Campian, Jian

Abstract α-PD-1 checkpoint blockade is a promising immunotherapeutic approach for many solid tumors; however, this strategy is minimally effective for GBM patients as a monotherapy. One potential reason why α-PD-1 checkpoint blockade is ineffective is the tumor microenvironment and systemic derangements of the immune system which are prevalent in GBM patients. We have successfully modeled peripheral immune derangements in experimental murine GBM models. These include low peripheral blood CD4 T cell counts, reduced MHC class II expression on monocytes, and atrophy of primary immune organs in animals harboring gliomas. We therefore hypothesized that extended half-life IL-2, a potent cytokine which promotes the proliferation, differentiation, and killing activity of T cells, could overcome immune derangements and could potentially synergize with α-PD-1 checkpoint blockade therapy. In cohorts of C57Bl/6 mice, we supplemented α-PD-1 checkpoint blockade with multiple bio-engineered extended half-life IL-2 molecules to treat GL261 and CT2A orthotopic glioma models which are normally resistant to monotherapy. We observe a statistically significant increase in survival in GL261-bearing animals receiving the combination of extended half-life IL-2 reagents and αPD-1 therapy relative to control-treated mice. Some animals receiving this combination therapy had a reduction in tumor burden to levels below detection. These long-term survivors underwent a rechallenge experiment with a second inoculation of GL261-Luc and effectively cleared tumor without further therapeutic intervention. This intervention causes a significant shift in the immune profile, including the formation of mature T cell responses, as well as restoring the diminished peripheral immune cell counts in GL261-bearing animals. Finally, combining extended half-life IL-2 with α-PD-1 checkpoint blockade is effective independently of the CD8 T cell response. Together, these data suggest that combination immunotherapies employing extended half-life IL-2 fusion proteins are translational to the clinic and do not require the identification of tumor specific antigens for efficacy

Abstract BACKGROUND Craniopharyngiomas, primary brain tumors of the pituitary-hypothalamic axis, can cause significant clinical sequelae. Treatment using surgery, radiation, or both often entails significant morbidity. In prior work, we demonstrated that ninety-five percent of papillary craniopharyngiomas (PCP) harbor BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). In this multicenter National Cancer Institute cooperative group trial (Alliance A071601), we evaluated the safety and efficacy of BRAF/MEK inhibition in patients with PCP without prior irradiation. METHODS Eligible patients, with measurable disease and whose PCP screened positively for BRAF mutations, without prior radiation, received the BRAF/MEK inhibitor combination vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of objective response rate at 4 months based on centrally determined volumetric data was evaluated in 16 patients on this single arm phase 2 trial. RESULTS Based on volumetric response criteria by central radiology review, 15 of 16 patients (94%; 95% CI: 70% to 100%) had a durable objective partial response to therapy. Thus, this study met primary endpoint for overall response rate. The median tumor reduction was 91% (range of 68% to 99%). Median follow-up was 22 months (95% CI: 19 to 30 months) and median number of treatment cycles was 8. Median progression-free survival and duration of response were not yet reached. Three patients progressed during follow-up after therapy was discontinued; none have died. The sole non-responder stopped treatment after eight days due to toxicity. Grade 3 toxicities at least possibly related to treatment occurred in 12 patients (rash in 6 patients). Grade 4 toxicities were observed in two patients: hyperglycemia (n=1) and increased creatine phosphokinase (n=1). Three patients discontinued treatment for adverse events. CONCLUSIONS Our study indicates that BRAF/MEK inhibitors are a safe and effective treatment for PCP without prior irradiation. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; . ClinicalTrials.gov Identifier: NCT03224767.

Abstract BACKGROUND Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity. METHODS The phase II component of ABTC 1801 examined the efficacy of the combination of pamiparib (BeiGene BGB-290) with low dose metronomic temozolomide in recurrent IDHmt grade 2 and 3 gliomas. In this two-stage design, Arm A enrolled patients who had failed two lines and Arm B a single line of alkylator therapy. Pamiparib and temozolomide doses based on phase I results was 60 mg BID and 20 mg daily. Primary endpoint was objective response rate (ORR). RESULTS 39 patients (Arm A 15, Arm B 24) enrolled in the phase II. Median age was 45 (range: 25-69), 56% male, and median KPS 90. 72% of tumors were MGMT methylated. There were no confirmed responses in Arm A and one in Arm B; neither arm met the threshold for additional accrual. One-third of subjects discontinued treatment for reasons other than progressive disease. Estimated median PFS was 5.8 months in Arm A and 11.3 months in Arm B. Seven subjects (Arm A 3, Arm B 4) developed DLT during treatment. Grade 3+ toxicity was principally hematologic; 9 patients had grade 3 anemia, 7 grade 3 and 3 grade 4 neutropenia, and 3 grade 3 thrombocytopenia. In enhancing and non-enhancing tumors from 8 surgical arm patients, median unbound drug tumor/plasma ratios were 0.98 and 0.92, respectively; and median unbound pamiparib tumor concentrations were 209 and 188 nmol/L (or nmol/kg), respectively, which were >20-fold the in vitro IC50 for PARP inhibition. CONCLUSIONS While pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial.

ABSTRACT Introduction Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. Methods In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. Results The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Conclusion Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Abstract Background Neurofibromatosis type 2 (NF2)-related schwannomatosis is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS). In patients with VS associated with NF2, vascular endothelial growth factor A inhibitor, bevacizumab, is a systemic treatment option. The aim of this study is to retrospectively evaluate NF2 patient responses to bevacizumab on VS growth and symptom progression. Methods This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Results Out of 76 patients with NF2 evaluated between 2020 and 2022, we identified 19 that received treatment with bevacizumab. Thirteen of these patients discontinued bevacizumab after median treatment duration of 12.2 months. The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March, 2023. Fifteen patients had evaluable brain MRI data, which demonstrated partial responses in 5 patients, stable disease in 8, and progression in 2. Within 6 months of bevacizumab discontinuation, 5 patients had rebound growth of their VS greater than 20% from their previous tumor volume, while 3 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management. Conclusions Our single-institution experience confirms prior studies that bevacizumab can control progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.

Abstract BACKGROUND D-2-hydroxyglutarate (D-2-HG) is a well-established oncometabolite of isocitrate dehydrogenase (IDH) mutant gliomas. While prior studies have demonstrated that D-2-HG is elevated in the cerebrospinal fluid (CSF) of patients with IDH-mutant gliomas, no study has evaluated the ability of CSF D-2-HG to quantitatively monitor tumor burden and therapeutic response. Toward this goal, we are routinely obtaining CSF samples from patients prior to, during, and after treatment via intra-operative collection and CSF-access devices. MATERIAL AND METHODS Patients were enrolled into our Ommaya reservoir study (NCT04692337), which enables longitudinal access to CSF. The catheter for the implanted reservoir was placed within the surgical resection cavity following a standard-of-care resection. Intra-operatively collected CSF samples were also biobanked through Mayo Clinic’s Neuro-Oncology biorepository. CSF samples were also acquired via clinically indicated ventriculoperitoneal shunts (VP shunts) or external ventricular drains via our ongoing CSF biomarkers study (NCT04692324). D-and-L-2-HG were assayed from each CSF sample via gas chromatography-mass spectrometry (GC-MS) at Mayo Clinic’s Biochemical Genetics Laboratory. RESULTS CSF was collected prior to and after resection in patients via Ommaya reservoirs or VP shunts, all of whom underwent near gross total resections (>95% of tumor volume). D-2-HG and the D/L ratio fell on average by 57.9% (range: 15.1%-98.6%) and 68.8% (range: 49.3%-98.9%), respectively, following resection. In one patient with a largely intraventricular grade 4 IDH-mutant astrocytoma, D-and-L-2-HG fell by 99.1% and 99.3% by post-operative day 2, consistent with the impact of ventricular contact on baseline CSF D-2-HG levels. In patients for whom CSF was collected throughout chemoradiation, with or without immunotherapy, D-2-HG and the D/L ratio continued to decrease over time, despite concern for pseudoprogression versus progression on imaging. CONCLUSION Our early experience with this strategy demonstrates the potential for intracranial CSF D-2-HG as a monitoring biomarker for IDH-mutant gliomas. Work is ongoing to evaluate the reproducibility of these findings in a larger cohort of patients with low or high-grade gliomas, in addition to the impact of tumor recurrence on 2-HG. Future studies will evaluate the impact of IDH inhibitors and other experimental therapies on CSF 2-HG levels for pharmacodynamic monitoring of treatment response.

Abstract BACKGROUND Although glioblastoma (GBM) is the most common malignant primary brain tumor in adults, extracranial metastasis is rare, occurring in <2% of cases. This rarity has been attributed to the blood brain barrier, immunologic factors, lack of traditional lymphatics in the brain, and the poor prognosis of GBM, limiting its opportunity to metastasize. When GBM does metastasize, bone is the most common destination. GBM may spread hematogenously to bone, especially to vertebral bodies via the surrounding venous plexus. In this single-institution study, we review the clinical characteristics of GBM patients with osseous metastases and evaluate potential risk factors and prognostic significance. MATERIAL AND METHODS Using an institutional database, we identified and retrospectively analyzed 6 GBM patients with osseous metastases and studied their demographics, tumor genetics, clinical courses, and outcomes. RESULTS Five of 6 (83%) GBM patients with osseous metastases were male, with a median age of 46 years at GBM diagnosis (range: 20-84). All patients had IDH wild type and MGMT unmethylated GBM with mutations in TP53. Two patients (33%) were initially diagnosed with gliosarcoma. All patients were treated with surgical resection followed by radiation with concurrent and adjuvant temozolomide. Five patients (83%) received bevacizumab for vasogenic edema (n=4) or intracranial tumor progression (n=1) prior to bone metastasis diagnosis. Bone metastases were diagnosed a median of 12.2 months (range: 5.3-35.2) after GBM diagnosis and 4.8 months after starting bevacizumab (range: 3.5-13.2). Two patients (33%) received immune checkpoint inhibitor therapy and two patients (33%) received tumor-treating fields prior to bone metastasis discovery. Bone metastases were symptomatic in 2 patients, presenting with back pain (n=1) and leg weakness and urinary incontinence (n=1). Three patients (50%) had concurrent metastases to other organs. Osseous metastases were biopsy-confirmed in 3 (50%) cases, while the other 3 patients had no known alternative malignancy to explain their bone metastases. After osseous metastasis discovery, the median survival was 27 days (range: 13-225). CONCLUSION Most of our GBM patients with osseous metastases were male and most, but not all, were young at GBM diagnosis. Tumor genetics common to all patients included IDH wild type, MGMT unmethylated status, and TP53 mutation, which may be important for osseous metastasis. Most patients received bevacizumab, which may be associated with earlier metastasis. While rare, metastatic GBM should be within the differential for GBM patients with bone pain or progressive neurologic symptoms, as osseous metastases portend a dismal prognosis in an already aggressive malignancy.

ImportanceSystematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.ObjectiveTo assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.ExposureTreatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.Main Outcomes and MeasuresMain outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.ResultsOf 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).Conclusions and RelevanceIn this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19–related thromboembolism in patients with cancer.