Nivolumab For Metastatic Melanoma Research Articles

Cytomegalovirus gastritis as a rare adverse event during combined ipilimumab and nivolumab in a patient with melanoma.

Immunotherapy has improvedsurvival outcomes of patients with advanced melanoma. Lower gastrointestinal tract immune-related adverse events (irAEs) are common during treatment; however, gastritis is not frequently observed. Herein, we report a case of severe cytomegalovirus (CMV)-related gastritis in a patient treated with ipilimumab and nivolumab for metastatic melanoma. This report presents a 60-year-old woman with stage IV BRAF wild-type melanoma. t. After the second course of ipilimumab-nivolumab, the patient reported epigastric discomfort after meals, anorexia, and subsequent nausea, vomiting, epigastric pain, and weight loss. Disease staging with PET/CT scan showed very good partial response and diffuse gastroduodenitis. The patient underwent esophagogastroduodenoscopy, showing severe esophageal candidiasis and diffuse hemorrhagic, edematous, and ulcerative mucosa in the whole gastric wall. Biopsies of the gastric wall were obtained. Before receipt of the final pathology report, the patient was empirically started on corticosteroids based on the clinical suspicion of immune-related gastritis, without improvement of symptoms. The hematoxylin-eosin staining demonstrated active gastritis with diffuse nuclear cytopathic viral inclusions in epithelial and interstitial cells; CMV infection was confirmed with immunohistochemical staining. The patient startedganciclovir and fluconazole, with rapid improvement of symptoms. This case presents a rare instance of CMV gastritis in a patient receiving combined anti-PD1 and anti-CTLA4 , in the absence of immune-suppression to manage an irAE. In the case of suggestive symptoms of irAEs, a high index of clinical suspicion is required to rule out concomitant or isolated infective disease. Guidelines for prophylaxis and treatment of these patients are needed, to optimize treatment results.

COMBINATORIAL IMMUNE CHECKPOINT BLOCKADE INCREASES MYOCARDIAL SECRETION OF H–FABP, NT–PRO–BNP, NLRP–3 INFLAMMASOME, INTERLEUKIN–1Β AND INTERLEUKIN–6: BIOCHEMICAL IMPLICATIONS IN CARDIO–IMMUNO–ONCOLOGY

Abstract Background Immune checkpoint blockade have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA–4 or PD–1 or PDL–1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti–LAG3 monoclonal antibody, Relatlimab, has been approved by FDA for combinatorial treatment with Nivolumab for metastatic melanoma. Moreover, anti PD–L1 blocking agent Atezolizumab is actually under study in association with Ipilimumab as innovative thearpy for metastatic lung cancer. Myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies and the use of new targets in immunotherapy could expose patients to more adverse cardiovascular events. Purpose In this study, we highlighted the cardiotoxic properties of new Combinatorial immune checkpoint blockade therapies. Methods Human cardiomyocytes co–cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD–L1 and CTLA–4 or PD–1 and LAG–3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H–FABP, NT–Pro–BNP), NLRP3–inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Results Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co–cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD–L1/CTLA–4 blocking agents, and 35.7% higher in PD–1/LAG–3 blocking agents compared to monotherapies. NT–Pro–BNP and H–FABP, were also strongly increased in combination therapy with respect to monotherapies. NLRP3, IL–6 and IL–1β levels were also increased by PDL–1/CTLA–4 and PD–1/LAG–3 combined blocking agents compared to untreated cells and monotherapies. Conclusion Data of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro– inflammatory phenotype, thus indicating that these therapies should be closely monitored by the multidisciplinary team consisting of oncologists, cardiologists and immunologists.

Immunotherapy associated Sweet syndrome in a patient with metastatic melanoma: A case report

AbstractImmunotherapy agents are now widely used in the treatment of metastatic melanoma. Immune‐related adverse events (irAEs) may occur, including cutaneous pathologies in 50% of patients. We report a case of Sweet syndrome (SS) in a patient who was prescribed ipilimumab and nivolumab for metastatic melanoma.

Abstract 15049: Combinatorial Immune Checkpoint Blockade Increases Myocardial Secretion of H-FABP, NT-Pro-BNP, NLRP-3 Inflammasome, Interleukin-1β and Interleukin-6: Biochemical Implications in Cardio-Immuno-Oncology

Background: Immune checkpoint blockade alone or in combination with chemotherapy or radiotherapy or other immune checkpoint blocking agents have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) human monoclonal antibody, Relatlimab, has been approved by FDA for combinatorial treatment with Nivolumab for metastatic melanoma. Moreover, anti PD-L1blocking agent Atezolizumab is actually under study in association with Ipilimumab as innovative thearpy for metastatic lung cancer. Cases of cardiotoxicity such as myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies and the use of new targets in immunotherapy could expose patients to more adverse cardiovascular events. Methods: human cardiomyocytes co-cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Results: Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. Biomarkers of cardiotoxicity, such as NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy with respect to monotherapies. NLRP3 inflammasome, IL-6 and IL-1β levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies. Conclusions: Data of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype.

Bilateral Hypotony Maculopathy Associated With Ipilimumab and Nivolumab Therapy Unresponsive to Corticosteroid Treatment

In rare instances, immunotherapy associated with hypotony and uveitis has been documented. We report the case of a 72-year-old man treated with 2 months of ipilimumab and nivolumab for metastatic melanoma who developed bilateral hypotony maculopathy and serous choroidal detachments without prominent initial uveitis. Despite treatment with topical, periocular, and intraocular corticosteroid injection, hypotony persisted 18 months after immunotherapy cessation. The patient's unresponsiveness to corticosteroids indicates the need to further explore the mechanism behind immune checkpoint inhibitor-associated hypotony. We hypothesize that immunotherapy significantly decreased aqueous humor production through ciliary body inflammation, disruption, or shutdown. [Ophthalmic Surg Lasers Imaging Retina 2023;54:301-304.].

Dabrafenib plus trametinib versus nivolumab for advanced melanoma

Introduction The incidence of cutaneous melanoma has increased worldwide over the years, and an incidence of 3 cases per 100,000 men and women is estimated in Chile. Though most of the patients are diagnosed at an early stage of the disease and have a good prognosis, advanced melanoma has poor survival results. For the treatment of melanoma, the combination of dabrafenib plus trametinib has been demonstrated to improve the outcome versus dabrafenib alone, but only indirect evidence is available for its efficacy and safety compared with immunotherapy, like nivolumab. The aim of this study is to review the available evidence to report results of efficacy and safety of dabrafenib plus trametinib in comparison with nivolumab in metastatic melanoma. Methods We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews selected, reanalyzed data of primary studies, and generated a summary of the findings table using the GRADE approach. Results and conclusions We identified five systematic reviews, including seven studies overall that included one intervention of our interest, of which all were randomized trials. We only found indirect evidence comparing dabrafenib plus trametinib versus nivolumab that came from Network Meta-Analyses. We concluded that it is not possible to decide if dabrafenib plus trametinib is a better strategy for advanced melanoma treatment than nivolumab because the certainty of the evidence is very low for efficacy and safety outcomes.

Robust group sequential designs for trials with survival endpoints and delayed response.

Randomized clinical trials in oncology typically utilize time-to-event endpoints such as progression-free survival or overall survival as their primary efficacy endpoints, and the most commonly used statistical test to analyze these endpoints is the log-rank test. The power of the log-rank test depends on the behavior of the hazard ratio of the treatment arm to the control arm. Under the assumption of proportional hazards, the log-rank test is asymptotically fully efficient. However, this proportionality assumption does not hold true if there is a delayed treatment effect. Cancer immunology has evolved over time and several cancer vaccines are available in the market for treating existing cancers. This includes sipuleucel-T for metastatic hormone-refractory prostate cancer, nivolumab for metastatic melanoma, and pembrolizumab for advanced nonsmall-cell lung cancer. As cancer vaccines require some time to elicit an immune response, a delayed treatment effect is observed, resulting in a violation of the proportional hazards assumption. Thus, the traditional log-rank test may not be optimal for testing immuno-oncology drugs in randomized clinical trials. Moreover, the new immuno-oncology compounds have been shown to be very effective in prolonging overall survival. Therefore, it is desirable to implement a group sequential design with the possibility of early stopping for overwhelming efficacy. In this paper, we investigate the max-combo test, which utilizes the maximum of two weighted log-rank statistics, as a robust alternative to the log-rank test. The new test is implemented for two-stage designs with possible early stopping at the interim analysis time point. Two classes of weights are investigated for the max-combo test: theFleming and Harrington (1981) weights and theMagirr and Burman (2019) modest weights.

Immune Checkpoint Inhibitor Induced Pericarditis and Encephalitis in a Patient Treated With Ipilimumab and Nivolumab for Metastatic Melanoma: A Case Report and Review of the Literature

Immune checkpoint inhibitors (ICIs) have dramatically improved outcomes in melanoma. Common ICI toxicities have become familiar to clinicians; however, rare delayed toxicities remain challenging given the paucity of data with such presentations. We present the unique case of a 61-year-old with metastatic melanoma with two rare, delayed ICI-induced toxicities. After resection of a large symptomatic parietal metastases, this patient received two doses of combination ipilimumab and nivolumab. Five weeks following his second dose, he developed ICI-induced pericarditis with associated pericardial effusion and early signs of tamponade. Corticosteroids were not administered due to a concurrent cerebral abscess. Administration of colchicine, ibuprofen, judicious monitoring, and cessation of immunotherapy led to the complete resolution of the effusion over several weeks. Seven months following his last dose of immunotherapy, the patient developed ICI-associated grade four autoimmune encephalitis, presenting as status epilepticus. High-dose steroid initiation led to rapid clinical improvement. The patient remains in near-complete response on imaging with no recurrence of pericardial effusion and partial resolution of neurological symptoms. ICI-induced pericardial disease and encephalitis carry substantial mortality rates and prompt diagnosis and management is critical. Clinicians must therefore remain vigilant for these rare toxicities regardless of duration of drug exposure or time since cessation of therapy.

A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma

Anti-programmed death (PD)-1 (aPD1) therapy is an effective treatment for metastatic melanoma (MM); however, over 50% of patients progress due to resistance. We tested a first-in-class immune-modulatory vaccine (IO102/IO103) against indoleamine 2,3-dioxygenase (IDO) and PD ligand 1 (PD-L1), targeting immunosuppressive cells and tumor cells expressing IDO and/or PD-L1 (IDO/PD-L1), combined with nivolumab. Thirty aPD1 therapy-naive patients with MM were treated in a phase 1/2 study (https://clinicaltrials.gov/, NCT03047928). The primary endpoint was feasibility and safety; the systemic toxicity profile was comparable to that of nivolumab monotherapy. Secondary endpoints were efficacy and immunogenicity; an objective response rate (ORR) of 80% (confidence interval (CI), 62.7–90.5%) was reached, with 43% (CI, 27.4–60.8%) complete responses. After a median follow-up of 22.9 months, the median progression-free survival (PFS) was 26 months (CI, 15.4–69 months). Median overall survival (OS) was not reached. Vaccine-specific responses assessed in vitro were detected in the blood of >93% of patients during vaccination. Vaccine-reactive T cells comprised CD4+ and CD8+ T cells with activity against IDO- and PD-L1-expressing cancer and immune cells. T cell influx of peripherally expanded T cells into tumor sites was observed in responding patients, and general enrichment of IDO- and PD-L1-specific clones after treatment was documented. These clinical efficacy and favorable safety data support further validation in a larger randomized trial to confirm the clinical potential of this immunomodulating approach.

Autoimmune hemolytic anemia during long‐term administration of nivolumab for metastatic melanoma

Autoimmune hemolytic anemia during long‐term administration of nivolumab for metastatic melanoma

Cost-effectiveness of nivolumab in advanced melanoma: a drug review

ABSTRACT Introduction: The immune checkpoint inhibitors, including nivolumab, and targeted agents have dramatically improved the outcome for patients with unresectable advanced melanoma. Areas covered: This is a narrative review of the published evidence on nivolumab in metastatic melanoma. Expert opinion: In ipilimumab pre-treated patients (CheckMate 037), nivolumab was associated with a higher response rate and a longer duration of response when compared to chemotherapy. In previously untreated patients, nivolumab improves survival when compared to chemotherapy (CheckMate 066) or to ipilimumab (CheckMate 067). The combination of nivolumab and ipilimumab also improves survival when compared to ipilimumab (CheckMate 067). CheckMate 067 was not designed to compare the nivolumab–ipilimumab combination to nivolumab alone. A modified regimen using a lower dose of ipilimumab in combination with standard dose nivolumab is better tolerated than nivolumab in combination with standard dose ipilimumab (CheckMate 511). In patients with previously untreated metastatic melanoma, the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab improve survival when compared to ipilimumab. Nivolumab is equally active in BRAF mutated and BRAF wild type melanoma. The optimal sequence of checkpoint inhibitors and BRAF/MEK inhibitors in BRAF mutated patients has not been established.

PCN265 Assessment of Different Methods for the Extrapolation of Survival Statistics for Nivolumab in Metastatic Melanoma: Implications for Cost-Effectiveness in HTA

Extrapolation of immature overall survival (OS) or progression-free survival (PFS) trial data using standard parametric (SP) models based on prior distributions (e.g. Exponential, Weibull, Gompertz) is commonly used for economic modelling in HTA. Due to complex hazard functions, SP models may produce a poor fit for OS and PFS for immuno-oncology (I-O) treatments. This project aims to compare SP models with cubic spline (CS) methods, to assess the impact of extrapolation methods on estimated cost-effectiveness of nivolumab compared to dacarbazine in metastatic melanoma. OS and PFS data were extracted from digitised Kaplan-Meier curves reported in the CheckMate 066 trial. SP and CS models were fitted to two data cut-offs at 16 and 52 months to assess the effect of different follow-up periods on model choice. Incremental cost-effectiveness ratios (ICERs) per QALY gained were estimated using a partitioned survival model with a lifetime horizon. ICERs for nivolumab vs. dacarbazine were similar for SP and CS models fitted to the 16-month data cut-off (£23,244, £24,026). Based on the 52-month cut-off, nivolumab was more cost-effective based on SP fit compared to CS (£22,269 vs. £34,850). CS models were a better fit to the KM data based on visual inspection. The choice of distribution for SP model of nivolumab 16-month OS presented a wide range of ICER estimates (£13,753-52,466). The Gompertz SP model often presented the lowest AIC, but also resulted in a significantly different predicted survival (and thus lower ICER) compared to other distributions. The choice of statistical fit in SP models had a large impact on lifetime ICER with short-term trial data. Both models provided a good fit for the plateau in OS using the long data cut-off. CS models provide a robust fit and less uncertainty for HTA in the absence of long-term survival endpoints for I-O treatments.

SUN-127 Diagnostic Challenges Associated with the Rising Incidence of Endocrine Toxicity in the Era of Combination Immunotherapy

Background: Immune checkpoint blockade is now established as standard of care in several malignancies. Trials involving combined cytotoxic T lymphocyte associated protein 4 (CTLA4) and programmed cell death protein 1 (PD1) blockade demonstrate improved tumour responses in melanoma but at the cost of severe grade 3-4 immune related adverse events (irAEs) in 55%, and endocrine irAEs in up to 10% [1]. Immune-mediated damage to endocrine glands can be a diagnostic and management challenge. We aimed to review the incidence, biochemical evolution and imaging findings of endocrine toxicity related to combined anti CTLA-4 and anti-PD-1 therapy. Methods: We undertook a retrospective chart review of patients who received combined ipilimumab and nivolumab for metastatic melanoma at a tertiary referral centre between 2016-2019. We recorded onset and duration of abnormal biochemistry in endocrine irAEs, reviewed all available MRI images for pituitary size (mm) and appearance and 18-F FDG PET images for features of hypophysitis, thyroiditis and pancreatitis. Results: 162 patients received combination therapy. At least one irAE was recorded in 135 patients (83%), 100 (62%) required glucocorticoids, and 84 (52%) had an unplanned hospital presentation due to irAEs. Thyroiditis occurred in 50 (30.9%), with median time to onset of 30.9 days (range 1-234 days). 35 cases were identified with routine biochemistry performed every 4-6 weeks. TSH receptor antibody was measured in 13 patients and all were negative. 29 (58%) developed permanent hypothyroidism. Central cortisol deficiency was documented in 31 (19%) with a median time to diagnosis of 67.5 days (range 5-286). 4 cases were diagnosed on routine biochemistry and 14 presented with symptoms prompting investigation. 13 were diagnosed after routine neuroimaging demonstrated a pituitary abnormality, and a further 27 patients without the clinical syndrome had features of hypophysitis on neuroimaging. New onset diabetes occurred in 3 people, in which pancreatic inflammation on imaging was found in 2. A further 3/5 patients with an asymptomatic elevated lipase were found to have abnormal pancreatic imaging. In one patient with no features of endocrine or exocrine failure, there was a significant increase in FDG uptake and a subsequent loss of pancreatic volume. Conclusion: We report real world incidence of endocrine irAEs with combination immunotherapy. Routine biochemistry leads to the detection of some but not all cases. Early recognition and avoidance of unplanned presentations remains a challenge. Opportunistic assessment of endocrine gland appearance on routine imaging studies may provide useful early diagnostic information. Reference: Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. (2015) 1:23-34. 10.1056/NEJMoa1504030

Nivolumab in Metastatic Melanoma: Good Efficacy and Tolerability in Elderly Patients

Nivolumab is an anti-PD-1 antibody that restores the antitumour immune function of T cells, blocking the binding of PD-1 with its ligand PD-L1. PD-1 is expressed on T cells and interacts with PD-L1 on tumour cells. The PD-1-PD-L1 link inhibits T cell activation. In metastatic melanoma, PD-1-PD-L1 binding plays a critical role, and the advent of the immune checkpoint inhibitor nivolumab has delivered new and effective treatment options with proven clinical benefit. In the present study, we evaluated the efficacy of nivolumab in elderly patients with metastatic melanoma. The study enrolled 55 elderly patients (75 years of age and older) with a diagnosis of metastatic melanoma. Primary endpoints of the study were progression-free survival (pfs) and the objective response rate; secondary endpoints were overall survival, reduction in serum lactate dehydrogenase (ldh) from before to after treatment, and tolerability. Nivolumab was well tolerated and resulted in good disease control, with a manageable toxicity profile and significant clinical benefit. The duration of pfs was 5.1 months (95% confidence interval: 3.5 months to 6.8 months). A significant correlation was observed between reduction in serum ldh and pfs: 0.60 (95% confidence interval: 0.28 to 0.86; p = 0.002). Nivolumab is an immunotherapy treatment that has proved to be an effective and well-tolerated therapeutic option in elderly patients with metastatic melanoma.

Autoimmune myositis and myasthenia gravis resulting from a combination therapy with nivolumab and ipilimumab for metastatic melanoma.

Checkpoint inhibitors are a novel option in the management of metastatic melanomas and many other malignancies. They are used to promote the activation of cytotoxic T-lymphocytes by inhibiting deactivation signals, enabling the immune response to the tumor. Numerous Immune-related adverse effects caused by checkpoint inhibitors have been reported in the literature. They are diverse in nature, and many are life threatening. We report a case of autoimmune myositis and myasthenia gravis following treatment with a combination of ipilimumab and nivolumab for metastatic melanoma.

Efficacy and safety of nivolumab in metastatic melanoma: real-world practice

Anti-PD1 antibodies have revolutionized the management of patients with advanced melanoma. In clinical trials, the efficacy of nivolumab is being tested in selected populations of patients. The aim of this study was to analyse the efficacy and safety of nivolumab in patients with advanced melanoma under real-life conditions. A retrospective, observational study was conducted in patients treated with nivolumab for advanced melanoma included in the RIC-Mel network. Overall survival and progression-free survival (PFS) were assessed using the Kaplan-Meier method. Eighty-seven patients were included with a median follow-up of 31 months. The median PFS was 13 months (95%CI: 7-28). Objective response rate was 33.3%. Among patients achieving a complete response, the response was maintained after treatment discontinuation in 80.7% of patients for a median duration of 21.7 months. Multivariate analysis showed that an increased lactate dehydrogenase level (p = 0.03; HR: 1.21; 95%CI: 1.02-1.45) and brain metastases (p = 0.024; HR: 2.78; 95%CI: 1.14-6.77) were correlated with a decrease in PFS. Grade 3 or 4 adverse events were found in 10.3% of patients. Based on our study, the efficacy and safety of nivolumab in patients with advanced melanoma are consistent with previously published data.

Development of Bell's Palsy After Treatment With Ipilimumab and Nivolumab for Metastatic Melanoma: A Case Report.

Ipilimumab is a human monoclonal antibody that targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and it is FDA approved for the treatment of unresectable or metastatic melanoma. Immune-related adverse events (irAEs) of gastrointestinal, dermatologic, and endocrine origin are commonly seen, ranging between 18% and 44%, with immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1). Rare irAEs include neurological, renal, and hematologic toxicities. Bell's palsy is a form of neurological toxicity that presents as an idiopathic paralysis of the muscles on one side of the face. We report a case of Bell's palsy in a 45-year-old male patient who received 1 dose of both ipilimumab and nivolumab for the treatment of metastatic melanoma. After the resolution of symptoms, ipilimumab was permanently discontinued and single-agent nivolumab administered. The patient has remained free of neurological symptoms. This case suggests that Bell's palsy is an irAE induced by ipilimumab.

Nivolumab-Induced Rapid Tumor Remission of Pulmonary Adenocarcinoma

We The immune checkpoint modulator, nivolumab (BMS-936558/ONO-4538), is the first PD-1 inhibitor to gain regulatory approval, for the treatment of patients with unresectable melanoma. Nivolumab received FDA approval for the treatment of melanoma in December 2014. On 24 April 2015, the Committee for Medical Products for Human Use of the European Medicine Agency recommended approval of Nivolumab for metastatic melanoma as a monotherapy. In March 2015, the US FDA approved it for the treatment of squamous non-small cell lung cancer. This case reports about a patient with metastatical pulmonary adenocarcinoma who benefited from the therapy with nivolumab. Already after 10 weeks of treatment with nivolumab, we registered rapid tumor remission.

Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma

ABSTRACTImmune checkpoint inhibitors blocking the interaction between programmed death-1 (PD-1) and PD-1 ligand-1 (PD-L1) are revolutionizing the cancer immunotherapies with durable clinical responses. Although high expression of PD-L1 in tumor tissues has been implicated to correlate with the better response to the anti-PD-1 therapies, this association has been controversial. In this study, to characterize immune microenvironment in tumors, we examined mRNA levels of immune-related genes and characterized T cell repertoire in the tumors of 13 melanoma patients before and after nivolumab treatment. We found that, in addition to the PD-L1 (p = 0.03), expression levels of PD-1 ligand-2 (PD-L2), granzyme A (GZMA) and human leukocyte antigen-A (HLA-A) in the pre-treatment tumors were significantly higher (p = 0.04, p = 0.01 and p = 0.006, respectively) in responders (n = 5) than in non-responders (n = 8). With nivolumab treatment, tumors in responders exhibited a substantial increase of CD8, GZMA and perforin 1 (PRF1) expression levels as well as increased ratio of TBX21/GATA3, suggesting dominancy of helper T cell type 1 (Th1) response to type 2 (Th2) response. T cell receptor β (TCR-β) repertoire analysis revealed oligoclonal expansion of tumor-infiltrating T lymphocytes (TILs) in the tumor tissues of the responders. Our findings suggest that melanoma harboring high PD-1 ligands (PD-L1 and PD-L2), GZMA and HLA-A expression may respond preferentially to nivolumab treatment, which can enhance Th1-skewed cellular immunity with oligoclonal expansion of TILs.

Pseudoprogression and Immune-Related Response in Solid Tumors

Emerging cancer therapeutics target the immune system, stimulating host antitumor response. Tumor cells generate an immunosuppressive milieu with multiple mechanisms to evade immune destruction, including disruption of effective antigen presentation, reduction of effector T-cell function, and upregulation of pathways that promote tolerance and T-cell anergy.1 The programmed death (PD) -1/PD ligand-1 (PD-L1) pathway is a critical component of tumor-mediated immunosuppression. Antibodies to PD-1 and PD-L1 have shown potential clinical benefit in advanced solid tumors.2 The US Food and Drug Administration approved the PD-1 inhibitors pembrolizumab and nivolumab for metastatic melanoma and also recently approved nivolumab for the treatment of metastatic squamous non–small-cell lung cancer. The US Food and Drug Administration has also designated the PD-L1 inhibitor MPDL3280A as a breakthrough therapy for bladder cancer and non–small-cell lung cancer. These drugs and additional immune checkpoint inhibitors are currently under investigation in multiple clinical trials as single-agent therapy and also in combination with other agents.