Focal radiation necrosis of the brain in patients with melanoma brain metastases treated with pembrolizumab

Abstract BACKGROUND Brain metastases represent the most common intracranial tumor in adults, occurring in 10-40% of cancer patients. Most patients undergo multimodal treatment approaches and post-treatment follow-up with conventional MRI (CE-T1-weighted and FLAIR/T2-weighted) of the brain is performed to monitor for disease recurrence. However, owing to the similar appearance of treatment-related changes like radiation necrosis with that of true recurrence, conventional MRI alone suffers from low specificity. Given the high mortality of patients with brain metastases and the considerable treatment-associated morbidity, a need remains for an imaging modality that accurately differentiates recurrence from treatment-related changes. Accurate imaging is key to preventing unnecessary surgery or changes in effective therapy in patients mistaken for disease progression as well as prevent continuation of ineffective therapy if radiation necrosis is incorrectly diagnosed. To this end, 18F-fluciclovine is a synthetic amino acid-based PET imaging agent that has potential to evaluate primary and metastatic brain cancers owing to its low normal background uptake in the brain and increased uptake in brain tumors. METHODS NCT04410367 is a prospective, open-label, single-arm, single-dose (185 MBq ± 20%) study with a primary objective to establish visual image interpretation criteria for 18F-fluciclovine PET studies of recurrent brain metastases. Forty subjects with solid tumor brain metastases who have undergone radiation therapy will be enrolled across ~8 US sites if they have a reference lesion considered equivocal on MRI for recurrent disease and are planned for craniotomy. Subjects will undergo 18F-fluciclovine PET <42 days after the MRI and 1–21 days before planned craniotomy. Outcome measures comprise the diagnostic performance of 18F-fluciclovine PET at different thresholds of 18F-fluciclovine uptake compared with histopathology, subject- and lesion-level diagnostic performance based on established image interpretation criteria, and safety evaluations. Enrolment began in August 2020 and the trial is open at the time of submission.

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Neurotrophin signaling and melanoma brain metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e13024 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e13024-e13024

Author(s):

Nicole Fortenbery ◽

Rajappa Kenchappa ◽

Peter A. J. Forsyth

Keyword(s):

Brain Metastases ◽

Cell Lines ◽

Melanoma Cell ◽

Neurotrophin Receptor ◽

Neurotrophin Receptors ◽

Melanoma Metastases ◽

Melanoma Brain Metastases ◽

Neurotrophin Signaling ◽

The Brain ◽

Melanoma Cell Lines

e13024 Background: Adult metastatic brain tumors occur more frequently than primary intracranial neoplasms. Melanoma is the third most common tumor type that metastasizes to the brain. Therefore, elucidating the underlying biological mechanisms of melanoma metastases is critical. Melanocytes and neurons share a neural ectodermal origin, and thus, melanoma may preferentially travel to the brain due to the expression of common neurotrophin receptors, namely p75 neurotrophin receptor (p75NTR) and Trks. Further, high concentrations of neurotrophic factors present in the brain may recruit metastatic melanoma. We hypothesize that neurotrophin signaling through p75NTR is required for the malignant phenotype of melanoma and melanoma brain metastases (MBM). Methods: We investigated the expression of several neutrophin receptors, signaling molecules, and neurotrophins that we hypothesize to be important in the process of MBM. Using 14 malignant melanoma cell lines and two primary MBMs grown under neurosphere conditions, we investigated the expression of these molecules using standard western blotting, flow cytometry, and RT-PCR. We also performed an in depth microarray using of 14 primary MBM patients from Moffitt’s Total Cancer Care project. Results: All melanoma lines examined have robust expression of p75NTR, Trks, and neurotrophins. We find melanoma cell lines resistant to the BRAF inhibitor, vemurafenib, have elevated expression of neurotrophins and neurotrophin receptors when compared to lines sensitive to vemurafenib. We also detect high levels of p75NTR in patient MBM, at both mRNA and protein levels. Finally, we find a significant level of expression of all 11 genes tested by microarray. Conclusions: Previous studies have demonstrated that p75NTR has a role in melanoma cell survival in vitro. Here we demonstrate p75NTR and Trk receptors have high expression in melanoma cell lines and importantly, primary MBM. These data suggest that signaling through neurotophin receptors may be important for melanoma metastases and survival in the brain. Moreover, increased expression by vemurafenib resistant lines may suggest that these cells upregulate the expression of neurotrophin signaling as a means of treatment resistant.

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Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases?

Journal of Neurosurgery ◽

10.3171/2015.6.jns142763 ◽

2016 ◽

Vol 125 (1) ◽

pp. 17-23 ◽

Cited By ~ 86

Author(s):

Rovel J. Colaco ◽

Pierre Martin ◽

Harriet M. Kluger ◽

James B. Yu ◽

Veronica L. Chiang

Keyword(s):

Brain Metastases ◽

Systemic Therapy ◽

Lower Risk ◽

Median Overall Survival ◽

Radiation Necrosis ◽

Cytotoxic Chemotherapy ◽

High Dose ◽

The Brain ◽

Dose Radiation

OBJECT Radiation necrosis (RN), or its imaging equivalent, treatment-related imaging changes (TRIC), is an inflammatory reaction to high-dose radiation in the brain. The authors sought to investigate the hypothesis that immunotherapy increases the risk of developing RN/TRIC after stereotactic Gamma Knife (GK) radiosurgery for brain metastases. METHODS A total of 180 patients who underwent GK surgery for brain metastases between 2006 and 2012 were studied. The systemic therapy they received was classified as cytotoxic chemotherapy (CT), targeted therapy (TT), or immunotherapy (IT). The timing of systemic therapy in relation to GK treatment was also recorded. Logistic regression was used to calculate the odds of developing RN according to type of systemic therapy received. RESULTS The median follow-up time was 11.7 months. Of 180 patients, 39 (21.7%) developed RN/TRIC. RN/TRIC rates were 37.5% (12 of 32) in patients who received IT alone, 16.9% (14 of 83) in those who received CT only, and 25.0% (5 of 20) in those who received TT only. Median overall survival was significantly longer in patients who developed RN/TRIC (23.7 vs 9.9 months, respectively). The RN/TRIC rate was increased significantly in patients who received IT alone (OR 2.40 [95% CI 1.06–5.44]; p = 0.03), whereas receipt of any CT was associated with a lower risk of RN/TRIC (OR 0.38 [95% CI 0.18–0.78]; p = 0.01). The timing of development of RN/TRIC was not different between patients who received IT and those who received CT. CONCLUSIONS Patients who receive IT alone may have an increased rate of RN/TRIC compared with those who receive CT or TT alone after stereotactic radiosurgery, whereas receiving any CT may in fact be protective against RN/TRIC. As the use of immunotherapies increases, the rate of RN/TRIC may be expected to increase compared with rates in the chemotherapy era.

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Improved Survival and Intracranial Control Associated With Radiation Necrosis After Ipilimumab and Stereotactic Radiosurgery for Melanoma Brain Metastases

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2017.06.872 ◽

2017 ◽

Vol 99 (2) ◽

pp. E115-E116 ◽

Cited By ~ 1

Author(s):

A. Wild ◽

A.P. Kiess ◽

T.J. Yang ◽

E.S. Weg ◽

Z.A. Kohutek ◽

...

Keyword(s):

Brain Metastases ◽

Stereotactic Radiosurgery ◽

Radiation Necrosis ◽

Melanoma Brain Metastases

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IMMU-01. SINGLE CELL SEQUENCING OF MELANOMA BRAIN METASTASES UNVEILS HETEROGENEITY OF THE TUMOR MICROENVIRONMENT IN RESPONSE TO IMMUNE CHECKPOINT BLOCKADE

Neuro-Oncology ◽

10.1093/neuonc/noaa215.432 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii104-ii104

Author(s):

Christopher Alvarez-Breckenridge ◽

Samuel Markson ◽

Jackson Stocking ◽

Matt Lastrapes ◽

Naema Nayyar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Brain Metastases ◽

Single Cell ◽

Immune Checkpoint ◽

Heterogeneous Distribution ◽

Single Cell Sequencing ◽

Melanoma Brain Metastases ◽

The Brain

Abstract Immune checkpoint inhibitors (ICI) have revolutionized oncologic treatment for metastatic melanoma. With improved systemic control, there has been increasing prevalence of patients with brain metastases. Recent evidence has demonstrated intracranial responses in a subset of these patients treated with ICI. We hypothesize that the response to ICI in melanoma brain metastases (MBM) is reflective of unique features within the tumor microenvironment of the brain. A cohort of 27 patients, encompassing 8 pre- and 19 post-immunotherapy MBM underwent single cell RNA sequencing (Smart-Seq2). The cohort includes patients with longitudinal cranial resections and simultaneously resected, spatially distinct tumors. Each tumor underwent unsupervised transcriptomic analysis, differential gene expression, inferred copy number variation, and T-cell receptor (TCR) clonotyping. Published extracranial melanoma single cell datasets were used to compare the tumor microenvironment of the brain and periphery in response to ICI. A total of 14,027 cells (6,189 malignant, 7,838 non-malignant) were sequenced. Brain metastases demonstrated a heterogeneous distribution of macrophage states. Intracranial macrophages were found to be more tumor-supportive than their extracranial counterparts. MBM also included a distribution of reactive neutrophils and astrocytes. Analysis across pre- and post-treatment MBM demonstrated an increase in clonally expanded T cells in patients responding to ICI. Across longitudinal brain metastases collected from the same patients, there was evidence of identical T cell clones across timepoints and locations. Single cell sequencing of MBM provides insights into the cellular composition of the tumor and microenvironment. Our data suggest the cellular heterogeneity within MBM is unique when compared to extracranial disease. Additionally, T cell clonal expansion is found following ICI and T cells of the same clonotype infiltrate spatially and temporally separated brain metastases. These findings raise potential therapeutic implications as we learn to target the differential features of the innate and adaptive immune system within brain metastases and their extracranial counterparts.

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OC-0513: Radiation necrosis following stereotactic RT and immunotherapy for melanoma brain metastases

Radiotherapy and Oncology ◽

10.1016/s0167-8140(17)30953-2 ◽

2017 ◽

Vol 123 ◽

pp. S271 ◽

Cited By ~ 1

Author(s):

O. Kaidar-Person ◽

T. Zagar ◽

A. Deal ◽

S. Moschos ◽

M. Ewend ◽

...

Keyword(s):

Brain Metastases ◽

Radiation Necrosis ◽

Melanoma Brain Metastases

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Emergent immunotherapy approaches for brain metastases

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab138 ◽

2021 ◽

Vol 3 (Supplement_5) ◽

pp. v43-v51

Author(s):

Jianbo Wang ◽

Hussein A Tawbi

Keyword(s):

Brain Metastases ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition ◽

Steroid Dependency ◽

Melanoma Brain Metastases ◽

Melanoma Patients ◽

The Brain ◽

Systemic Therapies

Abstract Brain metastases from solid tumors are increasing in incidence, especially as outcomes of systemic therapies continue to extend patients’ overall survival. The long-held notion that the brain is an immune sanctuary has now been largely refuted with increasing evidence that immunotherapy can induce durable responses in brain metastases. Single agent immune checkpoint inhibition with anti-CTLA4 and anti-PD1 antibodies induces durable responses in 15%–20% in melanoma brain metastases as long as patients are asymptomatic and do not require corticosteroids. The combination of anti-CTLA4 with anti-PD-1 antibodies induces an intracranial response in over 50% of asymptomatic melanoma patients, and much lower rate of otherwise durable responses (20%) in symptomatic patients or those on steroids. Data in other cancers, such as renal cell carcinoma, are accumulating indicating a role for immunotherapy. Emerging immunotherapy approaches will have to focus on increasing response rates, decreasing toxicity, and decreasing steroid dependency. The path to those advances will have to include a better understanding of the mechanisms of response and resistance to immunotherapy in brain metastases, the use of novel agents such as anti-LAG3 checkpoint inhibitors, targeted therapy (oncogene directed or TKIs), and possibly surgery and SRS to improve the outcomes of patients with brain metastases.

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Melanoma brain metastases have lower T-cell content and microvessel density compared to matched extracranial metastases

Journal of Neuro-Oncology ◽

10.1007/s11060-020-03619-0 ◽

2020 ◽

Author(s):

Sarah A. Weiss ◽

Christopher Zito ◽

Thuy Tran ◽

Kazuki Heishima ◽

Veronique Neumeister ◽

...

Keyword(s):

T Cell ◽

Brain Metastases ◽

B Cell ◽

Microvessel Density ◽

Immune Cell ◽

The Body ◽

Cell Content ◽

Melanoma Brain Metastases ◽

Extracranial Metastases ◽

The Brain

Abstract Background Although melanoma brain metastases (MBM) tend to respond to systemic therapy concordantly with extracranial metastases, little is known about differences in immune cell and vascular content between the brain and other metastatic sites. Here we studied infiltrating immune cell subsets and microvessel density (MVD) in paired intracerebral and extracerebral melanoma metastases. Methods Paired intracerebral and extracerebral tumor tissue was obtained from 37 patients with metastatic melanoma who underwent craniotomy between 1997 and 2014. A tissue microarray was constructed to quantify subsets of tumor-infiltrating T-cell, B-cell, and macrophage content, PD-L1 expression, and MVD using quantitative immunofluorescence. Results MBM had lower CD3+ (p = 0.01) and CD4+ (p = 0.003) T-cell content, lower MVD (p = 0.006), and a trend for lower CD8+ (p = 0.17) T-cell content compared to matched extracerebral metastases. There were no significant differences in CD20+ B-cell or CD68+ macrophage content, or tumor or stroma PD-L1 expression. Low MVD (p = 0.008) and high CD68+ macrophage density (p = 0.04) in intracerebral metastases were associated with improved 1-year survival from time of first MBM diagnosis. Conclusions Although responses to immune-modulating drugs in the body and the brain tend to be concordant, differences were found in MVD and T-cell content between these sites. Studies of these markers should be incorporated into prospective therapeutic clinical trials to determine their prognostic and predictive value.

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Anti–PD-1/anti–CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1714089115 ◽

2018 ◽

Vol 115 (7) ◽

pp. E1540-E1549 ◽

Cited By ~ 53

Author(s):

David Taggart ◽

Tereza Andreou ◽

Karen J. Scott ◽

Jennifer Williams ◽

Nora Rippaus ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Brain Metastases ◽

T Cell Activation ◽

Adhesion Molecule ◽

Immune Therapy ◽

Intercellular Adhesion Molecule ◽

Immune Checkpoints ◽

Melanoma Brain Metastases ◽

The Brain

Inhibition of immune checkpoints programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on T cells results in durable antitumor activity in melanoma patients. Despite high frequency of melanoma brain metastases (BrM) and associated poor prognosis, the activity and mechanisms of immune checkpoint inhibitors (ICI) in metastatic tumors that develop within the “immune specialized” brain microenvironment, remain elusive. We established a melanoma tumor transplantation model with intracranial plus extracranial (subcutaneous) tumor, mimicking the clinically observed coexistence of metastases inside and outside the brain. Strikingly, intracranial ICI efficacy was observed only when extracranial tumor was present. Extracranial tumor was also required for ICI-induced increase in CD8+ T cells, macrophages, and microglia in brain tumors, and for up-regulation of immune-regulatory genes. Combined PD-1/CTLA-4 blockade had a superior intracranial efficacy over the two monotherapies. Cell depletion studies revealed that NK cells and CD8+ T cells were required for intracranial anti–PD-1/anti–CTLA-4 efficacy. Rather than enhancing CD8+ T cell activation and expansion within intracranial tumors, PD-1/CTLA-4 blockade dramatically (∼14-fold) increased the trafficking of CD8+ T cells to the brain. This was mainly through the peripheral expansion of homing-competent effector CD8+ T cells and potentially further enhanced through up-regulation of T cell entry receptors intercellular adhesion molecule 1 and vascular adhesion molecule 1 on tumor vasculature. Our study indicates that extracranial activation/release of CD8+ T cells from PD-1/CTLA-4 inhibition and potentiation of their recruitment to the brain are paramount to the intracranial anti–PD-1/anti–CTLA-4 activity, suggesting augmentation of these processes as an immune therapy-enhancing strategy in metastatic brain cancer.

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