Citations

2031 Background: The mammalian target of rapamycin (mTOR) functions within the PI3K/Akt pathway as a critical modulator of cell survival. Preclinical studies in GBM indicate that the combination of mTOR inhibitors, such as everolimus (RAD001), with either radiation therapy (RT) or temozolomide (TMZ) provide increased tumor cell killing. Methods: Newly diagnosed GBM pts were eligible for the study. RAD001 was dosed orally at 70 mg/week weekly, starting 1 week prior to RT/TMZ, and continued throughout RT/TMZ, adjuvant TMZ and then until progression. This was a single arm phase II design powered to detect a true overall survival at 12 months (OS12) of 73% (vs 58% in historical controls). Secondary endpoints were toxicity, response rate, and time to progression (TTP). A subgroup of patients with measurable residual disease were eligible for the PET imaging component of the study, consisting of an 18FLT-PET/CT scan performed before and after the initial two doses of RAD001 but before the first dose of RT or TMZ. Results: 103 patients were accrued to phase II of which 100 were evaluable. The median age was 60.5 years (23-81), median ECOG PS was 1, 46 patients had GTR, 33 STR, and the remainder had biopsy at diagnosis. Treatment tolerance was acceptable: 17% patient had at least one grade 3 hematologic toxicity; 14% had at least one grade 4 hematologic toxicity, 42% had at least one grade 3 non-heme toxicity, while 12% had at least one grade 4 non-heme toxicity. No increased incidence of infectious complications was observed and there were no treatment related deaths. Median PFS was 5.3 months (1.3-21.4), with 22 patients progression free. Mature OS data will be available at the meeting. MGMT methylation status analysis is ongoing. Of the pts who had evaluable FLT-PET data, three of eight (37.5%) had a drop in SUVmax >25% after two treatments of RAD001. Conclusions: RAD001 with standard of care chemoradiation had moderate toxicity. Serial 18FLT-PET was feasible for evaluating drug-induced changes in tumor proliferation following RAD001. Final outcome data and association of MGMT status with outcome will be reported at the meeting.

Abstract Background Immunosuppression in glioblastoma (GBM) is an obstacle to effective immunotherapy. GBM-derived immunosuppressive monocytes are central to this. Programmed cell death ligand 1 (PD-L1) is an immune checkpoint molecule, expressed by GBM cells and GBM extracellular vesicles (EVs). We sought to determine the role of EV-associated PD-L1 in the formation of immunosuppressive monocytes. Methods Monocytes collected from healthy donors were conditioned with GBM-derived EVs to induce the formation of immunosuppressive monocytes, which were quantified via flow cytometry. Donor-matched T cells were subsequently co-cultured with EV-conditioned monocytes in order to assess effects on T-cell proliferation. PD-L1 constitutive overexpression or short hairpin RNA–mediated knockdown was used to determined the role of altered PD-L1 expression. Results GBM EVs interact with both T cells and monocytes but do not directly inhibit T-cell activation. However, GBM EVs induce immunosuppressive monocytes, including myeloid-derived suppressor cells (MDSCs) and nonclassical monocytes (NCMs). MDSCs and NCMs inhibit T-cell proliferation in vitro and are found within GBM in situ. EV PD-L1 expression induces NCMs but not MDSCs, and does not affect EV-conditioned monocytes T-cell inhibition. Conclusion These findings indicate that GBM EV-mediated immunosuppression occurs through induction of immunosuppressive monocytes rather than direct T-cell inhibition and that, while PD-L1 expression is important for the induction of specific immunosuppressive monocyte populations, immunosuppressive signaling mechanisms through EVs are complex and not limited to PD-L1.

Abstract Craniopharyngiomas are surgically challenging brain tumors. Postoperatively, quality of life is often significantly impaired due to neurological and endocrinological complications. Currently, FDA approved systemic treatments are not available for patients in whom craniopharyngiomas recur after surgery and radiation. Papillary craniopharyngiomas are characterized by the presence of BRAFV600E mutations. To date, five case reports have been published on the treatment of BRAFV600E mutant papillary craniopharyngiomas with BRAF and/or MEK inhibitors. In this presentation, authors from all five previously published reports share their collective experience and provide updated follow-up on their patients, thus generating an overview of all currently available information on targeted therapy in patients with BRAFV600E mutant papillary craniopharyngiomas. We have also included information on an additional patient with a papillary craniopharyngioma recently treated with BRAF and MEK inhibitors after tumor biopsy alone, in the absence of recurrence, highlighting the potential for a neo-adjuvant therapeutic approach. All six cases in our series showed dramatic responses to targeted treatment with BRAF (and MEK) inhibitors. Collectively, our cases are highly promising and informative for patient treatment, although uncertainty remains with regards to the optimal timing, the specific agents (single agent or dual therapy) to be used and the duration of treatment. The ongoing multicenter phase II Alliance A071601 trial (NCT03224767) of vemurafenib and cobimetinib for patients with biopsy-proven residual or recurrent papillary craniopharyngiomas should provide additional information to help guide patient management.

Abstract Panobinostat (PBST) is a histone deacetylase inhibitor with biologic rationale in the treatment of gliomas harboring H3 K27M mutation. METHODS We performed a retrospective medical record review of adult patients with H3 K27M mutant diffuse midline glioma treated with PBST at Mayo Clinic (Rochester, MN). RESULTS Four patients were identified with a mean age 40 years (range 22–62 years). Tumor location was: spinal cord (thoracic n=1, cervical n=1), brainstem (n=1), and thalamus (n=1).Two patients underwent biopsy alone while two underwent a partial resection. Three patients were treated with radiation (36–54 Gy) immediately prior to PBST monotherapy, and one patient was treated with PBST monotherapy without preceding radiation. All patients were otherwise chemotherapy naïve and did not receive any concurrent chemotherapy with PBST. PBST was dosed at either 10 mg (n=1) or 20mg (n=3) administered on days 1, 3, 5, 8, 10 and 12 of 21 day cycles. The mean duration of PBST therapy was 5 months (range 2–11 months). PBST was well tolerated overall. One patient experienced an objective response per RANO criteria. Two patients continue on therapy (5 cycles, 12 cycles) with stable disease. One patient rapidly progressed after 2 cycles of PBST therapy. In contrast with the patients who derived benefit from PBST, this patient was younger (22) and had multifocal disease with leptomeningeal involvement at treatment onset. The average progression free survival post PBST initiation was 8 months. CONCLUSION This single institution case series shows promise that PBST may have therapeutic benefit in adult patients with H3 K27M mutant diffuse midline glioma.

Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor, and novel therapeutic strategies that make a substantial impact on outcomes are sorely needed. Immunotherapies have shown great promise in the treatment of a number of cancers in recent year, and a concerted effort is being made to apply these treatment paradigms to GBM. However, many GBM patients exhibit profound immunosuppression, likely limiting the efficacy of such approaches. The mechanisms of this immunosuppression are poorly understood, but tumor-derived extracellular vesicles (EVs), may play a role. We demonstrate that GBM-derived EVs induce the development of myeloid-derived suppressor cells (MDSCs) and non-classical monocytes (NCMs). We further demonstrate that these EV-induced monocytic cells are immunosuppressive, resulting in impaired T cell proliferation upon co-culture. We found that the immunosuppressive effects of tumor-derived EVs appear to be driven by the induction of these immunosuppressive monocytes, as EV treatment of T cells did not significantly impact T cell proliferation. Further, we sought to characterize the important of programmed death ligand 1 (PD-L1) in the induction of these immunosuppressive monocyte populations. We found PD-L1 to be expressed in the EVs from GBM cell lines, and that modulation in PD-L1 expression via either constitutive overexpression or shRNA-mediated knockdown resulted in concordant changes in expression in tumor-derived EVs. We demonstrate that PD-L1 is important for the induction of NCM but not for MDSCs. Taken together, these findings point to a significant role for tumor-derived EVs in the induction of immunosuppressive monocytes in GBM, and that these cells may be a driving force of systemic immunosuppression. PD-L1 is one factor expressed in EVs that has immunomodulatory properties, but additional EV cargo likely plays a major role in the induction of immunosuppressive cells.

Abstract BACKGROUND The Tumor Treating Fields (TTF) mechanism of action is hypothesized act upon mitosis by disrupting the cell spindle apparatus. However, biomarkers and human tissue correlation of the effect of the TTF device are lacking. CASE: A 41 year-old previously healthy woman was found to have a right frontoparietal glioblastoma after she developed subacute onset of left hemiparesis and headache. The tumor was IDH wild type MGMT promoter unmethylated and TERT mutated. Chromosomal Microarray (CMA) was performed and demonstrated genome wide aneuploidy primarily characterized by hyperdiploidy. She underwent a gross total resection of the enhancing portion of the tumor and subsequent standard chemoradiotherapy (60 Gy IMRT with concomitant temozolomide) followed by initiation of the TTF device and adjuvant temozolomide. Six months after diagnosis, after 72 days of using the TTF device with 75% compliance and completion of the third cycle of temozolomide the patient had radiographic recurrence. She underwent a repeat resection. Pathology demonstrated recurrent tumor. Genetic analysis no longer demonstrated chromosomal losses or gains: the tumor was diploid. DISCUSSION This case may be a demonstration of effect of the TTF device applying a selective pressure to cells with multiple chromosomal gains and losses as the efficiency of mitosis in these cells may already be severely compromised. We are currently performing CMA on all patients with available tissue treated with the TTF device at our institution, with a planned retrospective analysis to explore this hypothesis further. CONCLUSION Repeat resection with detailed genetic analysis of GBM recurrence after therapies may help generate hypotheses regarding mechanisms of resistance, and in this case, mechanisms of action of the TTF.

Abstract INTRODUCTION. Although uncommon, involvement of the central nervous system (CNS) is the most common extramedullary manifestation of Chronic Lymphocytic Leukemia (CLL). Nonetheless, a broad array of conditions can lead to neurologic symptoms in CLL patients and distinguishing between clinically significant CLL involvement of the CNS and other etiologies can be challenging. The actual prevalence of CNS involvement by CLL is unknown, the only available data being case reports and small case series. METHODS. Between 01/1995 and 11/2014, 186 of the 4317 (4%) patients with CLL followed at our center underwent an MRI of the CNS (e.g. brain, spine) and/or a lumbar puncture (LP) with cerebral spinal fluid (CSF) analysis to evaluate neurologic symptoms. As the mere presence of CLL cells in the CSF is not diagnostic of clinically significant CNS disease, a final diagnosis of clinically significant CNS involvement by CLL was established by the collaborative review of the pathologist, neurologist and treating hematologist based on comprehensive work-up and multi-disciplinary evaluation. RESULTS. After evaluation, the etiology of neurologic symptoms was clinically significant involvement of the CNS by CLL in 19 (10%) patients, CNS Richter Syndrome (RS) in 15 (8%), infection in 42 (23%), autoimmune conditions in 31 (17%), other cancer in 9 (5%), and another etiology in 70 (37%). The sensitivity of LP to detect clinically significant CNS involvement by CLL was 89%, however its specificity was only 42% where CLL cells were also frequently observed in the CSF in concomitance with inflammatory processes, such as infections and autoimmune disease. Factors associated with clinically significant CNS involvement by CLL/RS were mutated IGHV (p=0.04), low CSF glucose (p=0.02), elevated CSF total nucleated cells (TNC)(p=0.004), lymphocytes (p=0.02) and CLL cells, both as absolute count (p=0.05) and percentage of TNC (p=0.02). Median OS among patients with clinically significant CNS involvement by CLL or RS were 21 and 11 months, respectively. Median OS for patients with neurological symptoms secondary to infection was 6 months, to autoimmune process was 63 months, to other cancers was 19 months, and to other non-CLL related etiologies was 37 months. CONCLUSIONS. Clinically significant CNS involvement by CLL and RS are rare conditions. Neurologic symptoms in patients with CLL are attributable to non-CLL-related etiologies in the majority of cases, even when CLL B-cells are present in the CSF. Analysis of the CSF has high sensitivity but limited specificity to distinguish clinically significant CNS involvement by CLL from other etiologies. Comprehensive evaluation is required before attributing neurologic symptoms to CLL. Disclosures No relevant conflicts of interest to declare.

Pilocytic astrocytomas (PA) are highly vascular tumors with vascular endothelial growth factor (VEGF)–vascular endothelial growth factor receptor-2 (VEGFR-2) signaling present in the tumor vasculature. PA may, therefore, be responsive to VEGF blockade with bevacizumab (BEV). Data regarding the use of BEV in refractory PA in adults are limited primarily to case reports and case series of patients with recurrent PA. We conducted a single-center, retrospective cohort study from 2009 to 2018. We screened 426 patients with pathologically confirmed PA. We identified 5 adult patients with PA who received BEV at our institution with sufficient clinical follow-up to derive evidence of the efficacy and toxicity. All 5 patients experienced tumor progression after initial therapies which included surgery, radiation, and chemotherapy. Four patients received BEV as monotherapy, whereas 1 received BEV with the continuation of previously initiated alkylating chemotherapy (temozolomide). The average duration of BEV therapy was 10.2 months (range, 1 to 20 mo) with an average follow-up of 47 months (range, 6 to 112 mo). One patient had a severe necrotizing rash in areas of skin contact and discontinued after 1 cycle of BEV. All patients had stabilization per RANO criteria, with 1 patient experiencing progression after 10 months on treatment. One patient had disease progression 5 years after completion of BEV, but the tumor responded to repeat treatment with BEV. Our institution’s experience with the use of BEV in recurrent PA is in line with previous reports of therapeutic benefit in recurrent adult PA.