks, a Karnofsky performance status of at least 70, and an adequately healed craniotomy. Those with serious uncontrolled concomitant disease, a history of serious hemorrhage, evidence of greater than grade 1 central nervous system hemorrhage, systemic autoimmune disease, or inadequate organ function are not eligible for study enrollment.

In an interview with Targeted Oncology, Khagi stressed the importance of quality of life for these patients, noting that the regimen is “intensive,” with visits to the clinic every 2 weeks and a cell therapy that can be “hours long.” However, he also noted that, so far, patients have been tolerating the treatment relatively well.

Mechanism of Action and Clinical Rationale

The therapeutic strategy hinges on a multipronged approach to stimulate the patient's immune system. Nogapendekin alfa is a first-in-class IL-15 agonist. IL-15 is a cytokine that plays a crucial role in the development and function of NK cells and CD8+ killer T cells, both of which are central to the anticancer immune response. By activating these key immune cells, nogapendekin alfa aims to overcome tumor-induced immunosuppression and restore the immune system’s ability to target and kill malignant cells. The combination with PD-L1 t-haNK cell therapy provides an additional layer of immune-mediated killing.

Nogapendekin alfa is approved by the FDA with Bacillus Calmette-Guérin (BCG) for the treatment of patients with BCG-unresponsive non–muscle-invasive bladder cancer with carcinoma in situ with or without papillary tumors.³ It is being evaluated alone and with other agents in multiple studies for non–small cell lung cancer, non-Hodgkin lymphoma, Lynch syndrome, ovarian cancer, and HPV-associated tumors. It is also being studied in HIV and lymphopenia.¹

REFERENCES:

1. Initial Data Shows 100% Disease Control in 5 Out of 5 Patients With Recurrent Glioblastoma With Two Patients in Near Complete Response Treated With ImmunityBio’s ANKTIVA®, NK Cell Therapy Plus Optune Gio® Device. News release. August 26, 2025. Accessed August 26, 2025. https://tinyurl.com/49zwv5yb

2. N-803 and PD-L1 t-haNK Combined With Bevacizumab for Recurrent or Progressive Glioblastoma. ClinicalTrials.gov. Updated August 1, 2025. Accessed August 26, 2025. https://clinicaltrials.gov/study/NCT06061809

3. FDA approves nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer. US FDA. April 22, 2024. Accessed August 26, 2026. https://tinyurl.com/3bcnrzwy