Rapid progression of intracranial melanoma metastases controlled with combined BRAF/MEK inhibition after discontinuation of therapy: a clinical challenge.

Novel systemic therapies with anti-tumor activity in the brain including small molecules targeting BRAF and MEK, and immune checkpoint inhibition, offer the possibility of improved control of intracranial disease. A number of prospective trials support the judicious use of modern systemic therapies in patients with melanoma and limited brain metastases .The intracranial clinical course of patients who progress extracranially on BRAF/MEK inhibition remains poorly described in the literature.

Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer.

Background: Preclinical and clinical studies suggest potential synergy between high dose per fraction focal radiation and immunotherapy. However, conventionally fractionated radiation regimens in combination with concurrent chemotherapy are more commonly administered to patients as definitive treatment and may have both immune-stimulating and -suppressive effects.

Methods: We prospectively collected longitudinal samples from head and neck squamous cell carcinoma patients receiving definitive radiation therapy.

Effects of definitive chemoradiation on circulating immunologic angiogenic cytokines in head and neck cancer patients.

Background: Preclinical studies suggest a synergistic effect between radiation, immunotherapy and anti-angiogenic therapy, although the mechanisms are unclear. Angiogenic cytokines are known to affect the immune system, and their levels may be associated with response to immunotherapy. Here, we assess changes in circulating VEGF, as well as angiogenic cytokines angiopoietin-1 and -2 (Ang1, Ang2), and placental growth factor (PLGF) that occur during definitive chemo-radiotherapy in HNSCC patients.

Immune Profiling of Adenoid Cystic Carcinoma: PD-L2 Expression and Associations with Tumor-Infiltrating Lymphocytes.

Adenoid cystic carcinoma (ACC) is among the most lethal salivary gland tumors, with no treatments for metastatic disease that prolong survival. We examined tissue from 28 primary and metastatic ACC deposits obtained from 21 patients for infiltrating immune cells and PD-L1/PD-L2 expression and determined mRNA profiles of over 1,400 oncogenic and immune-related genes. We also assessed the effect of chemoradiation on immune mediators in a patient who had serial biopsies available.

Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days.

Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial.

Background: Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy.

Methods: We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA.

Landscape of tumor-infiltrating T cell repertoire of human cancers.

We developed a computational method to infer the complementarity-determining region 3 (CDR3) sequences of tumor-infiltrating T cells in 9,142 RNA-seq samples across 29 cancer types. We identified over 600,000 CDR3 sequences, including 15% that were full length. CDR3 sequence length distribution and amino acid conservation, as well as variable gene usage, for infiltrating T cells in many tumors, except in brain and kidney cancers, resembled those for peripheral blood cells from healthy donors.

RECIST 1.1 - Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group.

Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical.

Tumour CD274 (PD-L1) expression and T cells in colorectal cancer.

Objective: Evidence suggests that CD274 (programmed death-ligand 1, B7-H1) immune checkpoint ligand repress antitumour immunity through its interaction with the PDCD1 (programmed cell death 1, PD-1) receptor of T lymphocytes in various tumours. We hypothesised that tumour CD274 expression levels might be inversely associated with T-cell densities in colorectal carcinoma tissue.

Design: We evaluated tumour CD274 expression by immunohistochemistry in 823 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study.

RECIST 1.1-Update and clarification: From the RECIST committee.

The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression.

Talimogene Laherparepvec for the Treatment of Advanced Melanoma.

Talimogene laherparepvec (T-VEC) is a first-in-class oncolytic virus that mediates local and systemic antitumor activity by direct cancer cell lysis and an "in situ vaccine" effect. Based on an increased durable response rate compared with granulocyte macrophage-colony stimulating factor in a randomized phase III trial, it was approved by the FDA for the treatment of melanoma metastatic to skin or lymph nodes. The drug is currently in clinical trials as monotherapy and in combination with immune-checkpoint inhibitors and radiotherapy in melanoma and other cancers.

Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma.

Importance: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab.

Objective: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma.

Design, Settings, And Participants: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013).

Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy.

Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab.

Purpose: We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study (clinical trial information: NCT01295827).

Genetic Basis for PD-L1 Expression in Squamous Cell Carcinomas of the Cervix and Vulva.

Importance: Patients with squamous cell carcinoma (SCC) of the cervix or vulva have limited therapeutic options, and the potential for immunotherapy for this population has not been evaluated. Recent trials suggest that tumors with a genetic basis for PD-1 (programmed cell death protein 1) ligand expression are highly sensitive to therapeutic antibodies targeting PD-1.

Objective: To determine the genetic status of CD274 (encoding PD-L1 [programmed cell death 1 ligand 1]) and PDCD1LG2 (encoding PD-L2 [programmed cell death 1 ligand 2]) in SCCs of the cervix and vulva and to correlate the findings with PD-L1 protein expression.

Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.

Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade.

Anti-PD-1 Inhibitor-Related Pneumonitis in Non-Small Cell Lung Cancer.

The recent approval of two PD-1 inhibitors for the treatment of non-small cell lung cancer (NSCLC) has rapidly led to the widespread use of these agents in oncology practices. Pneumonitis has been recognized as a potentially life-threatening adverse event among NSCLC patients treated with PD-1 inhibitors; however, the detailed clinical and radiographic manifestations of this entity remain to be described. We report on two cases of anti-PD-1 pneumonitis in advanced NSCLC patients treated with nivolumab after its FDA approval.

STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment.

STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes, such as STK11/LKB1, exerts similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC.

Expression of Programmed Cell Death 1 Ligands (PD-L1 and PD-L2) in Histiocytic and Dendritic Cell Disorders.

Programmed cell death 1 ligands 1 and 2 (PD-L1 and PD-L2) are cell surface proteins expressed by activated antigen-presenting cells and by select malignancies that bind PD-1 on T cells to inhibit immune responses. Antibodies targeting PD-1 or PD-L1 elicit antitumor immunity in a subset of patients, and clinical response correlates with PD-1 ligand expression by malignant or immune cells within the tumor microenvironment. We examined the expression of PD-1 ligands on subsets of antigen-presenting cells and 87 histiocytic and dendritic cell disorders including those that are benign, borderline, and malignant.

Radiologic Heterogeneity in Responses to Anti-PD-1/PD-L1 Therapy in Metastatic Renal Cell Carcinoma.

Radiologic assessment of tumor response remains a challenge in patients treated with immune checkpoint inhibitors. In metastatic melanoma, for example, a spectrum of imaging patterns in response to immunotherapies have been recognized and associated with clinical benefit. In metastatic renal cell carcinoma (mRCC), less than half of patients treated with immune checkpoint inhibitors achieve objective responses, but some of the responses have been durable.

CCR 20th Anniversary Commentary: Immune-Related Response Criteria--Capturing Clinical Activity in Immuno-Oncology.

To evaluate antitumor responses to chemotherapeutic agents, investigators would typically rely upon Response Evaluation Criteria in Solid Tumors (RECIST) or modified WHO criteria, which do not comprehensively capture responses with immunotherapeutic agents. In the December 1, 2009, issue of Clinical Cancer Research, Wolchok and colleagues reported their development of novel criteria, designated "Immune-related Response Criteria" (irRC), designed to better capture the response patterns observed with immunotherapies. Broad use of the irRC since then has allowed for a more comprehensive evaluation of immunotherapies in clinical trials, indicating that their concepts can be used in conjunction with either RECIST or WHO, and has shown irRC to be a powerful tool for improved clinical investigation.

Clinical development of talimogene laherparepvec (T-VEC): a modified herpes simplex virus type-1-derived oncolytic immunotherapy.

Tumor immunotherapy is emerging as a promising new treatment option for patients with cancer. T-VEC is an intralesional oncolytic virus therapy based on a modified herpes simplex virus type-1. T-VEC selectively targets tumor cells, causing regression in injected lesions and inducing immunologic responses that mediate regression at uninjected/distant sites.

Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model.

Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known.

PD-L1 Antibodies to Its Cytoplasmic Domain Most Clearly Delineate Cell Membranes in Immunohistochemical Staining of Tumor Cells.

Blocking the programmed death-1 (PD-1) pathway has clinical benefit in metastatic cancer and has led to the approval of the mAbs pembrolizumab and nivolumab to treat melanoma and nivolumab for non-small cell lung cancer. Expression of PD-L1 on the cell surface of either tumor cells or infiltrating immune cells is associated with a higher likelihood of response to PD-1 blockade in multiple studies. Most mAbs to PD-L1 in use are directed to its extracellular domain and immunohistochemically stain tumor tissue with a mixture of cytoplasmic and membrane staining.