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Background: In the phase II/III RELATIVITY-047 trial, a novel fixed-dose combination (FDC) of nivolumab plus relatlimab (NIVO + RELA; a programmed death-1 and a lymphocyte-activation gene 3 inhibitor, respectively) significantly improved progression-free survival (PFS) versus NIVO in patients with previously untreated unresectable or metastatic melanoma (median follow-up, 13.2 months) with stable health-related quality of life (HRQoL), although grade three or four treatment-related adverse events (TRAEs) were more frequent with the combination. Updated HRQoL results (median follow-up, 19.3 months) are presented. Methods: Patients were randomised to receive intravenous NIVO + RELA (480 mg and 160 mg, respectively) or NIVO (480 mg) every 4 weeks. HRQoL was assessed using the Functional Assessment of Cancer Treatment-Melanoma (FACT-M) and EQ-5D-3L questionnaires at baseline, before dosing at each treatment cycle, and at follow-up (posttreatment) visits. Results: Consistent with the initial analysis, HRQoL remained stable with NIVO + RELA on treatment and was similar to that with NIVO. Mean changes from baseline did not exceed clinically meaningful thresholds. HRQoL results were consistent across instruments and scales/subscales. Despite an increased rate of grade three or four TRAEs with NIVO + RELA versus NIVO, the proportion of patients reporting that they were bothered 'quite a bit' or 'very much' by TRAEs was low and comparable between treatments. Conclusion: Results from the RELATIVITY-047 trial show that the PFS benefit with NIVO + RELA FDC over NIVO was obtained with stable patient-reported HRQoL, supporting NIVO + RELA as a first-line treatment option for patients with advanced melanoma.

OBJECTIVE Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of patients with many tumor histologies. Simultaneously, stereotactic body radiotherapy (SBRT) provides excellent local control (LC) and plays an important role in the management of spine metastasis. Promising preclinical work suggests the potential therapeutic benefit of combining SBRT with ICI therapy, but the safety profile of combined therapy is unclear. This study aimed to evaluate the toxicity profile associated with ICI in patients receiving SBRT and, secondarily, whether ICI administration sequence with respect to SBRT affects LC or overall survival (OS) outcomes. METHODS The authors retrospectively reviewed patients with spine metastasis treated with SBRT at an academic center. Patients who received ICI at any point during their disease course were compared to those with the same primary tumor types who did not receive ICI by using Cox proportional hazards analyses. Primary outcomes were long-term sequelae, including radiation-induced spinal cord myelopathy, esophageal stricture, and bowel obstruction. Secondarily, models were created to evaluate OS and LC in the cohort. RESULTS Two hundred forty patients who received SBRT to 299 spine metastases were included in this study. The most common primary tumor types were non–small cell lung cancer (n = 59 [24.6%]) and renal cell carcinoma (n = 55 [22.9%]). One hundred eight patients received at least 1 dose of ICI, with the most common regimen being single-agent anti–PD-1 (n = 80 [74.1%]), followed by combination CTLA-4/PD-1 inhibitors (n = 19 [17.6%]). Three patients experienced long-term radiation-induced sequelae: 2 had esophageal stricture and 1 had bowel obstruction. No patients developed radiation-induced myelopathy. There was no association between receipt of ICI and development of any of these adverse events (p > 0.9). Similarly, ICI was not significantly associated with either LC (p = 0.3) or OS (p = 0.6). In the entire cohort, patients who received ICI prior to beginning SBRT had worse median survival, but ICI sequence with respect to SBRT was not significantly prognostic of either LC (p > 0.3) or OS (p > 0.07); instead, baseline performance status was most predictive of OS (HR 1.38, 95% CI 1.07–1.78, p = 0.012). CONCLUSIONS Treatment regimens that combine ICIs before, concurrent with, and after SBRT for spine metastases are safe, with minimal risk for increased rates of long-term toxicity.

BACKGROUND: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings. METHODS: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events. RESULTS: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%). CONCLUSIONS: Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.)

PURPOSE Nivolumab and relatlimab activity in advanced melanoma with prior progression on anti–programmed death-1/programmed death ligand 1 (PD-(L)1)-containing regimens is under investigation. RELATIVITY-047 demonstrated significantly improved progression-free survival (PFS) for nivolumab and relatlimab over nivolumab in previously untreated advanced melanoma. METHODS The phase I/IIa, open-label RELATIVITY-020 trial part D assessed efficacy and safety of nivolumab and relatlimab in advanced melanoma with progression during, or within 3 months of, 1 (D1) or ≥ 1 (D2) anti–PD-(L)1-containing regimens. Safety was a primary end point. Objective response rate (coprimary end point) and PFS by blinded independent central review (BICR) were assessed. RESULTS Five hundred eighteen patients (D1 = 354; D2 = 164) received nivolumab and relatlimab. Among evaluable patients, the objective response rate by BICR was 12.0% (95% CI, 8.8 to 15.8) in D1 (n = 351) and 9.2% (95% CI, 5.2 to 14.7) in D2 (n = 163). Responses appeared to be enriched among patients with tumors expressing programmed death ligand 1 or lymphocyte activation gene 3; however, responses were observed regardless of programmed death ligand 1 and lymphocyte activation gene 3 expression (1%). The median duration of response was not reached (95% CI, 12.9 to not reached) in D1 and 12.8 months (95% CI, 6.9 to 12.9) in D2. The median PFS by BICR was 2.1 months (95% CI, 1.9 to 3.5) in D1 and 3.2 months (95% CI, 1.9 to 3.6) in D2; the 6-month PFS rate was 29.1% (95% CI, 24.2 to 34.1) and 27.7% (95% CI, 20.5 to 35.4), respectively. The grade 3-4 treatment-related adverse event incidence was 15.0% in D1 and 12.8% in D2. One case of grade 3 myocarditis and no treatment-related deaths occurred across part D. CONCLUSION Nivolumab and relatlimab had a manageable safety profile and demonstrated durable clinical activity in a proportion of patients with heavily pretreated advanced melanoma with prior progression on anti–PD-(L)1-containing regimens. [Media: see text]

Cancer immunotherapy can result in lasting tumor regression, but predictive biomarkers of treatment response remain ill-defined. Here, we performed single-cell proteomics, transcriptomics, and genomics on matched untreated and IL2 injected metastases from patients with melanoma. Lesions that completely regressed following intralesional IL2 harbored increased fractions and densities of nonproliferating CD8+ T cells lacking expression of PD-1, LAG-3, and TIM-3 (PD-1−LAG-3−TIM-3−). Untreated lesions from patients who subsequently responded with complete eradication of all tumor cells in all injected lesions (individuals referred to herein as “extreme responders”) were characterized by proliferating CD8+ T cells with an exhausted phenotype (PD-1+LAG-3+TIM-3+), stromal B-cell aggregates, and expression of IFNγ and IL2 response genes. Loss of membranous MHC class I expression in tumor cells of untreated lesions was associated with resistance to IL2 therapy. We validated this finding in an independent cohort of metastatic melanoma patients treated with intralesional or systemic IL2. Our study suggests that intact tumor-cell antigen presentation is required for melanoma response to IL2 and describes a multidimensional and spatial approach to develop immuno-oncology biomarker hypotheses using routinely collected clinical biospecimens.

Supplementary Data from Systemic Immune Dysfunction in Cancer Patients Driven by IL6 Induction of LAG3 in Peripheral CD8+ T Cells

Supplementary Data from Tumor MHC Class I Expression Associates with Intralesional IL2 Response in Melanoma

Supplementary Table S1. Clinicopathologic characteristics of the cohort separated by death at the 5-year time point. Supplementary Table S2. Primary and secondary antibody information and TSA dye pairings for multiplex IF panel. Supplementary Table S3. Twenty highest ranking variables associating with overall survival by univariate Cox regression analysis. Supplementary Table S4. Density and proximity variables selected by least absolute shrinkage and selection operator (LASSO) methods using a 5-fold cross-validation. Supplementary Figure S1. Image cytometry to quantify immune cell biomarkers in metastatic melanoma. Supplementary Figure S2. The expression of PD-L1 on tumor cells and 'Other' cells is determined by their proximity to CD8+ cells. Supplementary Figure S3. Characterization of immune neighborhoods associated with overall survival. Supplementary Computational Methods. Survival and clinical statistical analysis - R markdown document.

Multiplex immunofluorescence (mIF) can detail spatial relationships and complex cell phenotypes in the tumor microenvironment (TME). However, the analysis and visualization of mIF data can be complex and time-consuming. Here, we used tumor specimens from 93 patients with metastatic melanoma to develop and validate a mIF data analysis pipeline using established flow cytometry workflows (image cytometry). Unlike flow cytometry, spatial information from the TME was conserved at single-cell resolution. A spatial uniform manifold approximation and projection (UMAP) was constructed using the image cytometry output. Spatial UMAP subtraction analysis (survivors vs. nonsurvivors at 5 years) was used to identify topographic and coexpression signatures with positive or negative prognostic impact. Cell densities and proportions identified by image cytometry showed strong correlations when compared with those obtained using gold-standard, digital pathology software (R2 > 0.8). The associated spatial UMAP highlighted “immune neighborhoods” and associated topographic immunoactive protein expression patterns. We found that PD-L1 and PD-1 expression intensity was spatially encoded—the highest PD-L1 expression intensity was observed on CD163+ cells in neighborhoods with high CD8+ cell density, and the highest PD-1 expression intensity was observed on CD8+ cells in neighborhoods with dense arrangements of tumor cells. Spatial UMAP subtraction analysis revealed numerous spatial clusters associated with clinical outcome. The variables represented in the key clusters from the unsupervised UMAP analysis were validated using established, supervised approaches. In conclusion, image cytometry and the spatial UMAPs presented herein are powerful tools for the visualization and interpretation of single-cell, spatially resolved mIF data and associated topographic biomarker development.

Many cancer patients do not develop a durable response to the current standard-of-care immunotherapies, despite substantial advances in targeting immune inhibitory receptors. A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer. Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8+ T-cell dysfunction, characterized by suboptimal T-cell proliferation and chronic expression of IRs (e.g., PD1 and LAG3). Here, we demonstrated that approximately a third of cancer patients analyzed in this study have peripheral CD8+ T cells that expressed robust intracellular LAG3 (LAG3IC), but not surface LAG3 (LAG3SUR) due to a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) cleavage. This is associated with poor disease prognosis and decreased CD8+ T-cell function, which could be partially reversed by anti-LAG3. Systemic immune dysfunction was restricted to CD8+ T cells, including, in some cases, a high percentage of peripheral naïve CD8+ T cells, and was driven by the cytokine IL6 via STAT3. These data suggest that additional studies are warranted to determine if the combination of increased LAG3IC in peripheral CD8+ T cells and elevated systemic IL6 can serve as predictive biomarkers and identify which cancer patients may benefit from LAG3 blockade.

Figure S6. Differential abundance analysis of antibiotic resistance genes and virulence factors between R and NR for WGS datasets.

Figure S6 shows phylogenies based on point mutations with UV signature mutations removed.

140 Illumina probes corresponding to138 unique genes differentially expressed in regressing (R) vs. progressing (P) cutaneous metastases based on whole genome microarray analysis (fold change magnitude {greater than or equal to}1.7, p value {less than or equal to}0.05 )

Purpose: PD-L1 expression in the pretreatment tumor microenvironment enriches for response to anti-PD-1/PD-L1 therapies. The purpose of this study was to quantitatively compare the performance of five monoclonal anti-PD-L1 antibodies used in recent landmark publications.Experimental Design: PD-L1 IHC was performed on 34 formalin-fixed paraffin-embedded archival melanoma samples using the 5H1, SP142, 28-8, 22C3, and SP263 clones. The percentage of total cells (including melanocytes and immune cells) demonstrating cell surface PD-L1 staining, as well as intensity measurements/H-scores, were assessed for each melanoma specimen using a computer-assisted platform. Staining properties were compared between antibodies.Results: Strong correlations were observed between the percentage of PD-L1(+) cells across all clones studied (R2 = 0.81–0.96). When present, discordant results were attributable to geographic heterogeneity of the melanoma tissue section rather than differences in PD-L1 antibody staining characteristics. PD-L1 intensity/H-scores strongly correlated with percentage of PD-L1(+) cells (R2 > 0.78, all clones).Conclusions: The 5H1, SP142, 28-8, 22C3, and SP263 clones all demonstrated similar performance characteristics when used in a standardized IHC assay on melanoma specimens. Reported differences in PD-L1 IHC assays using these antibodies are thus most likely due to assay characteristics beyond the antibody itself. Our findings also argue against the inclusion of an intensity/H-score in chromogenic PD-L1 IHC assays. Clin Cancer Res; 23(16); 4938–44. ©2017 AACR.

Supplemental Figures S1 Figure S2, Figure S3 and Table S1 and Table S2

Supplemental figure and table legends

Supplementary Tables S1-S8 show the samples used for study (Table S1), the somatic single nucleotide variants, small insertions and small deletions (Table S2), the somatic copy number alterations anallyzed (Table S3), the gene list used to analyze somatic mutations (Table S4), putative driver genes, immunotherapy related genes, and mutation-targeted therapy genes affected by mutations in each case (Table S5), mutation signatures detected with a cosine score {greater than or equal to}0.80 (Table S6), Jaccard similarity coefficients (Table S7), and putative neoantigens in each case (Table S8).

Purpose: To explore factors associated with response and resistance to anti–PD-1 therapy, we analyzed multiple disease sites at autopsy in a patient with widely metastatic melanoma who had a heterogeneous response.Materials and Methods: Twenty-six melanoma specimens (four premortem, 22 postmortem) were subjected to whole exome sequencing. Candidate immunologic markers and gene expression were assessed in 10 cutaneous metastases showing response or progression during therapy.Results: The melanoma was driven by biallelic inactivation of NF1. All lesions had highly concordant mutational profiles and copy number alterations, indicating linear clonal evolution. Expression of candidate immunologic markers was similar in responding and progressing lesions. However, progressing cutaneous metastases were associated with overexpression of genes associated with extracellular matrix and neutrophil function.Conclusions: Although mutational and immunologic differences have been proposed as the primary determinants of heterogeneous response/resistance to targeted therapies and immunotherapies, respectively, differential lesional gene expression profiles may also dictate anti–PD-1 outcomes. Clin Cancer Res; 23(12); 3168–80. ©2017 AACR.See related commentary by Wilmott et al., p. 2921

Supplemental Appendix (Figures S1 and S2, Table S1)

Table S1

Purpose:Pathologic response assessment of tumor specimens from patients receiving systemic treatment provides an early indication of therapeutic efficacy and predicts long-term survival. Grading systems for pathologic response were first developed for chemotherapy in select tumor types. Immunotherapeutic agents have a mechanism of action distinct from chemotherapy and are being used across a broad array of tumor types. A standardized, universal scoring system for pathologic response that encompasses features characteristic for immunotherapy and spans tumor types is needed.Experimental Design:Hematoxylin and eosin–stained slides from neoadjuvant surgical resections and on-treatment biopsies were assessed for features of immune-related pathologic response (irPR). A total of 258 specimens from patients with 11 tumor types as part of ongoing clinical trials for anti-PD-(L)1 were evaluated. An additional 98 specimens from patients receiving anti-PD-(L)1 in combination with other treatments were also reviewed, including those from three additional tumor types.Results:Common irPR features (immune activation, cell death, tissue repair, and regression bed) were present in all tumor types reviewed, including melanoma, non–small cell lung, head and neck squamous cell, Merkel cell, and renal cell carcinoma, among others. Features were consistent across primary tumors, lymph nodes, and distant metastases. Specimens from patients treated with anti-PD-(L)1 in combination with another agent also exhibited irPR features.Conclusions:irPR features are consistent across tumor types and treatment settings. Standardized, pan-tumor irPR criteria (irPRC) are defined and associated specimen-handling considerations are described. Future, prospective studies are merited to validate irPRC in larger datasets and to associate pathologic features with long-term patient outcomes.

Supplementary methods

Purpose:While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%–30% of treated patients respond and the ability to predict clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations.Experimental Design:We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (n = 303 unique patients) using a uniform computational approach.Results:Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NR-associated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (P < 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers (n = 105).Conclusions:Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.

Purpose:Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes.Experimental Design:Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression.Results:For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance.Conclusions:In 4 patients who received immunotherapy, we found 1–3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective.

Many cancer patients do not develop a durable response to the current standard-of-care immunotherapies, despite substantial advances in targeting immune inhibitory receptors. A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer. Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8+ T-cell dysfunction, characterized by suboptimal T-cell proliferation and chronic expression of IRs (e.g., PD1 and LAG3). Here, we demonstrated that approximately a third of cancer patients analyzed in this study have peripheral CD8+ T cells that expressed robust intracellular LAG3 (LAG3IC), but not surface LAG3 (LAG3SUR) due to a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) cleavage. This is associated with poor disease prognosis and decreased CD8+ T-cell function, which could be partially reversed by anti-LAG3. Systemic immune dysfunction was restricted to CD8+ T cells, including, in some cases, a high percentage of peripheral naïve CD8+ T cells, and was driven by the cytokine IL6 via STAT3. These data suggest that additional studies are warranted to determine if the combination of increased LAG3IC in peripheral CD8+ T cells and elevated systemic IL6 can serve as predictive biomarkers and identify which cancer patients may benefit from LAG3 blockade.

Cancer immunotherapy can result in lasting tumor regression, but predictive biomarkers of treatment response remain ill-defined. Here, we performed single-cell proteomics, transcriptomics, and genomics on matched untreated and IL2 injected metastases from patients with melanoma. Lesions that completely regressed following intralesional IL2 harbored increased fractions and densities of nonproliferating CD8+ T cells lacking expression of PD-1, LAG-3, and TIM-3 (PD-1−LAG-3−TIM-3−). Untreated lesions from patients who subsequently responded with complete eradication of all tumor cells in all injected lesions (individuals referred to herein as “extreme responders”) were characterized by proliferating CD8+ T cells with an exhausted phenotype (PD-1+LAG-3+TIM-3+), stromal B-cell aggregates, and expression of IFNγ and IL2 response genes. Loss of membranous MHC class I expression in tumor cells of untreated lesions was associated with resistance to IL2 therapy. We validated this finding in an independent cohort of metastatic melanoma patients treated with intralesional or systemic IL2. Our study suggests that intact tumor-cell antigen presentation is required for melanoma response to IL2 and describes a multidimensional and spatial approach to develop immuno-oncology biomarker hypotheses using routinely collected clinical biospecimens.

As the administration of COVID-19 vaccines continues to increase, so too does awareness of the associated ipsilateral axillary lymphadenopathy. This has created a diagnostic challenge in the field of radiology, in particular among patients with cancer, as post-vaccination reactive adenopathy has been reported to be mistakenly interpreted as malignancy. As radiology departments improve their protocols for obtaining vaccine-related patient history, and radiologists become acclimated to attributing axillary lymphadenopathy to recent COVID-19 vaccination, there is a risk of the pendulum swinging too far and under-diagnosing true oncologic disease. This report describes an otherwise healthy 53-year-old man who presented with discomfort due to ipsilateral axillary lymphadenopathy shortly after receiving a COVID-19 vaccine. Fine needle aspiration performed within 2 months of receiving the vaccine revealed metastatic melanoma and subsequent 18F-FDG PET/CT demonstrated intensely avid axillary and supraclavicular adenopathy without visualization of a primary lesion. This case serves as a cautionary report to remind clinicians to remain suspicious of possible underlying malignancy with the presence of axillary adenopathy, despite a history of recent COVID-19 vaccination.

Purpose: While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%–30% of treated patients respond and the ability to predict clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations. Experimental Design: We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (n = 303 unique patients) using a uniform computational approach. Results: Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NR-associated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (P < 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers (n = 105). Conclusions: Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.

Metastatic melanoma may be included in the differential diagnosis of hyoid masses in patients with a history of melanoma. Hyoid resection is well tolerated and of diagnostic and therapeutic benefit in patients with tumors metastatic to the hyoid bone., Metastatic melanoma may be included in the differential diagnosis of hyoid massess in patients with a history of melanoma. Hyoid resection is well tolerated and of diagnostic and therapeutic benefit in patients with tumors metastatic to the hyoid bone.

Nonmelanoma skin cancers (NMSCs) are some of the most commonly diagnosed malignancies. In general, early-stage NMSCs have favorable outcomes; however, a small subset of patients develop resistant, advanced, or metastatic disease, or aggressive subtypes that are more challenging to treat successfully. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC). Although ICIs have demonstrated activity against NMSCs, the routine clinical use of these agents may be more challenging due to a number of factors including the lack of predictive biomarkers, the need to consider special patient populations, the management of toxicity, and the assessment of atypical responses. With the goal of improving patient care by providing expert guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their own clinical experience to develop recommendations for healthcare professionals on important aspects of immunotherapeutic treatment for NMSCs, including staging, biomarker testing, patient selection, therapy selection, post-treatment response evaluation and surveillance, and patient quality of life (QOL) considerations, among others. The evidence- and consensus-based recommendations in this CPG are intended to provide guidance to cancer care professionals treating patients with NMSCs.

In this report, we describe the first kidney retransplantation performed after anti-programmed cell death-1 (PD-1)-related allograft rejection. In 2014, we administered pembrolizumab (anti-PD-1) for ~9 months to a 57-year-old kidney transplant recipient with metastatic cutaneous squamous cell carcinoma (CSCC). The patient experienced both a complete anti-tumor response and T cell-mediated allograft rejection requiring reinitiation of hemodialysis. Four-and-a-half years after initiating pembrolizumab, the patient remained without evidence of CSCC relapse and received a kidney transplant from a living unrelated donor. Ten-and-a-half months after kidney retransplantation, the allograft is functioning well and the patient’s CSCC remains in remission. This case illustrates the potential for PD-1 blockade to bring about durable immune-mediated tumor control in chronically-immunosuppressed patients, and begins to address the feasibility of kidney retransplantation in patients who have previously received immune checkpoint inhibitor therapy for cancer. Results from this and future cases may help elucidate mechanisms of anti-tumor immunity and allograft tolerance, and inform updates to transplant decision models. Our report also underscores the need for clinical trials testing novel immunotherapy combinations in solid organ transplant recipients designed to uncouple anti-tumor and anti-allograft immunity.

Robust CD8+ T cell memory is essential for long-term protective immunity but is often compromised in cancer, where T cell exhaustion leads to loss of memory precursors. Immunotherapy via checkpoint blockade may not effectively reverse this defect, potentially underlying disease relapse. Here we report that mice with a CD8+ T cell–restricted neuropilin-1 (NRP1) deletion exhibited substantially enhanced protection from tumor rechallenge and sensitivity to anti-PD1 immunotherapy, despite unchanged primary tumor growth. Mechanistically, NRP1 cell-intrinsically limited the self-renewal of the CD44+PD1+TCF1+TIM3− progenitor exhausted T cells, which was associated with their reduced ability to induce c-Jun/AP-1 expression on T cell receptor restimulation, a mechanism that may contribute to terminal T cell exhaustion at the cost of memory differentiation in wild-type tumor-bearing hosts. These data indicate that blockade of NRP1, a unique ‘immune memory checkpoint’, may promote the development of long-lived tumor-specific Tmem that are essential for durable antitumor immunity. T cell exhaustion limits antitumor immune responses. Vignali and colleagues identify neuropilin-1 as a novel immune checkpoint that cell-intrinsically operates to limit memory cell formation and can be targeted to enhance antitumor responses.

Purpose: Pathologic response assessment of tumor specimens from patients receiving systemic treatment provides an early indication of therapeutic efficacy and predicts long-term survival. Grading systems for pathologic response were first developed for chemotherapy in select tumor types. Immunotherapeutic agents have a mechanism of action distinct from chemotherapy and are being used across a broad array of tumor types. A standardized, universal scoring system for pathologic response that encompasses features characteristic for immunotherapy and spans tumor types is needed. Experimental Design: Hematoxylin and eosin–stained slides from neoadjuvant surgical resections and on-treatment biopsies were assessed for features of immune-related pathologic response (irPR). A total of 258 specimens from patients with 11 tumor types as part of ongoing clinical trials for anti-PD-(L)1 were evaluated. An additional 98 specimens from patients receiving anti-PD-(L)1 in combination with other treatments were also reviewed, including those from three additional tumor types. Results: Common irPR features (immune activation, cell death, tissue repair, and regression bed) were present in all tumor types reviewed, including melanoma, non–small cell lung, head and neck squamous cell, Merkel cell, and renal cell carcinoma, among others. Features were consistent across primary tumors, lymph nodes, and distant metastases. Specimens from patients treated with anti-PD-(L)1 in combination with another agent also exhibited irPR features. Conclusions: irPR features are consistent across tumor types and treatment settings. Standardized, pan-tumor irPR criteria (irPRC) are defined and associated specimen-handling considerations are described. Future, prospective studies are merited to validate irPRC in larger datasets and to associate pathologic features with long-term patient outcomes.

BACKGROUND: Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation. METHODS: In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group. CONCLUSIONS: The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.).

ObjectivePatients with inflammatory arthritis (IA) associated with immune checkpoint inhibitor (ICI) treatment for cancer are typically seronegative for anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor, but little is known about the presence of other autoantibodies in this patient population. We investigated the prevalence and characteristics of anti-RA33 antibodies in patients with ICI-induced IA.MethodsAnti-RA33 ELISAs were performed on sera from four groups of patients: 79 with ICI-induced IA, 52 with rheumatoid arthritis (RA), 35 treated with ICIs without IA during follow-up and 50 healthy controls. Anti-RA33 positivity and level, clinical and demographic data were compared across groups.ResultsAnti-RA33 antibodies were found in 9/79 (11.4%) patients with ICI-induced IA but in 0/35 patients treated with ICIs who did not develop IA (0%; p=0.04). Of the patients positive for anti-RA33, two had sera available from before ICI treatment; anti-RA33 antibodies were present in both pre-ICI treatments. In patients with RA, 7.7% were positive for anti-RA33 antibodies as were 2% of healthy controls. In ICI-induced IA, anti-RA33 antibodies were associated with anti-CCP antibodies (p=0.001). We found no statistically significant differences in other clinical characteristics in those with and without anti-RA33 antibodies.ConclusionsAnti-RA33 antibodies are present in a subset of patients with ICI-induced IA, absent in other ICI-treated patients and may be a biomarker for developing IA. Additional studies evaluating serial samples before and after ICI treatment will further establish the temporal relationship of these antibodies to IA development.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.