scholarly journals TMOD-05. EXTRACRANIAL TUMORS INFLUENCE INTRACRANIAL RESPONSE TO IMMUNE CHECKPOINT INHIBITORS IN PRE-CLINICAL MODELS OF MELANOMA BRAIN METASTASIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii228-ii228
Author(s):  
Naema Nayyar ◽  
Mohini Singh ◽  
Jackson Stocking ◽  
Michael Brehm ◽  
Priscilla Brastianos
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Checkpoint Blockade ◽  
Intracranial Tumors ◽  
Clinical Model ◽  
Melanoma Brain Metastasis ◽  
Syngeneic Mouse Model

Abstract Melanomas frequently spread to the brain, with up to 75% of patients developing brain metastases. Treatment of metastatic melanoma has been revolutionized by the advent of immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA-4. However, responses to ICI within the immune-specialized brain environment are not well understood owing to the lack of immunocompetent animal models for the investigation of intracranial responses to checkpoint blockade. We studied the effect of ICI in a syngeneic mouse model of melanoma brain metastasis with concurrent intracranial and subcutaneous tumors. Either D3UV3 cells, derived from a UVB irradiated clone of D4M.3A melanoma cell line, or vehicle were subcutaneously injected into the flank of C57BL/6 mice. 3 days later, D3UV3 cells tagged with firefly luciferase were implanted into the striatum using stereotactic injection. Mice were then treated with anti-PD-1 antibody, anti-CTLA-4 antibody, a combination of anti-PD-1 and anti-CTLA-4 antibodies, or isotype controls. We observed striking differences in survival between mice with concurrent intracranial and subcutaneous tumors compared to intracranial tumors alone. Mice with intracranial tumors alone experienced no benefit in survival following monotherapy with anti-PD-1 (p=1) or anti-CTLA-4 (p=0.1) compared to isotype-treated mice, and only a slight benefit with combination treatment (p=0.049). In contrast, mice with concurrent tumors experienced a significant increase in overall survival with anti-CTLA-4 monotherapy (p=0.01) and combination anti-CTLA-4 and anti-PD-1 treatment (p=0.01) compared to isotype-treated mice, although treatment with anti-PD-1 alone did not increase survival (p=0.28). These results indicate that the presence of extracranial disease can modulate intracranial immune responses following checkpoint blockade. We have therefore established a pre-clinical model with concurrent intracranial and extracranial tumors to better recapitulate the clinically observed context of brain metastases. We hope this model will lead to a better understanding of the setting in which ICI is effective for patients with melanoma brain metastases.

scholarly journals 62. PRESENCE OF EXTRACRANIAL TUMORS INFLUENCES RESPONSE TO IMMUNE CHECKPOINT INHIBITORS IN A PRE-CLINICAL MODEL OF MELANOMA BRAIN METASTASIS

2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii13-ii13
Author(s):  
Naema Nayyar ◽  
Mohini Singh ◽  
Jackson Stocking ◽  
Michael Brehm ◽  
Priscilla Brastianos
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Intracranial Tumors ◽  
Clinical Model ◽  
Melanoma Brain Metastasis ◽  
Syngeneic Mouse Model ◽  
The Brain

Abstract Up to 75% of patients with melanoma develop brain metastases. While immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA4 have revolutionized the treatment of metastatic melanoma, responses within the immune-specialized microenvironment of the brain are not well understood and there is a paucity of animal models to investigate the effect of ICI intracranially. We characterized responses to checkpoint inhibitors in a syngeneic mouse model of melanoma brain metastasis with concurrent intracranial and subcutaneous melanoma. D3UV3 cells (obtained from David Fisher’s laboratory) were derived using UVB irradiation from D4M.3A melanoma cell line and implanted into the striatum using stereotactic injection or subcutaneously injected into the flank of C57BL/6 mice. Mice were then treated with anti-PD-1 antibody, anti-CTLA4 antibody, a combination of anti-PD-1 and anti-CTLA4, or isotype controls. While mice with intracranial melanoma alone had no response to monotherapy with anti-PD-1 or anti-CTLA4 antibody (p=1 and 0.1, respectively), and only a slight response to combination therapy (p=0.049), mice with concurrent subcutaneous tumors had significantly improved responses to anti-PD-1, anti-CTLA4 and combination treatment (p=0.002, 0.01 and 0.01 respectively compared to mice with intracranial tumors alone with equivalent treatment). These results demonstrate that the presence of an extracranial tumor influences response to ICI in pre-clinical mouse models of melanoma brain metastasis. We have therefore established a pre-clinical model with concurrent intracranial and extracranial tumors to better recapitulate the clinically observed context of melanoma brain metastases and lead to a better understanding of the setting in which ICI are effective for patients with this devastating complication.

scholarly journals Acute motor axonal neuropathy after ipilimumab and nivolumab treatment in melanoma brain metastases: A case report and review of the literature

2021 ◽  
Vol 9 ◽  
pp. 2050313X2110422
Author(s):  
Yolanda Piña ◽  
Brittany R. Evernden ◽  
Nikhil Khushalani ◽  
Kim Margolin ◽  
Hussein Tawbi ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Axonal Neuropathy ◽  
Braf V600e ◽  
Acute Motor Axonal Neuropathy ◽  
Melanoma Brain Metastasis ◽  
First Case

The use of immune checkpoint inhibitors including ipilimumab and nivolumab has expanded for several tumors including melanoma brain metastasis. These have resulted in a growing spectrum of neurologic immune-related adverse events, including ones that are rare and difficult to diagnose and treat. Here, we present a patient with melanoma brain metastasis who was treated with immune checkpoint inhibitors and developed an Acute Motor Axonal Neuropathy. To our knowledge, this is the first case of Acute Motor Axonal Neuropathy as an immune-related adverse event associated with combination treatment of ipilimumab and nivolumab, who was successfully treated. A 28-year-old woman with metastatic BRAF V600E melanoma developed melanoma brain metastasis and was enrolled on Checkmate 204, a Phase 2 clinical trial using ipilimumab (3 mg/kg intravenous) and nivolumab (1 mg/kg intravenous) every 3 weeks for four cycles, followed by monotherapy with nivolumab (240 mg intravenous) every 2 weeks. A few days after Cycle 2 of ipilimumab and nivolumab, she developed a pure motor axonal neuropathy consistent with Acute Motor Axonal Neuropathy. She was treated with several immunosuppressive treatments including high dose methylprednisolone, immune globulin, and infliximab, and her motor neuropathy eventually improved several months after onset of symptoms. Unfortunately, she had progression of her systemic disease and died several months later. This is the first case reported of Acute Motor Axonal Neuropathy associated with ipilimumab and nivolumab, successfully treated with immune-suppressive therapy. As the field of immunotherapy expands with the increasing use of the immune checkpoint inhibitors, it is critical to increase our knowledge and understanding of the neurologic immune-related adverse events associated with immune checkpoint inhibitors. This includes the spectrum of rare neurologic immune-related adverse events, which can be quite difficult to recognize and treat. Early consultations with neurology may expedite a diagnosis and treatment plan in patients with unexplained weakness receiving immune checkpoint inhibitor therapy.

scholarly journals IMMU-04. IMMUNE-RELATED ADVERSE EVENTS STRONGLY PREDICT SUPERIOR OUTCOMES IN BRAIN METASTASES PATIENTS RECEIVING LOCAL TREATMENT AND IMMUNE CHECKPOINT INHIBITORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii105-ii105
Author(s):  
Alexander Hulsbergen ◽  
Asad Lak ◽  
Yu Tung Lo ◽  
Nayan Lamba ◽  
Steven Nagtegaal ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Adverse Events ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Local Treatment ◽  
Sensitivity Analyses ◽  
Immortal Time Bias ◽  
The Brain

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p < 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values < 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

scholarly journals Immune Checkpoint Inhibitors for Brain Metastases: A Primer for Neurosurgeons

Neurosurgery ◽  
2020 ◽  
Vol 87 (3) ◽  
pp. E281-E288
Author(s):  
Elisa Aquilanti ◽  
Priscilla K Brastianos
Keyword(s):  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Standard Of Care ◽  
Nonsmall Cell Lung Cancer ◽  
Immune Recognition ◽  
Therapeutic Modalities ◽  
Programmed Death 1

Abstract Immune checkpoint inhibitors enhance immune recognition of tumors by interfering with the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed death 1 (PD1) pathways. In the past decade, these agents brought significant improvements to the prognostic outlook of patients with metastatic cancers. Recent data from retrospective analyses and a few prospective studies suggest that checkpoint inhibitors have activity against brain metastases from melanoma and nonsmall cell lung cancer, as single agents or in combination with radiotherapy. Some studies reported intracranial response rates that were comparable with systemic ones. In this review, we provide a comprehensive summary of clinical data supporting the use of anti-CTLA4 and anti-PD1 agents in brain metastases. We also touch upon specific considerations on the assessment of intracranial responses in patients and immunotherapy-specific toxicities. We conclude that a subset of patients with brain metastases benefit from the addition of checkpoint inhibitors to standard of care therapeutic modalities, including radiotherapy and surgery.

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