Assessing Response of High-Grade Gliomas to Immune Checkpoint           Inhibitors

e13575 Background: Hyperprogressive disease (HPD) has been described in solid tumor patients treated with immune checkpoint inhibitors (ICI). HPD is defined as a ≥2-fold increase in tumor growth rate (TGR) following initiation of ICI. HPD has not been explored in patients with high grade gliomas (HGG) on ICI or standard cytotoxic regimens. In advanced cancer patients receiving ICI, MDM2/4 amplification or EGFR alterations, both found in HGG, correlated with HPD. We compared the rate of HPD in recurrent HGG patients receiving ICIs to those treated with non-immunotherapy agents. Methods: Patients with HGG on ICIs for 1st or 2nd recurrence were compared to a control group receiving other therapies at 1st recurrence. Patients with prior or concurrent bevacizumab or anti-VEGFR were excluded due to pseudoresponse and decreased enhancement with these drugs. HPD was calculated by comparing TGR immediately before and after treatment. Results: 49 patients met inclusion criteria (27 ICI, 25 control). 25/27 patients treated with ICIs and 20/22 patients in the control group had complete imaging and were eligible for analysis. In the ICI group, 60% were men (15/25) and 88% (22/25) had a diagnosis of GBM. 68% were treated at first progression (17/25). Controls were 80% male (16/20) and all had a diagnosis of GBM. 30% (6/20) were 65 years or older at diagnosis in the control group compared to 28% (7/25) in the ICI group. In total, 7/25 patients met criteria for HPD in the ICI group (28%) compared to 4/20 patients in the control group (20%). 10/25 patients (5/7 with HPD) in the ICI group and 8/20 patients (2/4 with HPD) in the control group had next generation sequencing of their tumors. EGFR alterations and MDM2/4 amplifications were not associated with HPD whereas PTEN mutations were more common in the HPD group (71% HPD vs. 33.3% no HPD). Conclusions: HPD is observed in patients with HGG treated with ICI at comparable rates to those with other cancers, but was also observed in 20% of patients receiving other therapies. While the numbers are small, PTEN mutations may be associated with HPD in patients with HGG. In contrast to other solid tumors, EGFR alterations and MDM2/4 amplifications were not associated with HPD in HGG.

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PATH-17. HYPERPROGRESSIVE DISEASE IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS TREATED WITH IMMUNE CHECKPOINT INHIBITORS OR CYTOTOXIC THERAPIES

Neuro-Oncology ◽

10.1093/neuonc/noz175.613 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi146-vi146

Author(s):

Laura Donovan ◽

Samuel Gedailovich ◽

Adela Joanta-Gomez ◽

Andrew Lassman ◽

Fabio Iwamoto

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Fold Increase ◽

Tumor Growth Rate ◽

Control Group ◽

High Grade ◽

Before And After ◽

High Grade Gliomas ◽

Hyperprogressive Disease

Abstract BACKGROUND Hyperprogressive disease (HPD), defined as a ≥ 2-fold increase in tumor growth rate (TGR) compared to baseline following initiation of immune checkpoint inhibitors (ICI), has been described in solid tumors but is not well explored high grade gliomas (HGG). We investigated the rate of HPD in HGG patients receiving ICIs for first or second recurrence compared to those treated with non-immunotherapy agents. METHODS Patients with HGG receiving ICIs for 1st or 2nd recurrence compared to a controls receiving other therapies at first progression. Prior or concurrent bevacizumab or anti-VEGFR were exclusionary due to pseudoresponse and decreased enhancement with these drugs. HPD was calculated by comparing TGR immediately before and after treatment. RESULTS 49 patients met inclusion criteria (27 ICI, 25 control). 25/27 patients receiving ICIs and 20/22 patients in the control group were evaluable in the analysis. The ICI group included 60% men (15/25) and 80% (20/25) had a diagnosis of primary GBM. 68% were treated at first progression (17/25). Controls were 80% male (16/20) and all had a diagnosis of primary GBM. 28% (7/25) of patients met criteria for HPD in the ICI group compared to 4/20 controls (20%). Median OS in patients with primary GBM was 26mo in the ICI group vs. 15.9mo in controls. Median survival past progression in patients with primary GBM receiving ICI for 1st recurrence (13/25) was 12mo vs. 10.6mo in controls. 40% of patients in both groups had next generation sequencing (5/7 with HPD in ICI and 2/4 in control). EGFR alterations and MDM2/4 amplifications were not associated with HPD whereas PTEN mutations were more common in HPD (71% vs. 33.3%). CONCLUSION HPD is observed in patients with HGG treated with ICI at comparable rates to those with other cancers, but was also observed in 20% of patients receiving other therapies.

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PD-L1 expression of high grade glial tumors at diagnosis and change of expression status at recurrence.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2035 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2035-2035 ◽

Cited By ~ 1

Author(s):

Basak Oyan ◽

Seyma Eren ◽

Ozlem Sonmez ◽

Ferda Ozkan ◽

Kaan Yaltırak ◽

...

Keyword(s):

Tumor Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

High Grade ◽

Cross Sectional ◽

Glial Tumors ◽

The Impact ◽

Expression Status ◽

Over Time

2035 Background: PD-L1 expression status is the main predictive factor for response to immune checkpoint inhibitors. PD-L1 status may change over time with the impact of therapies. The aim of this study is to determine if PD-L1 expression status changes in recurrent gliomas after chemoradiotherapy. Methods: Thirty eight patients with recurrent high grade gliomas who had surgical excision at least two times were included in this retrospective cross-sectional study. Nine patients were excluded because of the lack of appropriate pathology slides for pathologic evaluation. PD-L1 expression of 29 patients was evaluated by an expert pathologist with immunohistochemical methods. PD-L1 positivity was defined as expression in ≥1% of tumor cells. Change in PD-L1 expression status was defined as an absolute 5% difference between two resections. Results: Of the 29 patients, 15 patients (51.7%) had PD-L1 expression in ≥1% of tumor cells and 7 patients (24.1%) had PD-L1 expression in ≥10% of tumor cells. Tumor PD-L1 expression (defined as expression in ≥1% of tumor cells) was positive in 15 (51.7%) of 29 patients at diagnosis and at the time of recurrence. The PD-L1 status did not change in 17 patients (58.6%). 8 patients had PD-L1 negative tumors both at diagnosis and at recurrence, while 9 patients had PD-L1 positive tumors both at diagnosis and at recurrence. In 6 patients (20.7%) a negative-to-positive switch and in 6 patients (20.7%) a positive to negative switch were seen. Tumor PD-L1 expression increased in 7 of 29 patients (24.1%) and decreased in 9 of 29 patients (31.1%). PD-L1 expression remained stable in 13 of 29 patients (34.4%). The change in PD-L1 status over time was not statistically significant. Conclusions: More than 50% of high grade glial tumors express PD-L1 at diagnosis, so these tumors are good candidates for immune checkpoint inhibitors. The expression status changes in more than 40% of high grade glial tumors at recurrence, so immune responsiveness of glial tumors can be modified by treatments like chemotherapy and radiotherapy.

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Multidisciplinary team management for high grade immune-related adverse events (irAEs): A single center experience.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15076 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15076-e15076

Author(s):

PRABHSIMRANJOT SINGH ◽

Osama Abu-Shawer ◽

Amanda Brito ◽

Eric Yenulevich ◽

Shilpa Grover ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Massachusetts General Hospital ◽

Average Length ◽

Immunosuppressive Agents ◽

Future Research ◽

Inpatient Service ◽

High Grade

e15076 Background: Immune checkpoint inhibitors (ICIs) are increasingly used in the management of cancer. High grade irAEs are uncommon but can be severe and require hospital admission. There is an urgent need for early identification and triage of patients with irAEs in order to improve their management and outcomes. Methods: We established Immunotherapy toxicity (ITOX) team as the first in nation inpatient service at DFCI and Brigham and Women's Hospital (BWH) along with our partners at Massachusetts General Hospital (MGH) that is specifically devoted to mitigating irAEs. The ITOX service is consistent of 2 PAs and a medical oncology attending with an expertise in immunotherapy. The service utilizes algorithms that are modified from the ASCO and NCCN guidelines by our medical subspecialty experts at BWH. The service uses a multi-disciplinary approach with around the hour consulting service from experts in the field including GI, pulmonary, endocrinology and others. We leveraged EPIC to triage patients who are admitted to BWH and have ever received or currently on immune checkpoint inhibitors (ICIs). The daily list generated by EPIC is then curated manually by a PA to identify patients with potential irAEs. Results: A total of 138 patients with high grade irAEs were admitted to BWH between June 2018 and June 2019. Seventy percent of the 201 irAEs- related admissions were to ITOX service (70% accuracy in triaging). Most common irAEs was colitis (31%), pneumonitis (28%) and hepatitis (13%) which is consistent with the most common reported irAEs due to ICIs. Eighty five percent of the patients had grade 3 irAEs and 15% were admitted with life threatening grade 4 adverse events. About half of the patient had received ICI monotherapy; 33% received combination of ICI and non-ICI (chemotherapy or targeted therapy) and 17% received combination of ICIs. Most patients responded to steroids and only 9% had steroid-refractory irAEs requiring other immunosuppressive agents. The average length of stay for irAEs-related admission was 11 days with readmission rate of 26% within a year. Over 50 patients consented for tissue and blood biospecimen collection at the time of toxicity. Conclusions: We demonstrated the feasibility of empowering EMR to accurately triage patients with suspected irAEs to the ITOX service that is supported by institution developed guidelines and specialists. Our model is adaptable in major academic centers and can have major impact on quality improvement and future research studies that can be conducted in this unique setting.

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Proposed diagnostic and treatment paradigm for high-grade neurological complications of immune checkpoint inhibitors

Neuro-Oncology Practice ◽

10.1093/nop/npy039 ◽

2018 ◽

Vol 6 (5) ◽

pp. 340-345 ◽

Cited By ~ 1

Author(s):

Dustin Anderson ◽

Grayson Beecher ◽

Nabeela Nathoo ◽

Michael Smylie ◽

Jennifer A McCombe ◽

...

Keyword(s):

Nervous System ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Neurological Complications ◽

High Grade ◽

Small Cell Lung ◽

Cytotoxic Lymphocyte ◽

Programmed Cell Death 1 ◽

Treatment Paradigm

Abstract Immune checkpoint inhibitors such as antibodies to cytotoxic lymphocyte-associated protein 4 (ipilimumab) and programmed cell-death 1 (pembrolizumab, nivolumab) molecules have been used in non-small cell lung cancer, metastatic melanoma, and renal-cell carcinoma, among others. With these agents, immune-related adverse events (irAEs) can occur, including those affecting the neurological axis. In this review, high-grade neurological irAEs associated with immune checkpoint inhibitors including cases of Guillain-Barré syndrome (GBS) and myasthenia gravis (MG) are analyzed. Based on current literature and experience at our institution with 4 cases of high-grade neurological irAEs associated with immune checkpoint inhibitors (2 cases of GBS, 1 case of meningo-radiculitis, and 1 case of myelitis), we propose an algorithm for the investigation and treatment of high-grade neurological irAEs. Our algorithm incorporates both peripheral nervous system (meningo-radiculitis, GBS, MG) and central nervous system presentations (myelitis, encephalopathy). It is anticipated that our algorithm will be useful both to oncologists and neurologists who are likely to encounter neurological irAEs more frequently in the future as immune checkpoint inhibitors become more widely used.

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Checkpoint Inhibitors as High-Grade Gliomas Treatment: State of the Art and Future Perspectives

Journal of Clinical Medicine ◽

10.3390/jcm10071367 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1367

Author(s):

Pasquale Persico ◽

Elena Lorenzi ◽

Angelo Dipasquale ◽

Federico Pessina ◽

Pierina Navarria ◽

...

Keyword(s):

Immune Checkpoint ◽

State Of The Art ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Immune Checkpoint Blockade ◽

High Grade ◽

Current Standard ◽

Advanced Malignancies ◽

The Status ◽

High Grade Gliomas

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Despite significant efforts, no therapies have demonstrated valuable survival benefit beyond the current standard of care. Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape and improved patient survival in many advanced malignancies. Unfortunately, these clinical successes have not been replicated in the neuro-oncology field so far. This review summarizes the status of ICI investigation in high-grade gliomas, critically presenting the available data from preclinical models and clinical trials. Moreover, we explore new approaches to increase ICI efficacy, with a particular focus on combinatorial strategies, and the potential biomarkers to identify patients most likely to benefit from immune checkpoint blockade.

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Geometric Network Analysis Provides Prognostic Information in Patients with High Grade Serous Carcinoma of the Ovary Treated with Immune Checkpoint Inhibitors

10.1101/2021.06.10.447889 ◽

2021 ◽

Author(s):

Rena Elkin ◽

Jung Hun Oh ◽

Ying L Liu ◽

Pier Selenica ◽

Britta Weigelt ◽

...

Keyword(s):

High Risk ◽

Network Analysis ◽

Immune Checkpoint ◽

Gene Networks ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Serous Carcinoma ◽

High Grade ◽

Kaplan Meier ◽

Risk Of Mortality

Purpose: Network analysis methods can potentially quantify cancer disturbances in gene networks without introducing fitted parameters or variable selection. A new network curvature-based method is introduced to provide an integrated measure of variability within cancer gene networks. The method is applied to high grade serous ovarian cancers (HGSOCs) to predict response to immune checkpoint inhibitors (ICIs), and to rank key genes associated with prognosis. Methods: Copy number alterations (CNAs) from targeted and whole exome sequencing data were extracted for HGSOC patients (n = 45) treated with ICIs. CNAs at a gene level were represented on a protein-protein interaction network to define patient-specific networks with a fixed topology. A version of Ollivier-Ricci curvature was used to identify genes that play a potentially key role in response to immunotherapy and further to stratify patients at high risk of mortality. Overall survival (OS) was defined as the time from the start of ICI treatment to either death or last follow-up. Kaplan-Meier analysis with log-rank test was performed to assess OS between the high and low curvature classified groups. Results: The network curvature analysis stratified patients at high risk of mortality with p=0.00047 in Kaplan-Meier analysis. Genes with high curvature were in accordance with CNAs relevant to ovarian cancer. Conclusion: Network curvature using CNAs has the potential to be a novel predictor for OS in HGSOC patients treated with immunotherapy.

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Clinical and Hematological Predictors of High-Grade Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors

Journal of Clinical Medicine Research ◽

10.14740/jocmr4511 ◽

2021 ◽

Vol 13 (5) ◽

pp. 268-275

Author(s):

Ashish Manne ◽

Madhuri S. Mulekar ◽

Daisy E. Escobar ◽

Alhareth Alsayed ◽

Gaurav Sharma ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

High Grade

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Gastrointestinal, pancreatic, and hepatic toxicity profile of CTLA-4 immune checkpoint inhibitors alone and in combination with PD-1/PD-L1 inhibitors: A meta-analysis of clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14117 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14117-e14117 ◽

Cited By ~ 1

Author(s):

Faisal Ali ◽

Maryam R Hussain ◽

Aman Deep ◽

Hamzah Abu-Sbeih ◽

Taha Alrifai ◽

...

Keyword(s):

Clinical Trials ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Cochrane Library ◽

High Grade ◽

Hepatic Toxicity ◽

Treatment Related Mortality ◽

Related Mortality

e14117 Background: Cytotoxic T-lymphocyte activator-4 immune checkpoint inhibitors (CTLA-4-ICPI) is believed to cause more toxicity than programmed cell death/Ligand-1 (PD-1/PD-L1) ICPIs. We conducted a meta-analysis to outline the gastrointestinal (GI), pancreatic, and hepatic toxicity of CTLA-4 ICPIs when used alone and in combination with PD-1/PD-L1 ICPIs (C-ICPI). Methods: Ovid MEDLINE, EMBASE, Cochrane Library, SCOPUS, Web of Science, ClinicalTrials.gov, and WHO ICTRP were queried from January 2007-October 2018. Clinical trials reporting ICPI associated adverse events (AEs) were included. Colitis was defined as the development of diarrhea or documented colitis of any grade. Pancreatitis was defined as an elevation of amylase or lipase. Hepatitis was defined as elevation of ALT, AST, or transaminitis of any grade. A meta-analysis of proportions was conducted to report pooled AEs rate with 95% confidence intervals (CI) using a random effects model. Results: Overall, 30 study arms (20 CTLA-4, 10 C-ICPI) enrolling 3721 patients were included. There were a total of 3944 and 3317 AEs with CTLA-4 and C-ICPI use, respectively, with a pooled incidence of high grade AEs (grade 3-5; HAEs) of 23% (95% CI 16-33%) with CTLA-4 use and 52% (95% CI 37-67%) with C-ICPI use ( Table). The incidence of high-grade colitis was higher among patients treated with CTLA-4 ICPI. The proportion of high-grade pancreatitis was higher among patient who received C-ICPI. Two GI perforations were reported with CTLA-4 use. Pooled incidence of treatment related mortality was 1% in both groups. Conclusions: Though the overall GI, hepatic and pancreatic safety profile of CTLA-4 is comparable to C-ICPI, a higher incidence of high-grade colitis was found with CTLA-4. Two GI perforations were reported with CTLA-4 and warrant further investigation. No difference in treatment related mortality was found among the two groups. [Table: see text]

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Geometric network analysis provides prognostic information in patients with high grade serous carcinoma of the ovary treated with immune checkpoint inhibitors

npj Genomic Medicine ◽

10.1038/s41525-021-00259-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Rena Elkin ◽

Jung Hun Oh ◽

Ying L. Liu ◽

Pier Selenica ◽

Britta Weigelt ◽

...

Keyword(s):

High Risk ◽

Network Analysis ◽

Immune Checkpoint ◽

Gene Networks ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Serous Carcinoma ◽

High Grade ◽

Kaplan Meier ◽

Risk Of Mortality

AbstractNetwork analysis methods can potentially quantify cancer aberrations in gene networks without introducing fitted parameters or variable selection. A new network curvature-based method is introduced to provide an integrated measure of variability within cancer gene networks. The method is applied to high-grade serous ovarian cancers (HGSOCs) to predict response to immune checkpoint inhibitors (ICIs) and to rank key genes associated with prognosis. Copy number alterations (CNAs) from targeted and whole-exome sequencing data were extracted for HGSOC patients (n = 45) treated with ICIs. CNAs at a gene level were represented on a protein–protein interaction network to define patient-specific networks with a fixed topology. A version of Ollivier–Ricci curvature was used to identify genes that play a potentially key role in response to immunotherapy and further to stratify patients at high risk of mortality. Overall survival (OS) was defined as the time from the start of ICI treatment to either death or last follow-up. Kaplan–Meier analysis with log-rank test was performed to assess OS between the high and low curvature classified groups. The network curvature analysis stratified patients at high risk of mortality with p = 0.00047 in Kaplan–Meier analysis in HGSOC patients receiving ICI. Genes with high curvature were in accordance with CNAs relevant to ovarian cancer. Network curvature using CNAs has the potential to be a novel predictor for OS in HGSOC patients treated with immunotherapy.

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