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NIH grant 1UG3NS140118-01A1: Augmenting immunotherapy pharmacodynamics in glioma
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Terry Burns. Award: $712838.
Start: 2026-09-11T00:00:00.
Immunotherapies have had significant success in many cancers. However, the glioma microenvironment is
notoriously immunosuppressive, limiting the efficacy of such agents. Our preclinical studies demonstrated that
glioma-associated myeloid cells depend on polyamines for survival, promoting both immunosuppression and
tumor growth. Polyamines are synthesized by ornithine decarboxylase (ODC), an enzyme that is overexpressed
in cancers, including gliomas. ODC inhibition via difluoromethylornithine (DFMO), or eflornithine, reduces
immunosuppression in multiple cancer models, including gliomas, by increasing T cell recruitment and
decreasing tumor-associated myeloid cells. A combination of DFMO with immune checkpoint inhibitors like anti-
PD-1 or anti-PD-L1 has significantly improved survival in mouse models of grade 4 astrocytoma. DFMO and
anti-PD-1 are well-tolerated alone in clinical trials and standard-of-care treatments, but have never been
deployed in combination for patients with grade 4 astrocytomas, including glioblastoma. Rather than relying
solely on outcome measures of survival which provide no biological insights regarding therapeutic success or
failure, we propose to evaluate efficacy of DFMO+pembrolizumab based on immunotherapeutic impact within
tissue and cerebrospinal fluid (CSF) in a phase I/IIa trial. We hypothesize that inhibiting polyamine biosynthesis
with DFMO can safely augment the impact of pembrolizumab in patients with grade 4 astrocytomas by increasing
T cell recruitment. The phase I trial will involve 18 patients with glioblastoma or grade 4 IDH-mutant astrocytoma,
combining DFMO with pembrolizumab to assess intratumoral drug concentrations (1A) and early
immunotherapeutic impact based on T cell infiltration and myeloid cell abundance via a surgical window-of-
opportunity component (1B). The phase I trial will also evaluate the incidence and severity of adverse events
related to DFMO and pembrolizumab (2A) in the patient population, in addition to identifying the drug dosage
with acceptable toxicity (2B). A Bayesian Optimal Interval design will be used to identify the optimal dose
balancing dose-limiting toxicities and early signals of immunotherapeutic impact, defined as at least a 50%
increase in T cell/myeloid cell ratio relative to each patient’s baseline biopsy. Identification of this optimal dose
will serve as the go/no-go criterion for progressing to the phase IIa trial. In the phase IIa trial, a surgical window-
of-opportunity component will assess the effectiveness of DFMO+pembrolizumab based on immunotherapeutic
impact (Aim 3), namely the changes in the T cell/myeloid cell ratio with DFMO+pembrolizumab compared to
pembrolizumab alone (3A). Pro-inflammatory profiles in CSF samples acquired prior to versus after treatment
will also be used to identify potential biomarkers for the immunotherapeutic impact (3B). Long-term safety and
efficacy of DFMO+pembrolizumab will be assessed (Aim 4), based on the long-term safety profile of the
combination (4A), the change in tumor-derived mutations and proinflammatory cytokines in CSF cell-free DNA
(4B), and if progression occurs, correlation of CSF to post-progression tissue for resistance mechanisms (4C).document fetched 2026-09-20 02:42