Response in first-in-human chemotherapy-free combination immunotherapy targeting lymphopenia in recurrent glioblastoma multiform (GBM): Nogapendekin alfa inbakicept (NAI) and PD-L1 t-haNK plus bevacizumab (BEV).

e14079 Background: Treatment for recurrent GBM is limited and associated with high mortality. We hypothesize that standard of care for GBM induces severe lymphopenia and, by treating lymphopenia both through in-vivo activation of NK & T cells (via NAI subcutaneous injection) and ex-vivo infusion of NK cells (PD-L1 CAR-NK cells), OS can be prolonged. We hypothesize that lymphocytes, responsible for immunogenic cell death and measured by absolute lymphocyte count (ALC), is key to prolonged survival. NAI, an IL-15 receptor agonist, is the first treatment to address lymphopenia by activating and proliferating NK and T-cells. Methods: Phase 2 QUILT-3.078 trial (NCT06061809) of participants with GBM ( IDH WT) who recurred after surgery and temozolomide/XRT. Fourteen participants received PD-L1 t-haNK, an off-the-shelf NK cell therapy with a chimeric antigen receptor (CAR) for PD-L1, NAI and BEV, every two weeks, as outpatients. Five patients also received concurrent tumor treating fields. ALC levels were measured through data cutoff (January 13, 2026). Results: 14 participants have received 139 total doses, with 7/14 (50%) remaining on therapy. One participant had radiographic complete response after four doses. ALC trend increased from baseline and was maintained through cycle 9 among evaluable participants. Median follow-up is 6.75 months (range 2.4-9.3 months) with four deaths on-study, mOS has not been reached. Ten patients had any SAE, of which one was suspected to be related to BEV (pulmonary embolism) and two SAEs were suspected to be related to the experimental therapy (encephalopathy, temporal arteritis). No CRS or ICANS were observed. Conclusions: These findings support that reconstituting lymphocytes (NK & T cells) results in response, including complete response, in recurrent GBM. This is the first report of disease response in participants with recurrent GBM who received orchestrated systemic immunotherapy with CAR-NK cells combined with an IL-15 agonist and BEV. The potential of reversing lymphopenia induced by SOC treatment, prolonging survival, and improving prognosis across tumor types, may be a paradigm change in cancer care. The QUILT-3.078 Phase 2B expansion study is ongoing and a randomized clinical trial in first and second line GBM patients is in development. At the time of submission, 23/34 participants have enrolled on the QUILT-3.078 Phase 2/2B study and updated data will be presented. Clinical trial information: NCT06061809 .