Immune Checkpoint Blockade Is Active in Melanoma Brain Metastases

Abstract Background The interaction between immune checkpoint blockade (ICB) and radiation (RT) for brain metastases has not been well understood. Given that acute neurotoxicity from this combination is not well characterized, we reviewed patients receiving ICB and RT for brain metastases. Methods Patients treated with ICB and cranial RT from 2010 through 2017 were reviewed. ICB and RT must have been administered within 30 days of each other. Treatment parameters, performance status, symptoms prior to treatment, and toxicity were extracted from the electronic medical record. Survival was calculated from the end of RT to last follow-up or death. Results Seventy-eight patients were included. Median follow-up was 177 days (range, 12-1603). Median age was 64 years old (range, 29-98) and 47 (63%) were male. The main tumor types were melanoma (n = 47) and nonsmall-cell lung cancer (n = 19). Fifty-seven patients were treated with stereotactic radiosurgery (SRS) and 21 with whole-brain radiotherapy (WBRT). Most patients received single-agent ICB, though 4 patients received nivolumab and ipilimumab. Forty-one (53%) patients reported no neurologic toxicity. Grade 2 or greater neurologic toxicities were reported in 12 (21%) and 8 (38%) patients in the SRS and WBRT groups, respectively. WBRT was associated with a greater risk of any neurotoxicity, though there was no correlation between ICB agent and toxicity. Sequencing of ICB and RT (ie, <30 days vs <7) did not influence rates of toxicity. Conclusions ICB during SRS or WBRT does not appear to worsen acute neurotoxicity compared to historical controls of RT alone.

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Review: Brain Metastases in Bladder Cancer

Bladder Cancer ◽

10.3233/blc-200304 ◽

2020 ◽

Vol 6 (3) ◽

pp. 237-248

Author(s):

Randall J. Brenneman ◽

Hiram A. Gay ◽

John P. Christodouleas ◽

Paul Sargos ◽

Vivek Arora ◽

...

Keyword(s):

Central Nervous System ◽

Bladder Cancer ◽

Nervous System ◽

Brain Metastases ◽

Urothelial Carcinoma ◽

Stereotactic Radiosurgery ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Metastatic Urothelial Carcinoma

Nearly 50% of bladder cancer patients either present with metastatic disease or relapse distantly following initial local therapy. Prior to platinum-based chemotherapy, the incidence of bladder cancer central nervous system metastases was approximately 1%; however, their incidence has increased to 3–16% following definitive treatment as platinum-based regimens have changed the natural history of the disease. Bladder cancer brain metastases are generally managed similarly to those from more common malignancies such as non-small cell lung cancer, with surgery +/–adjuvant radiotherapy, or radiotherapy alone using stereotactic radiosurgery or whole brain radiotherapy. Limited data suggest that patients with inoperable urothelial carcinoma brain metastases who are not candidates for stereotactic radiosurgery may benefit from shorter whole brain radiation therapy courses compared to other histologies, but data is hypothesis-generating. Given improvements in the efficacy of systemic therapy and supportive care strategies for metastatic urothelial carcinoma translating in improved survival, the incidence of intracranial failures may increase. Immune checkpoint blockade therapy may benefit cisplatin-ineligible metastatic urothelial carcinoma patients as first-line therapy; however, the effectiveness of immune checkpoint blockade to treat central nervous system disease has not been established. In this review, we discuss the incidence and management of bladder cancer brain metastases and considerations regarding variations in management relative to more commonly encountered non-urothelial histologies.

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The CD8+ T cell landscape of human brain metastases

10.1101/2021.08.03.455000 ◽

2021 ◽

Author(s):

Lisa J. Sudmeier ◽

Kimberly B. Hoang ◽

Edjah K. Nduom ◽

Andreas Wieland ◽

Stewart G. Neill ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Brain Metastasis ◽

Brain Metastases ◽

Immune Checkpoint ◽

Expression Patterns ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Antigen Specificity ◽

Inhibitory Molecules

Despite improved outcomes with checkpoint blockade immunotherapy, patients with brain metastases have the worst prognosis among patients with metastatic cancer. Immune checkpoint blockade agents target inhibitory receptors, such as PD-1, on exhausted CD8+ T cells to restore their anti-cancer function. Many patients, however, either do not respond or progress after an initial response to immune checkpoint blockade, and distant intracranial failure is common despite excellent options for local treatment of brain metastasis. To develop more effective therapeutic strategies for the treatment of brain metastases, an understanding of the phenotype of brain metastasis-infiltrating CD8+ T cells is essential. Here we performed a detailed characterization of the CD8+ T cells contained in brain metastases. Brain metastases were densely infiltrated by CD8+ T cells; blood contamination of tumor samples was rare. Compared to patient-matched circulating cells, brain metastasis-infiltrating CD8+ T cells had a distinct phenotype characterized by more frequent expression of PD-1, with subpopulations defined by expression of additional co-inhibitory molecules and the residence marker CD69. Single cell RNA-sequencing identified four phenotypic subpopulations within brain metastasis-infiltrating PD-1+ CD8+ T cells. Two of these populations - a terminally-differentiated and a dividing population - were characterized by high expression of co-inhibitory molecules and lacked expression of progenitor markers such as TCF-1. There was significant T cell receptor (TCR) overlap between the terminally-differentiated and dividing populations, suggesting that the dividing cells give rise to the terminally-differentiated cells. There was minimal TCR overlap between these two populations and other brain metastasis-infiltrating PD-1+ CD8+ T cells. T cell clones from brain metastasis-infiltrating CD8+ T cells were rare in circulation, particularly clones from the terminally-differentiated and dividing populations. We systematically identified bystander CD8+ T cells specific for microbial antigens; these cells infiltrated brain metastases and expressed genes shared with exhausted progenitor CD8+ T cells, such as TCF7 and IL7R. We performed spatial transcriptomics on brain metastases and used a novel method to obtain TCR sequences from spatial transcriptomics data. These data revealed distinct niches within the TME defined by their gene expression patterns and cytokine profiles. Terminally-differentiated CD8+ T cells preferentially occupied niches within the tumor parenchyma. Together, our results show that antigen-specificity restricts the spatial localization, phenotypic states, and differentiation pathways available to CD8+ T cells within the brain metastasis TME.

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Mismatch repair-deficient prostate cancer with parenchymal brain metastases treated with immune checkpoint blockade

Molecular Case Studies ◽

10.1101/mcs.a006094 ◽

2021 ◽

pp. mcs.a006094

Author(s):

Laura A Sena ◽

Daniela C Salles ◽

Elizabeth L Engle ◽

Qingfeng Zhu ◽

Hanna Tukachinsky ◽

...

Keyword(s):

Prostate Cancer ◽

Brain Metastases ◽

Mismatch Repair ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade

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Outcomes of melanoma brain metastases treated with stereotactic radiosurgery with and without concurrent immune checkpoint therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e21026 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e21026-e21026

Author(s):

Jessica Yang ◽

Laurent Dercle ◽

Andrew M. Yaeh ◽

Randy Yeh ◽

Daniel K. Manson ◽

...

Keyword(s):

Brain Metastases ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Gamma Knife Radiosurgery ◽

Median Number ◽

Immune Checkpoint Blockade ◽

Tumor Growth Rate ◽

Best Response ◽

Melanoma Brain Metastases

e21026 Background: Evidence supports a synergistic effect between immunotherapy and radiotherapy. In this single-institution study, we compared outcomes of patients (pts) with melanoma brain metastases (BMs) who received Gamma Knife Radiosurgery (GKRS) with and without concurrent immune checkpoint blockade (ICB). Methods: Using an IRB-approved protocol, we identified pts with melanoma BMs who received GKRS from 5/2000 to 8/2016. Treatment was deemed concurrent if patients had GKRS within 4 weeks of ICB. Irradiated lesion control, tumor growth rate (TGR; percent change in product diameters per month), distant brain control, overall response rate (ORR) by modified WHO criteria, best response, and overall survival (OS) were compared. Results: 28 pts were identified: 17 (34 BMs total) received GKRS alone; 11 (23 BMs total) received concurrent GKRS/ICB. ICB included: ipilimumab (n = 3), anti-programmed death-1 (anti-PD-1) therapy (n = 4), and combined ipilimumab + nivolumab (n = 4). In comparing baseline characteristics between the GKRS alone and GKRS/ICB groups: median age was 65 v. 59 years, proportion of males was 53% v. 73%, 41% v. 45% had prior neurosurgery, and median number of prior systemic therapies was 1 v. 0. There was no difference in irradiated lesion control (6-month control rate 86% v. 96%; n = 57; p = 0.65), median TGR (-14% [range -100% to +61%] v. -20% [range -71% to 0%]; n = 42 lesions, p = 0.38), or distant brain control (6-month control rate 68% v. 60%; p = 0.51; median follow-up 8.6 months v. 8.0 months) with GKRS/ICB v. GKRS alone. The ORR with GKRS alone v. GKRS/ICB was 61% v. 47% (p = 0.33), and the median maximum reduction in BM bidimensional measurement was -69% v. -45% (p = 0.43). Median OS from the date of GKRS was not reached for the GKRS/ICB group and was 16.6 months for the GKRS alone group (p = 0.03). Conclusions: There was no difference in local lesion control, TGR, or distant brain control with concurrent GKRS/ICB compared to GKRS alone, but the study was limited by small patient numbers and biased by closer follow-up in the GKRS/ICB group. OS was longer with concurrent ICB, likely reflecting the survival improvement with immune checkpoint inhibitors.

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