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INTRODUCTION Anti-PD-1 immunotherapy induces clinical responses in a subset of glioblastoma (GBM) patients. We previously reported that ERK1/2 phosphorylation (p-ERK) in pre-treatment tumor samples is predictive of overall survival (OS) following adjuvant anti-PD-1 therapy in two independent cohorts of recurrent GBM patients. METHODS Following the Remark criteria for biomarker validation, we investigated p-ERK as a predictive of OS in 24 evaluable tumor samples of recurrent GBM patients from a clinical trial. These patients underwent intracerebral administration of immune checkpoint inhibitors as part of a phase I clinical trial where intracerebral administration of ipilimumab (10 mg) or ipilimumab (5 mg) and nivolumab (10 mg) followed by postsurgical intravenous nivolumab (10 mg) was evaluated (NCT03233152; Duerinck J, et al. JITC, 2021). We quantified cell density of p-ERK+ cells in tumor regions. For exploratory purposes, patients were divided in 3 groups (n=8 per group) bases on p-ERK cell density. RESULTS We observed an incremental OS with high p-ERK GBM patients exhibiting a median OS of 81.6 weeks (95% CI 33.86-NA), intermediate p-ERK median OS of 43.1 weeks (95% CI 33.14-NA), and low p-ERK group with a median OS of 19.3 weeks (95% CI 16.14-NA). A Cox proportional hazards model adjusted for age and IDH mutant status showed a trend for p-ERK association with favorable OS (HR= 0.77, 95% CI 0.6-=1.01, P=0.056). CONCLUSIONS While the number of patients analyzed is relatively small, this study suggests the potential predictive power of p-ERK in an independent prospective GBM cohort treated with an alternative and unique administration approach of immune checkpoint blockade.

BACKGROUND Intra-operative intracerebral (iCE) administration of ipilimumab (IPI) and nivolumab (NIVO) after resection of rGB is safe and resulted in encouraging survival (NCT03233152J; Duerinck et al. JITC 2021). METHODS Eligible patients (pts) underwent a maximal safe resection followed by iCE administration of 5 mg IPI plus 10 mg NIVO and implantation of an Ommaya reservoir through which NIVO (10 mg) and IPI (cohort defined doses of 1-, 5- and 10 mg of IPI) were administered intracavitary (iCA) in combination with NIVO (10 mg) intravenously pre- and postoperatively and Q2w thereafter for up to 24w. RESULTS 20 pts (13 male; median age 58y) were enrolled. One patient was excluded due to an intra-operatively diagnosed epidural bacterial infection. Respectively 4 pts were treated at the 1-, 4 pts at the 5-, and 11 pts at the 10 mg iCA IPI dose level. Median number and range of postoperative iCA administrations of IPI/NIVO was 2 (0-4) at the 1 mg dose level, 5 (1-10) at the 5 mg dose level, and pending for the 10 mg dose level. Most important treatment related adverse events were symptomatic aseptic neutrophilic pleocytosis (3 pts, all treated at the 10 mg IPI dose level), subacute cerebral edema necessitating corticosteroid treatment (5 pts), and bacterial colonization of the Ommaya reservoir (3 pts). There were no G5 AE. Nine pts have progressed and 4 pts died from progressive disease. Molecular-genetic characterization of rGB tissues, analysis of cellular and cytokine content, and NIVO/IPI concentrations in CSV samples are ongoing. CONCLUSION Repeated iCA administration of 10 mg NIVO plus 10 mg IPI resulted in treatment limiting aseptic neutrophilic pleocytosis. Safety of the presumed MTD of repeated 10 mg NIVO plus 5 mg IPI iCA will be further investigated.

Patients with Failed Back Surgery Syndrome (FBSS) report a considerably lower health- related quality of life (HRQoL), compared to the general population. Spinal cord stimulation (SCS) is an effective treatment to offer pain relief in those patients. Despite initial treatment success of SCS, its effect sometimes wears off over time. This study investigates the added value of high dose SCS (HD-SCS) in patients with unsatisfactory conventional SCS, from a quality of life perspective. Seventy-eight FBSS patients who were treated with conventional SCS that failed to provide pain relief, were recruited in 15 centers. HRQoL was assessed before converting to HD-SCS (baseline) and three times after converting to HD-SCS using the EuroQol-5D-3L. Quality adjusted life years (QALY) were calculated and compared with conventional SCS. An overall significant increase over time was seen in utility values of the EQ5D-3L, as the mean value at baseline 0.283 (&plusmn, 0.21) increased to 0.452 (&plusmn, 0.29) at 12 months of HD-SCS. This average increase in utility coincides with an average increase of 0.153 (&plusmn, 0.24) QALY&rsquo, s in comparison to continued conventional SCS. Besides the potential of HD-SCS to salvage patients with failed responses to conventional SCS, this treatment seems to be a more efficient treatment than conventional SCS.

BACKGROUND: Intracerebral (iCE) administration of nivolumab (NIVO) and ipilimumab (IPI) after resection of recurrent glioblastoma (rGB), followed by repeated intravenous(IV) NIVO was recently shown to be feasible, safe and associated with encouraging survival. Subsequent cohorts were defined to investigate the addition of biweekly intracavitary (iCA) or intrathecal (iTH) NIVO +/- IPI administrations. METHODS Four groups were defined according to rGB resectability and postoperative treatment schedule. Group A and D underwent biopsy, B and C maximal safe resection. All patients received iCE injections of 10 mg/1ml NIVO + 5 mg/1ml IPI at the end of surgery, after which an Ommaya catheter was implanted iCA (A, B and C) or iTH (D). Following surgery, all patients received biweekly IV low-dose NIVO(10mg) combined with iCA/iTH 10 mg NIVO (A and B) + 1, 5 or 10 mg IPI (C and D) for up to 24 weeks. NIVO/IPI concentrations were dosed in the cerebrospinal fluid (CSF). Gene sequencing and RNA gene expression profiling were performed on all tissue samples RESULTS 39pts(27 male; 16 in A, 16 in B, 4 in C, 3 in D; recruitment ongoing in C+D) were enrolled. All patients received the predefined dose of iCE IPI/NIVO. Most frequent AEs were fatigue (n=30), headache (n=19), confusion (n=14), dysphasia (n=13), and fever (n=10). Ommaya infection occurred in 5patients, subacute neurological deterioration requiring corticosteroids in 6patients. There were no G5 AEs. irAEs were infrequent and mild. Median PFS and OS were 5w(95% CI 1-8) and 23w(95% CI 0-53) in A and 13w(95% CI 7-19) and 42w(95% CI 30-54) in B, respectively. >90% of CSF samples had elevated protein levels and lymphocytic pleocytosis. There was no evidence for accumulation of NIVO/IPI in the CSF. CONCLUSION Repeated intracavitary or intrathecal administration of NIVO +/- IPI in rGB is feasible and safe. Favourable survival outcome is seen in patients amenable to surgical resection.

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2033 Background: Intracerebral administration of ipilimumab (IPI) and nivolumab (NIVO) following resection of rGB was demonstrated to be safe and resulted in encouraging survival (Duerinck, Schwarze et al. JITC 2021; Neyns et al. ESMO 2021). CD1c(BDCA-1)+ and CD141(BDCA-3)+ myDC play a pivotal role in initiating an adaptive anti-tumor immune response by re-licensing cytotoxic T lymphocytes within the tumor microenvironment. Methods: Eligible patients (pts)(diagnosed with rGB following radiation and temozolomide treatment; not in need of steroids) underwent a leukapheresis followed by immunomagnetic bead isolation and cryopreservation of CD1c (BDCA-1)+ / CD141(BDCA-3)+ myDC. At the time of surgery, an escalating number of myDC (1, 10, and 20x106 myDC) were injected into the brain tissue lining the resection cavity following maximal safe resection of the rGB (ICer) or injected intratumorally (ITum) following stereotactic biopsy (STx). IPI (5 mg) plus NIVO (10 mg) were co-injected with myDC. NIVO was administered intracavitary (ICav, 10mg) using an Ommaya port and intravenously (IV, 10mg) Q2w (max 12x). Results: Fourteen pts (9 male; median 48y [range 20-78]) were recruited (resection n = 11; STx n = 2) and underwent a successful leukapheresis and isolation of myDC; peroperative administration of myDC was preceded by resection in 10 pts (1 pt did not undergo surgery due to clinical deterioration/cerebral edema), and by STx in 2 pts. Respectively 6 (incl both pts who underwent a STx), 3, and 4 pts were treated at the 3 dose levels. All pts received ITum/ICer/IV-administrations of IPI and NIVO as planned. Median number of postoperative ICav/IV NIVO-administrations was 7 (range 2-11). Most frequent adverse events (AE) were headache (n = 11), fatigue (n = 9), transient dysphasia (n = 6), and nausea (n = 5). Bacterial colonization of the Ommaya occurred in 3 pts necessitating removal. Immune-related AE were infrequent and mild. No G5 AE occurred. No dose-limiting toxicities were seen with increasing numbers of myDC. After a median follow-up of 54w, 3 pts remain progression-free (after 42+, 51+, 54+ weeks of FU), 6 (46%) pts have died; median PFS is 13w (95% CI 0-26), median OS has not been reached; 6-months PFS- and OS-rate are respectively 30% and 84%, 12-months PFS- and OS-rate are respectively 23% and 51%. OS compares favorably to an historical cohort of Belgian rGB patients (n = 469; Log-Rank p = 0.018). Gene expression profiling of resected tissue, analysis of cellular counts, cytokines, NIVO/IPI-concentrations in on-treatment cerebrospinal fluid samples is ongoing. Conclusions: Intracranial administration of autologous myDC plus IPI and NIVO in combination with IV NIVO was found to be feasible, sufficiently safe and associated with encouraging survival justifying further investigation in pts with resectable rGB. Clinical trial information: NCT03233152.