A novel immunotherapy combination has demonstrated remarkable early efficacy in patients with recurrent glioblastoma (GBM), achieving 100% disease control in the first five patients treated in a pilot study. The chemotherapy-free regimen combines nogapendekin alfa inbakicept-pmln (Anktiva), an interleukin-15 (IL-15) agonist, with natural killer (NK) cell therapy and tumor treating fields (TTFields).
Initial data from the pilot study (NCT06061809) showed that all five patients with GBM who had progressed after standard of care achieved disease control, with three patients experiencing objective responses. Notably, two patients achieved near-complete responses, while the remaining two maintained stable disease. Additionally, treatment increased absolute lymphocyte count (ALC) in all five patients who had experienced lymphopenia after standard of care radiation and chemotherapy.
Unprecedented Clinical Response
"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," said Simon Khagi, MD, medical director of neuro-oncology at the Hoag Family Cancer Institute and principal investigator for the study. "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."
The findings are particularly significant given GBM's devastating prognosis. Approximately 12,000 Americans are diagnosed annually with GBM, making it one of the most common types of brain tumor. The disease has the lowest five-year survival rate of any common brain tumor—just 9% for patients aged 45-54 and 6% for ages 55-64.
Study Design and Treatment Protocol
The phase 2, open-label study is recruiting patients at two sites in California. The treatment regimen consists of nogapendekin alfa at 1 mg subcutaneously, PD-L1 t-haNK at approximately 2 x 10^9 cells intravenously, and bevacizumab at 10 mg/kg intravenously during 28-day cycles on days 1 and 15 for a maximum treatment period of 76 weeks/19 cycles.
Eligible patients must have progressive or recurrent disease, have received previous first-line treatment of at least radiotherapy and temozolomide, recovered from prior treatment-related toxicities to grade 2 or less, have a life expectancy of at least 12 weeks, and maintain a Karnofsky performance status of at least 70.
Mechanism of Action
The therapeutic strategy employs a multipronged approach to stimulate the patient's immune system. Nogapendekin alfa, a first-in-class IL-15 agonist, plays a crucial role in the development and function of NK cells and CD8+ killer T cells, both central to the anticancer immune response. By activating these key immune cells, the treatment aims to overcome tumor-induced immunosuppression and restore the immune system's ability to target and kill malignant cells.
"There is compelling evidence that ANKTIVA's mechanism of proliferating NK and T cells plays an important role in treating patients with cancer independent of tumor type," said Patrick Soon-Shiong, MD, founder, executive chairman and global chief scientific and medical officer at ImmunityBio. "By activating the immune system the goal of providing durable responses is at hand. We believe these preliminary results in patients with GBM, whose lymphocyte counts (NK and T cells) are low as a consequence of radiation and chemotherapy after first-line treatment, can be rescued following ANKTIVA and NK cell therapy."
Regulatory Status and Future Development
Nogapendekin alfa is currently FDA-approved with Bacillus Calmette-Guérin (BCG) for treating patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ. The drug 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.
Based on these encouraging early findings, ImmunityBio plans to initiate a randomized trial targeting second-line GBM patients who have recurring disease following standard of care. The primary endpoints of the current study include incidences of treatment-emergent adverse events and serious adverse events, along with clinically significant changes in comprehensive metabolic panel, hematology blood panel, and vital signs.
