Phase IB Study of Avelumab and Whole Brain Radiotherapy (WBRT) in Patients with Leptomeningeal Disease (LMD) from Solid Tumors: Results and Molecular Analyses.

Background: Leptomeningeal disease (LMD) from solid tumors has a dismal prognosis, even following treatment with anti-PD-1 therapy. We performed a phase IB study evaluating the safety of Avelumab with whole brain radiotherapy (WBRT) in LMD (NCT03719768).

Methods: Fifteen patients were enrolled with LMD from breast, lung, nasopharyngeal, ovary, and pancreatic tumors.

Intravenous Immunoglobulin (IVIG) for Patients with Severe Neurotoxicity Associated with Chimeric Antigen Receptor T-Cell (CAR-T) Therapy.

Severe immune effector cell-associated neurotoxicity syndrome (ICANS) occurs in about 30% of all patients with large B-cell lymphoma (LBCL) who are treated with axicabtagene ciloleucel (axi-cel). There are currently limited treatment strategies other than the standard corticosteroids, and it is essential to find additional therapies to manage severe ICANS. We conducted a retrospective study of neurologic outcomes among patients who received axi-cel for LBCL from May 2015 to February 2019.

Nivolumab and stereotactic radiosurgery for patients with breast cancer brain metastases: long-term results and biomarker analysis from a non-randomized, open-label, phase Ib study.

Background: We hypothesized treatment with nivolumab and stereotactic radiosurgery (SRS) would be feasible, well tolerated, and may improve intracranial tumor control over SRS alone for breast cancer brain metastases (BCBM).

Methods: The study is a phase Ib trial of nivolumab and SRS for BCBM.

Clinical Trial Information: NCT03807765.

Phase 1 trial of hypofractionated stereotactic re-irradiation in combination with nivolumab, ipilimumab, and bevacizumab for recurrent high-grade gliomas.

Background: Our previous clinical investigation suggested that hypofractionated stereotactic re-irradiation (HFSRT) and PD-1 blockade may act synergistically to enhance the immune response against glioma. This subsequent trial investigated the dual blockade of CTLA4 and PD-1 in combination with HFSRT and bevacizumab.

Methods: This phase I study enrolled eligible patients with bevacizumab-naïve recurrent glioblastoma or anaplastic astrocytoma.

Phase II trial of brain MRI surveillance in stage IV breast cancer.

Background: Screening of asymptomatic stage IV breast cancer with brain MRIs is currently not recommended by National Comprehensive Cancer Network Guidelines. The incidence of asymptomatic brain metastasis is not well documented.

Methods: The study is designed as a single-arm, phase II trial, with the goal of investigating surveillance brain MRIs in neurologically asymptomatic patients with metastatic breast cancer.

Spatial transcriptomics analysis identifies a tumor-promoting function of the meningeal stroma in melanoma leptomeningeal disease.

Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. Here, we characterize the tumor microenvironment of LMD and patient-matched extra-cranial metastases using spatial transcriptomics in a small number of clinical specimens (nine tissues from two patients) with extensive in vitro and in vivo validation. The spatial landscape of melanoma LMD is characterized by a lack of immune infiltration and instead exhibits a higher level of stromal involvement.

Clinical Outcomes of Patients with Non-Small Cell Lung Cancer Leptomeningeal Disease Following Receipt of EGFR-Targeted Therapy, Immune-Checkpoint Blockade, Intrathecal Chemotherapy, or Radiation Therapy Alone.

Background: EGFR-targeted therapy (ETT) and immune-checkpoint blockade (ICB) have shown promising results in treating NSCLC brain metastases (BM). However, little is known of their effect in treating leptomeningeal disease (LMD).

Patients And Methods: This is a retrospective review of 80 patients diagnosed with NSCLC LMD from January 2014 to March 2021.

Ex Vivo Culture of Circulating Tumor Cells in the Cerebral Spinal Fluid from Melanoma Patients to Study Melanoma-Associated Leptomeningeal Disease.

Melanoma-associated leptomeningeal disease (M-LMD) occurs when circulating tumor cells (CTCs) enter into the cerebral spinal fluid (CSF) and colonize the meninges, the membrane layers that protect the brain and the spinal cord. Once established, the prognosis for M-LMD patients is dismal, with overall survival ranging from weeks to months. This is primarily due to a paucity in our understanding of the disease and, as a consequence, the availability of effective treatment options.

Clinical outcomes of melanoma brain metastases treated with nivolumab and ipilimumab alone versus nivolumab and ipilimumab with stereotactic radiosurgery.

Purpose: Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS.

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease.

Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omics analyses of CSF from patients with lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment and identified dysregulations in proteins and lipids indicating neurodegenerative processes. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD.

Differential requirements for CD4+ T cells in the efficacy of the anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combinations in melanoma flank and brain metastasis models.

Background: Although the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combinations are effective in advanced melanoma, it remains unclear whether their mechanisms of action overlap.

Methods: We used single cell (sc) RNA-seq, flow cytometry and IHC analysis of responding SM1, D4M-UV2 and B16 melanoma flank tumors and SM1 brain metastases to explore the mechanism of action of the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combination. CD4+ and CD8+ T cell depletion, tetramer binding assays and ELISPOT assays were used to demonstrate the unique role of CD4+T cell help in the antitumor effects of the anti-PD-1+LAG-3 combination.

HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis.

Melanomas can adopt multiple transcriptional states. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity. Here, we identify stress-induced HDAC8 activity as driving melanoma brain metastasis development.

Stereotactic radiosurgery and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors, or conventional chemotherapy for the management of melanoma brain metastases.

Background: Immunotherapy and targeted BRAF/MEK inhibitors (i) have revolutionised the systemic management of advanced melanoma. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and various systemic therapies.

Methods: Patients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1+CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy.

Leptomeningeal disease in melanoma: An update on the developments in pathophysiology and clinical care.

Leptomeningeal disease (LMD) remains a major challenge in the clinical management of metastatic melanoma patients. Outcomes for patient remain poor, and patients with LMD continue to be excluded from almost all clinical trials. However, recent trials have demonstrated the feasibility of conducting prospective clinical trials in these patients.

Tucatinib and stereotactic radiosurgery in the management of HER2 positive breast cancer brain metastases.

Purpose: HER2-positive breast cancer has a high risk of brain metastasis. Stereotactic radiosurgery (SRS) is standard of care for limited brain metastases. Tucatinib, a HER2-targeted tyrosine kinase inhibitor, has demonstrated intracranial efficacy in the HER2-CLIMB Trial.

A Brain, A Heart, and the Courage: Balancing Benefit and Toxicity of Immunotherapy in Melanoma.

The overall survival of advanced melanoma has improved dramatically. Immunotherapies, specifically checkpoint inhibitors, have played a large role in this improvement. These agents have also shown benefit in the adjuvant setting, are approved for treatment of resected stage II, III, and IV melanoma, and play an evolving role in the neoadjuvant setting.

Leptomeningeal Disease (LMD) in Patients with Melanoma Metastases.

Leptomeningeal disease (LMD) is a devastating complication caused by seeding malignant cells to the cerebrospinal fluid (CSF) and the leptomeningeal membrane. LMD is diagnosed in 5-15% of patients with systemic malignancy. Management of LMD is challenging due to the biological and metabolic tumor microenvironment of LMD being largely unknown.

Improving Brain Metastases Outcomes Through Therapeutic Synergy Between Stereotactic Radiosurgery and Targeted Cancer Therapies.

Brain metastases are the most common form of brain cancer. Increasing knowledge of primary tumor biology, actionable molecular targets and continued improvements in systemic and radiotherapy regimens have helped improve survival but necessitate multidisciplinary collaboration between neurosurgical, medical and radiation oncologists. In this review, we will discuss the advances of targeted therapies to date and discuss findings of studies investigating the synergy between these therapies and stereotactic radiosurgery for non-small cell lung cancer, breast cancer, melanoma, and renal cell carcinoma brain metastases.

Evolving management of HER2+ breast cancer brain metastases and leptomeningeal disease.

Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at a particularly high risk of breast cancer brain metastasis (BCBM) and leptomeningeal disease (LMD). Improvements in systemic therapy have translated to improved survival for patients with HER2-positive BCBM and LMD. However, the optimal management of these cases is rapidly evolving and requires a multidisciplinary approach.

A preclinical model of patient-derived cerebrospinal fluid circulating tumor cells for experimental therapeutics in leptomeningeal disease from melanoma.

Background: Leptomeningeal disease (LMD) occurs as a late complication of several human cancers and has no rationally designed treatment options. A major barrier to developing effective therapies for LMD is the lack of cell-based or preclinical models that recapitulate human disease. Here, we describe the development of in vitro and in vivo cultures of patient-derived cerebrospinal fluid circulating tumor cells (PD-CSF-CTCs) from patients with melanoma as a preclinical model to identify exploitable vulnerabilities in melanoma LMD.

Advances in Diagnosis and Treatment for Leptomeningeal Disease in Melanoma.

Purpose Of Review: Melanoma has one of the highest incidences of causing leptomeningeal disease (LMD) among solid tumors. LMD patients have very poor prognosis with a dismal survival despite aggressive management. In this article, we review the current approaches in the management of patients with LMD secondary to melanoma, including updates in diagnosis, treatment, up-to-date clinical studies, and future directions.

Nivolumab and Stereotactic Radiosurgery for Patients With Breast Cancer Brain Metastases: A Nonrandomized, Open-Label Phase 1b Study.

Purpose: We hypothesize treatment with nivolumab and stereotactic radiosurgery (SRS) will be feasible and well tolerated, and may improve intracranial tumor control rates compared with SRS alone.

Methods And Materials: The study was designed as a prospective, single-arm, nonrandomized, open-label, phase 1b trial of nivolumab and SRS among patients with metastatic breast cancer brain metastases. Key eligibility criteria included patients with breast cancer brain metastases of all subtypes, age ≥18, Eastern Cooperative Oncology Group Performance Status ≤2 with ≤10 brain metastases.

Identification of Immunogenic MHC Class II Human HER3 Peptides that Mediate Anti-HER3 CD4 Th1 Responses and Potential Use as a Cancer Vaccine.

The HER3/ERBB3 receptor is an oncogenic receptor tyrosine kinase that forms heterodimers with EGFR family members and is overexpressed in numerous cancers. HER3 overexpression associates with reduced survival and acquired resistance to targeted therapies, making it a potential therapeutic target in multiple cancer types. Here, we report on immunogenic, promiscuous MHC class II-binding HER3 peptides, which can generate HER3-specific CD4 Th1 antitumor immune responses.

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study.

Background: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial.

Methods: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter).