Intratumoral vidutolimod in combination with PD-1 blockade in locoregionally advanced melanoma.

Combinatorial immunotherapy may improve the efficacy of neoadjuvant checkpoint inhibitors in locoregionally advanced melanoma. In this issue of Cancer Cell, Davar and colleagues report a promising phase 2 neoadjuvant trial of the TLR9 agonist vidutolimod in combination with nivolumab. Analyses suggest a unique myeloid expression signature is associated with response.

Spatial Immunophenotyping from Whole-Slide Multiplexed Tissue Imaging Using Convolutional Neural Networks.

The multiplexed immunofluorescence (mIF) platform enables biomarker discovery through the simultaneous detection of multiple markers on a single tissue slide, offering detailed insights into intratumor heterogeneity and the tumor-immune microenvironment at spatially resolved single cell resolution. However, current mIF image analyses are labor-intensive, requiring specialized pathology expertise which limits their scalability and clinical application. To address this challenge, we developed CellGate, a deep-learning (DL) computational pipeline that provides streamlined, end-to-end whole-slide mIF image analysis including nuclei detection, cell segmentation, cell classification, and combined immuno-phenotyping across stacked images.

Intrapatient variation in PD-L1 expression and tumor mutational burden and the impact on outcomes to immune checkpoint inhibitor therapy in patients with non-small-cell lung cancer.

Background: Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited.

Patients And Methods: Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included.

Early On-Treatment Assessment of T Cells, Cytokines, and Tumor DNA with Adaptively Dosed Nivolumab + Ipilimumab: Final Results from the Phase 2 ADAPT-IT Study.

Purpose: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported.

A General Approach to Patients Presenting With Locally Advanced or Distant Metastatic Disease.

The widespread adoption of immune checkpoint inhibitors and small molecule inhibitors of the MAP kinase pathway has transformed the management of locally advanced and metastatic melanoma. Here, we provide a broad overview on the use of these agents in the first-line setting, incorporating a review of the clinical literature as well as the practice patterns of our respective melanoma groups. Throughout, we highlight areas of uncertainty that provide opportunities for future clinical investigation and additional improvement in outcomes for patients with melanoma.

Integration of peripheral blood- and tissue-based biomarkers of response to immune checkpoint blockade in urothelial carcinoma.

As predictive biomarkers of response to immune checkpoint inhibitors (ICIs) remain a major unmet clinical need in patients with urothelial carcinoma (UC), we sought to identify tissue-based immune biomarkers of clinical benefit to ICIs using multiplex immunofluorescence and to integrate these findings with previously identified peripheral blood biomarkers of response. Fifty-five pretreatment and 12 paired on-treatment UC specimens were identified from patients treated with nivolumab with or without ipilimumab. Whole tissue sections were stained with a 12-plex mIF panel, including CD8, PD-1/CD279, PD-L1/CD274, CD68, CD3, CD4, FoxP3, TCF1/7, Ki67, LAG-3, MHC-II/HLA-DR, and pancytokeratin+SOX10 to identify over three million cells.

CD16+ Macrophages: An Emerging Biomarker for Combined CTLA-4 and PD-1 Blockade.

In a retrospective analysis of patients with unresectable melanoma, higher pretreatment tissue densities of CD16+ macrophages were associated with clinical benefit from combined CTLA-4 and PD-1 blockade. With further validation, this biomarker could serve as a tool in selecting between immune checkpoint inhibitor regimens. See related article by Lee et al.

Ensuring equity in the era of HLA-restricted cancer therapeutics.

In January 2022, the US Food and Drug Administration granted regulatory approval to tebentafusp, a bispecific T cell receptor protein that targets melanoma antigen gp100 in the context of the human leucocyte antigen (HLA) A*0201 allele. This approval generated significant excitement, given the relative paucity of effective systemic therapies for advanced uveal melanoma. More broadly, tebentafusp represents the first T cell receptor agent to improve overall survival in any solid tumor.

Adjuvant PD-1 Blockade in Resected Melanoma: Is Preventing Recurrence Enough?

Grossmann and colleagues report the results of a large randomized trial demonstrating improved recurrence-free survival with adjuvant pembrolizumab in resected melanoma compared with adjuvant ipilimumab or IFNα2b. However, it remains unclear whether adjuvant immunotherapies extend overall survival as outcomes for patients with advanced melanoma continue to improve. See related article by Grossmann et al.

Factors Determining Long-Term Antitumor Responses to Immune Checkpoint Blockade Therapy in Melanoma.

With the increasing promise of long-term survival with immune checkpoint blockade (ICB) therapies, particularly for patients with advanced melanoma, clinicians and investigators are driven to identify prognostic and predictive factors that may help to identify individuals who are likely to experience durable benefit. Several ICB combinations are being actively developed to expand the armamentarium of treatments for patients who may not achieve long-term responses to ICB single therapies alone. Thus, negative predictive markers are also of great interest.

Adaptive Dosing of Nivolumab + Ipilimumab Immunotherapy Based Upon Early, Interim Radiographic Assessment in Advanced Melanoma (The ADAPT-IT Study).

Purpose: Nivolumab + ipilimumab (nivo + ipi) is highly efficacious but has high toxicity. Standard treatment in advanced melanoma is four doses of nivo + ipi followed by nivo alone. Whether four doses of nivo + ipi are needed is unclear.

Facts and Hopes in Prediction, Diagnosis, and Treatment of Immune-Related Adverse Events.

Over the past decade, the use of immune checkpoint inhibitors (ICI) has expanded across a wide spectrum of oncology indications. Immune-related adverse events (irAE) from ICIs represent a significant source of morbidity, and in rare instances, can lead to treatment-related mortality. There are significant opportunities to better identify patients at increased risk for immune-related toxicity, diagnose irAEs more accurately and earlier in their course, and develop more individualized therapeutic strategies once complications arise.

Pancreas cancer: Therapeutic trials in metastatic disease.

Metastatic pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality in 2021. Cytotoxic therapies are the therapeutic mainstay for PDAC. The recent approval of olaparib as maintenance therapy for germline BRCA1/2-mutated PDAC and pembrolizumab for mismatch repair deficient PDAC represent molecularly targeted approaches for this disease.

Identification of Racial Inequities in Access to Specialized Inpatient Heart Failure Care at an Academic Medical Center.

Background: Racial inequities for patients with heart failure (HF) have been widely documented. HF patients who receive cardiology care during a hospital admission have better outcomes. It is unknown whether there are differences in admission to a cardiology or general medicine service by race.

Closed system RT-qPCR as a potential companion diagnostic test for immunotherapy outcome in metastatic melanoma.

Background: In melanoma, there is no companion diagnostic test to predict response to programmed cell death 1 (PD-1) axis immune checkpoint inhibitor (ICI) therapy. In the adjuvant setting, only one in five patients may benefit from ICI, so a biomarker is needed to select those that may or may not benefit. Here, we test a new 4-gene multiplex immunotherapy panel with research use only (RUO) prototype mRNA expression profile on the GeneXpert closed system using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) for association with clinical benefit after treatment with ICI therapy in metastatic melanoma patients.

Multiplex quantitative analysis of cancer-associated fibroblasts and immunotherapy outcome in metastatic melanoma.

Background: The cancer-associated fibroblast (CAF) population is implicated in immune dysregulation. Here, we test the hypothesis that CAF profiles in pretreatment tumor specimens are associated with response to immune checkpoint blockade of programmed cell death 1 (PD-1).

Methods: Pretreatment whole tissue sections from 117 melanoma patients treated with anti-PD-1 therapy were assessed by multiplex immunofluorescence to detect CAFs defined by Thy1, smooth muscle actin (SMA), and fibroblast activation protein (FAP).

High-Plex Predictive Marker Discovery for Melanoma Immunotherapy-Treated Patients Using Digital Spatial Profiling.

Purpose: Protein expression in formalin-fixed, paraffin-embedded tissue is routinely measured by IHC or quantitative fluorescence (QIF) on a handful of markers on a single section. Digital spatial profiling (DSP) allows spatially informed simultaneous assessment of multiple biomarkers. Here we demonstrate the DSP technology using a 44-plex antibody cocktail to find protein expression that could potentially be used to predict response to immune therapy in melanoma.

Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes and Immunotherapy Outcome in Metastatic Melanoma.

Purpose: Because durable response to programmed cell death 1 (PD-1) inhibition is limited to a subset of melanoma patients, new predictive biomarkers could have clinical utility. We hypothesize that pretreatment tumor-infiltrating lymphocyte (TIL) profiles could be associated with response.

Experimental Design: Pretreatment whole tissue sections from 94 melanoma patients treated with anti-PD-1 therapy were profiled by multiplex immunofluorescence to perform TIL quantification (CD4, CD8, CD20) and assess TIL activation (CD3, GZMB, Ki67).

Immune Marker Profiling and Programmed Death Ligand 1 Expression Across NSCLC Mutations.

Introduction: Programmed death 1/programmed death ligand 1 (PD-L1) axis inhibitors have been proven effective, especially in patients with tumors expressing PD-L1. Their clinical efficacy in patients with EGFR-activating mutations is still unclear, whereas KRAS mutations seem to be associated with good response.

Methods: We used multiplexed quantitative immunofluorescence to investigate PD-L1 expression and to characterize tumor infiltrating lymphocyte (TIL) populations and their activation status in more than 150 NSCLC patients with known mutation status.

Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma.

PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response. Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery ( = 24) and validation ( = 142) cohorts.

Postneoadjuvant adjuvant chemotherapy in resected N1 non-small cell lung cancer with residual nodal disease.

Background And Objectives: Nodal positivity following neoadjuvant chemotherapy in locally advanced non-small cell lung cancer (NSCLC) is considered a poor prognostic sign, but little data are available on the efficacy of adjuvant chemotherapy in these cases. This analysis sought to determine whether adjuvant chemotherapy was associated with increased survival in NSCLC patients with residual N1 disease at resection.

Methods: Patients from the National Cancer Database (NCDB) with cN1T1-2M0 NSCLC treated with neoadjuvant chemotherapy and definitive resection between 2006 and 2012 were identified.