Low-dose Paclitaxel with Pembrolizumab Enhances Clinical and Immunologic Responses in Platinum-refractory Urothelial Carcinoma.

Purpose: Single-agent checkpoint inhibition is effective in a minority of patients with platinum-refractory urothelial carcinoma; therefore, the efficacy of combining low-dose paclitaxel with pembrolizumab was tested.

Materials And Methods: This was a prospective, single-arm phase II trial with key inclusion criteria of imaging progression within 12 months of platinum therapy and Eastern Cooperative Oncology Group ≤1. Treatment was pembrolizumab 200 mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21-day cycle for up to eight cycles unless progression or unacceptable adverse events (AE).

Targeting the CD47/thrombospondin-1 signaling axis regulates immune cell bioenergetics in the tumor microenvironment to potentiate antitumor immune response.

Background: CD47 is an integral membrane protein that alters adaptive immunosurveillance when bound to the matricellular glycoprotein thrombospondin-1 (TSP1). We examined the impact of the CD47/TSP1 signaling axis on melanoma patient response to anti-PD-1 therapy due to alterations in T cell activation, proliferation, effector function, and bioenergetics.

Methods: A syngeneic B16 mouse melanoma model was performed to determine if targeting CD47 as monotherapy or in combination with anti-PD-1 impacted tumor burden.

Phase 1/2 study of epacadostat in combination with durvalumab in patients with metastatic solid tumors.

Background: Targeting programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) pathways is an appealing option for cancer treatment.

Methods: The open-label, phase 1/2 ECHO-203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti-PD-L1 monoclonal antibody in adult patients with advanced solid tumors.

Results: The most common treatment-related adverse events were fatigue (30.

A First Suspected Case of Fibrosing Mediastinitis After Anti-PD-1 Therapy.

We describe a first suspected case of fibrosing mediastinitis following anti-programmed death (PD)-1 therapy, pembrolizumab. Multimodality imaging, including cardiac magnetic resonance imaging, and a multidisciplinary team approach were integral to the diagnosis. If further substantiated, systematic surveillance after anti-PD-1 therapy for fibrosing mediastinitis may be warranted.

Prognostic attributes of immune signatures in soft tissue sarcomas show differential dependencies on tumor mutational burden.

Background: Cellular and intrinsic markers of sarcoma immunogenicity are poorly understood. To gain insight into whether tumor-immune interactions correlate with clinical aggressiveness, the authors examined the prognostic significance of immune gene signatures in combination with tumor mutational burden (TMB) and cancer-testis antigen (CTA) expression.

Methods: RNA sequencing and clinical data of 259 soft tissue sarcomas from The Cancer Genome Atlas project were used to investigate associations between published immune gene signatures and patient overall survival (OS) in the contexts of TMB, as computed from whole-exome sequencing data, and CTA gene expression.

Circulating Immune Bioenergetic, Metabolic, and Genetic Signatures Predict Melanoma Patients' Response to Anti-PD-1 Immune Checkpoint Blockade.

Purpose: Immunotherapy with checkpoint inhibitors is improving the outcomes of several cancers. However, only a subset of patients respond. Therefore, predictive biomarkers are critically needed to guide treatment decisions and develop approaches to the treatment of therapeutic resistance.

hDirect-MAP: projection-free single-cell modeling of response to checkpoint immunotherapy.

There is a lack of robust generalizable predictive biomarkers of response to immune checkpoint blockade in multiple types of cancer. We develop hDirect-MAP, an algorithm that maps T cells into a shared high-dimensional (HD) expression space of diverse T cell functional signatures in which cells group by the common T cell phenotypes rather than dimensional reduced features or a distorted view of these features. Using projection-free single-cell modeling, hDirect-MAP first removed a large group of cells that did not contribute to response and then clearly distinguished T cells into response-specific subpopulations that were defined by critical T cell functional markers of strong differential expression patterns.

Metabolic Implications of Immune Checkpoint Proteins in Cancer.

Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism.

A prospective trial of adjuvant therapy for high-risk uveal melanoma: assessing 5-year survival outcomes.

Background/aims: Survival after diagnosis of metastasis from uveal melanoma is poor. Identifying individuals at high risk for metastasis and developing adjuvant therapy to prevent clinically apparent metastasis could improve survival. We conducted an adjuvant trial of sequential, low-dose dacarbazine (DTIC) and interferon-alpha-2b (IFN-α-2b) in patients with cytogenetic high-risk uveal melanoma.

Melanocortin 1 Receptor-Targeted α-Particle Therapy for Metastatic Uveal Melanoma.

New effective therapies are greatly needed for metastatic uveal melanoma, which has a very poor prognosis with a median survival of less than 1 y. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases, and a MC1R-specific ligand (MC1RL) with high affinity and selectivity for MC1R was previously developed. The Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity and was tested in vitro for biostability and for MC1R-specific cytotoxicity in uveal melanoma cells, and the lanthanum-DOTA-MC1RL analog was tested for binding affinity.

Circulating immune biomarkers as predictors of the response to pembrolizumab and weekly low dose carboplatin and paclitaxel in NSCLC and poor PS: An interim analysis.

The combination of standard-dose chemotherapy and immunotherapy has been shown to be beneficial for patients with non-small cell lung cancer (NSCLC) with good performance status (PS). However, treatment options for patients with poor PS are limited. In the present study, the feasibility and immunological effects of low-dose chemotherapy with carboplatin and paclitaxel combined with immunotherapy with pembrolizumab were examined in patients with metastatic NSCLC and a poor PS.

Addressing the Adult Soft Tissue Sarcoma Microenvironment with Intratumoral Immunotherapy.

Sarcoma is comprised of a heterogeneous group of tumors originating from the mesenchyme. Sarcoma is also the first tumor that responded to immunotherapeutic agents often termed as "Coley's toxins." However, immunotherapy is yet to establish its presence in sarcomas.

Practical Guidelines for Cerenkov Luminescence Imaging with Clinically Relevant Isotopes.

Cerenkov luminescence imaging (CLI) is a relatively new imaging modality that utilizes conventional optical imaging instrumentation to detect Cerenkov radiation derived from standard and often clinically approved radiotracers. Its research versatility, low cost, and ease of use have increased its popularity within the molecular imaging community and at institutions that are interested in conducting radiotracer-based molecular imaging research, but that lack the necessary resources and infrastructure. Here, we provide a description of the materials and procedures necessary to conduct a Cerenkov luminescence imaging experiment using a variety of imaging instrumentation, radionuclides, and animal models.

Unfolded protein response signaling impacts macrophage polarity to modulate breast cancer cell clearance and melanoma immune checkpoint therapy responsiveness.

The unfolded protein response (UPR) is a stress pathway controlled by GRP78 to mediate IRE1, PERK, and ATF6 signaling. We show that targeting GRP78, IRE1, and PERK differentially regulates macrophage polarization. Specifically, PERK targeting enhanced macrophage proliferation and macrophage-mediated killing but not GRP78 or IRE1.

Expression of natural killer cell regulatory microRNA by uveal melanoma cancer stem cells.

Natural killer (NK) cells are implicated in the control of metastasis in uveal melanoma, a process that has been ascribed to its cancer stem cell subpopulation. NK cell activation is regulated by specific microRNA (miR). The NK cell sensitivity and regulatory miR production of uveal melanoma cancer stem cells was examined.

Association of tumor and plasma microRNA expression with tumor monosomy-3 in patients with uveal melanoma.

Background: Epigenetic events mediated by methylation and histone modifications have been associated with the development of metastasis in patients with uveal melanoma. The role of epigenetic events mediated by microRNA (miR) is less clear. Tumor and plasma miR expression was examined in patients with primary uveal melanoma with tumor monosomy-3, a predictor of metastasis.

Depression, Anxiety, and Regret Before and After Testing to Estimate Uveal Melanoma Prognosis.

Importance: To our knowledge, longitudinal assessment of depression, anxiety, and decision regret (a sense of disappointment or dissatisfaction in the decision) in patients undergoing prognostication for uveal melanoma does not exist.

Objective: To report on depression, anxiety, and decision regret before and after testing to estimate uveal melanoma prognosis.

Design, Setting, And Participants: Prospective interventional case series conducted at an institutional referral practice of 96 patients with clinical diagnosis of uveal melanoma who underwent prognostication at the time of primary therapy.

Spontaneous cellular and humoral tumor antigen responses in patients with uveal melanoma.

Antigens that may be involved in the immune response to uveal melanoma have not been identified. Cellular and humoral responses to melanoma differentiation antigens, as well as to BRCA1-associated protein 1 (BAP1) and α-enolase, alterations of which are associated with metastatic disease, were examined in patients with uveal melanoma. Blood was collected from 66 patients with primary and 13 patients with metastatic uveal melanoma.

Fine-needle aspiration biopsy of uveal melanoma: outcomes and complications.

Purpose: To report outcomes and complications of fine-needle aspiration biopsy (FNAB) of uveal melanoma performed for diagnostic and prognostic purposes.

Methods: Prospective interventional case series of 150 consecutive patients with a clinical diagnosis of uveal melanoma. The FNAB approach (transcorneal (TCO), transscleral (TSC) and transvitreal (TVT) was primarily determined by the location of the tumour.

Genomic microarray analysis on formalin-fixed paraffin-embedded material for uveal melanoma prognostication.

Cytogenetic alterations are strong outcome prognosticators in uveal melanoma (UVM). Monosomy 3 (-3) and MYC amplification at 8q24 are commonly tested by fluorescence in situ hybridization (FISH). Alternatively, microarray analysis provides whole genome data, detecting partial chromosome loss, loss of heterozygosity (LOH), or abnormalities unrepresented by FISH probes.

Molecular profiling of primary uveal melanomas with tumor-infiltrating lymphocytes.

In contrast to other cancers, the presence of tumor-infiltrating lymphocytes (TILs) in uveal melanoma is associated with a poor prognosis. However, how TILs may promote disease progression and what regulates their infiltration has not yet been established. To address these clinically relevant outstanding questions, T cell, immune regulatory, and chemokine gene expression profiles of 57 enucleated uveal melanoma tumors were compared, encompassing 27 with TILs and 30 without,.

Adjuvant Therapy of Uveal Melanoma: Current Status.

The survival of patients with uveal melanoma remains poor because of the development of metastatic disease. Adjuvant therapy after treatment of the primary tumor has been tested but has not been shown to prevent the development of metastasis. Several new approaches are being developed.

Biology of advanced uveal melanoma and next steps for clinical therapeutics.

Uveal melanoma is the most common intraocular malignancy although it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15-yr period.

Enrichment of circulating melanoma cells (CMCs) using negative selection from patients with metastatic melanoma.

Circulating tumor cells have emerged as prognostic biomarkers in the treatment of metastatic cancers of epithelial origins viz., breast, colorectal and prostate. These tumors express Epithelial Cell Adhesion Molecule (EpCAM) on their cell surface which is used as an antigen for immunoaffinity capture.