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Re-irradiation is therapeutically considered for select rGBM patients and may induce immunogenic cell death to stimulate anti-tumor immune responses. Our phase 2 study of re-irradiation with pembrolizumab among rGBM patients evaluated the efficacy and safety of this regimen. METHODS Adult rGBM patients with KPS ≥ 70, a maximum supratentorial tumor diameter of 6 cm who were on ≤ 2mg dexamethasone/day and were ≥ 6 months from initial conventional radiation therapy were eligible. Cohort A (bevacizumab [BEV]-naïve) had ≤ 2 prior progressions while cohort B (BEV-refractory) allowed unlimited progressions but only one on prior BEV. Re-irradiation included 35 Gy over 10 fractions to residual enhancing (cohort A) as well as enhancing + non-enhancing (cohort B) disease. Pembrolizumab was administered at 200 mg every three weeks beginning within one week of re-irradiation start. BEV was administered at 15 mg/kg every three weeks for cohort B only. RESULTS Sixty patients enrolled (n = 30 per cohort) with a median age of 61 years (range 20-76), 47% were female and 53% enrolled after 2 or more progressions. Grade 3 events deemed at least possibly related to study therapy in > one patient for cohort A included headache (n = 2) and for cohort B included elevated ALT (n = 2) and hypertension (n = 5). No grade 4 events occurred in more than single patients per cohort and no grade 5 events occurred. Median PFS and PFS-6 were 4.9 months (95% CI: 3.5, 5.6) and 26.0% (95% CI: 12.3%, 43.0%) for cohort A and 4.14 months (95% CI: 3.45, 5.42) and 16.9% (95% CI: 5.4, 33.7) for cohort B. Median survival for cohorts A and B were 11.5 months (95% CI: 9.6, 14.1) and 7.6 months (95% CI 5.5, 9.3), respectively. CONCLUSIONS Re-irradiation with pembrolizumab was overall well tolerated and achieved comparable efficacy to historical salvage therapy established with lomustine.

BACKGROUND: Absolute quantification of metabolites in MR spectroscopic imaging (MRSI) requires a stable reference signal of known concentration. The Electronic REference To access In vivo Concentrations (ERETIC) has shown great promise but has not been applied in patients and 3D MRSI. ERETIC hardware has not been integrated with receive arrays due to technical challenges, such as coil combination and unwanted coupling between multiple ERETIC and receive channels, for which we developed mitigation strategies. PURPOSE: To develop absolute quantification for whole-brain MRSI in glioma patients. STUDY TYPE: Prospective. POPULATION: Five healthy volunteers and three patients with isocitrate dehydrogenase mutant glioma (27% female). Calibration and coil loading phantoms. FIELD STRENGTH/SEQUENCE: A 3T; Adiabatic spin-echo spiral 3D MRSI with real-time motion correction, Fluid Attenuated Inversion Recovery (FLAIR), Gradient Recalled Echo (GRE), Multi-echo Magnetization Prepared Rapid Acquisition of Gradient Echo (MEMPRAGE). ASSESSMENT: Absolute quantification was performed for five brain metabolites (total N-acetyl-aspartate [NAA]/creatine/choline, glutamine + glutamate, myoinositol) and the oncometabolite 2-hydroxyglutarate using a custom-built 4x-ERETIC/8x-receive array coil. Metabolite quantification was performed with both EREIC and internal water reference methods. ERETIC signal was transmitted via optical link and used to correct coil loading. Inductive and radiative coupling between ERETIC and receive channels were measured. STATISTICAL TESTS: ERETIC and internal water methods for metabolite quantification were compared using Bland–Altman (BA) analysis and the nonparametric Mann–Whitney test. P < 0.05 was considered statistically significant. RESULTS: ERETIC could be integrated in receive arrays and inductive coupling dominated (5–886 times) radiative coupling. Phantoms show proportional scaling of the ERETIC signal with coil loading. The BA analysis demonstrated very good agreement (3.3% ± 1.6%) in healthy volunteers, while there was a large difference (36.1% ± 3.8%) in glioma tumors between metabolite concentrations by ERETIC and internal water quantification. CONCLUSION: Our results indicate that ERETIC integrated with receive arrays and whole-brain MRSI is feasible for brain metabolites quantification. Further validation is required to probe that ERETIC provides more accurate metabolite concentration in glioma patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1

BACKGROUND: Survivin is an anti-apoptotic protein that is highly expressed in glioblastoma (GBM). We conducted a single-arm, multi-center phase II trial in newly diagnosed GBM (nGBM) to determine 6-month progression-free survival (PFS-6), 12-month overall survival (OS-12) and immunologic response in patients treated with surgery, chemoradiation, adjuvant temozolomide (TMZ) and survivin-targeted immunization. METHODS: Patients with nGBM who hadwith HLA-A*02, -A*03, -A*11 and -A*24 haplotypes and, Karnofsky performance status ≥70 were included. Following craniotomy (3 residual contrast enhancement) and chemoradiation, patients received 4 prime-boost doses of SurVaxM (500 mcg) every 2 weeks, followed by adjuvant TMZ and maintenance SurVaxM every 12 weeks until progression. Immunogenicity of SurVaxM was assessed by measuring anti-survivin antibody levels and survivin-specific CD8+ T-cells using multimers. RESULTS: Sixty-three patients, median age 60 years (range, 20–82), including 38 males were treated. Survivin expression was detectable in all patients (1–40% ([median = 12%]) of tumor cells by immunohistochemistry). The vaccine was highly immunogenic and produced survivin-specific CD8+ T-cells and antibody (IgG) titers. The regimen was well-tolerated and immunogen-related adverse events were mild with no regimen limiting toxicity attributable to SurVaxM. PFS-6 was 96.7% (C.I. = 87.6%- 99.1%) and OS-12 was 94.2% (C.I. =83.0%-98.1%) as measured from diagnosis. In MGMT methylated, PFS6 of 96.9% (C.I. = 99.6% to 79.8%); OS12 of 98.1% (C.I. = 99.0% to 97.2%) and in unmethylated tumors, PFS6 of 96.6% (C.I. = 99.6% to 78%); OS12 of 88.9% (C.I. = 99% to 77.2%) was observed. Methylated patients with higher survivin levels had significantly better PFS-6 than those with low survivin levels (r = 0.4). CONCLUSIONS: SurVaxM is safe and a promising adjunct therapy in nGBM. Compared to historical matched controls, addition of SurVaxM improved PFS-6 and OS-12 in nGBM. Patients with poor prognostic factors (unmethylated MGMT, higher survivin levels) treated with SurVaxM achieved better survival than expected.