Inhibitor Ipilimumab Research Articles

Immune checkpoint inhibitors for brain metastases in non-small-cell lung cancer: from rationale to clinical application.

Brain metastases (BM) is common in non-small-cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors (ICIs)have gradually become a routine treatment for NSCLC BM patients. Currently, three PD-1 inhibitors (pembrolizumab, nivolumab and cemiplimab), one PD-L1 inhibitor (atezolizumab) and one CTLA-4 inhibitor (ipilimumab) have been approved for the first-line treatment of metastatic NSCLC. It is still controversial whether PD-L1, tumor infiltrating lymphocytes, and tumor mutation burden can be used as predictive biomarkers for immune checkpoint inhibitorsin NSCLC patients with BM. In addition, clinical data on NSCLC BM were inadequate. Here, we review the theoretical basis and clinical data for the application of ICIsin the therapy of NSCLC BM.

GL-1 Clinical recommendations on the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair (dMMR) tumors

Historically, cancer care has been conducted based on the multifaceted evaluation of a case, such as the pathological diagnosis and staging of the disease, benefits and risks of treatments, and the patient's preference. A recent advance in molecular biology has revealed the various biological characteristics of tumors and has enabled clinical development of tumor-agnostic drugs beyond the organ-specificity of diseases. In recent years, many clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of advanced solid tumors with dMMR. In Japan, programmed cell death-1 (PD-1) inhibitor pembrolizumab monotherapy for advanced/recurrent microsatellite instability-high (MSI-H) solid tumors, regardless of the primary tumor site, has been approved. Moreover, combination of cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) inhibitor ipilimumab and PD-1 inhibitor nivolumab have also approved for MSI-H unresectable advanced or recurrent colorectal cancer. Among with this, we are facing several clinical questions (CQs) regarding MSI/MMR tests and how this will influence the treatment and management for patients with dMMR advanced solid tumors. Therefore, we developed the clinical practice guideline. The CQs regarding medical care were formulated for patients with dMMR advanced solid tumors. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. Then, the committee members voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other factors. The guideline describes 2 clinical questions and 9 recommendations for whom, when, and how MMR status should be tested, and what is recommended for patients with dMMR advanced solid tumors. In this session, I would like to present clinical recommendations with their underlying scientific evidence as well as future perspective in this space.

Immunological Correlates of Treatment with the CTLA-4 Inhibitor Ipilimumab in Patients with Refractory Myelodysplastic Syndromes (MDS)

Introduction: Failure of hypomethylating agents (HMAs) in patients with myelodysplastic syndromes (MDS) is associated with dismal survival and there are no currently approved therapies in this setting. We recently presented the results of a multi-center phase 1b study of the immune checkpoint blocker (ICB) ipilimumab given as monotherapy after HMA failure in 29 MDS patients. Eight doses of 3mg/kg administered in induction and maintenance phases were safe and well tolerated. Very limited data has been reported on immunologic correlates of response after ICB therapy among patients with hematologic malignancies. Here we present a detailed analysis of the immunological correlates of achieving clinical benefit with ipilimumab.Methods: We defined patients who achieved marrow complete response (mCR) or prolonged stable disease (PSD) for ≥46 weeks as having achieved meaningful clinical benefit (MCB) for analyses of immunologic studies. 11 patients were treated during the dose escalation phase (6 patients at 3mg/kg dose and 5 patients at 10 mg/kg), while another 18 patients were treated in the dose expansion part at the 3 mg/kg dose. Correlative immunologic studies were performed on mononuclear cells from both peripheral blood (PBMC) and bone marrow (BMMC) samples that were collected at baseline and at pre-determined timepoints after ipilimumab treatment (after induction cycle 2 and 4; after each maintenance cycle 1-4, and end of treatment or study discontinuation). Correlative assays included immunophenotyping of PBMCs and BMMCs by multicolor flow cytometry, as well as high throughput sequencing of the T cell antigen receptor (TCR) repertoire. T cell percentages, absolute numbers, and ratios were summarized by time point for patients and overall for healthy controls using descriptive statistics (mean, SD). Differences in log-transformed T cell values were compared between healthy controls and patients at pre-treatment using two-sample t tests. Differences from pre-treatment to cycle 2 and cycle 4 were estimated for patients and tested for positive or negative changes with paired t tests. Analyses were completed using R version 3.3.2.Results: MCB was observed in 28% of patients, 2 (7%) patients with mCR and 6 (21%) patients with PSD, respectively. Immunologic studies were performed on 16 patients who had samples available from at least two time points. Compared to solid tumor literature, we did not observe a correlation between early dynamic changes in serial absolute lymphocyte count and probability of achieving MCB. Expression of co-stimulatory molecules (ICOS - Inducible T Cell CO-Stimulator) and co-inhibitory molecules (PD-1 and CTLA-4) showed that a higher fraction of CD4+ and CD8+ T-cells in PB expressed ICOS in patients who achieved MCB following ipilimumab treatment (P=0.05 and P=0.01, respectively, Figure 1]. Similarly, expression of the immune co-inhibitory receptor CTLA-4 followed a similar pattern showing a trend of increased expression in both CD4+ and CD8+ T-cells (average increase of 6% and 2.4% respectively, P=ns.) over the first 4 cycles of ipilimumab treatment among patients who achieved MCB, followed by a gradual decrease. In contrast to CTLA-4, there was a wide range in frequencies of CD4+ and CD8+ T-cells expressing PD-1 in both patients and HC and PD-1 levels remained stable throughout ipilimumab treatment suggesting that the lack of T-cell activation in non-responders was not due to increased expression of other co-inhibitory molecules. There was a significantly higher frequency of CD3+CD4+Foxp3+ and activated effector Tregs (eTregs) prior to treatment which persisted throughout the examined time points and neither their levels, nor the CD8 T-cell to Treg (CD8/Treg) ratio were impacted by ipilimumab treatment.Conclusions: These data represent, to our knowledge, the first detailed analysis of immunologic correlates of response to ICB therapy in MDS patients. Our data suggest that ICOS expression is positively correlated with achievement of MCB with single agent ipilimumab in patients with MDS and should be further explored as a biomarker for response. The results of the high throughput sequencing of the T cell antigen receptor (TCR) repertoire are currently being analyzed and will be presented at the meeting. [Display omitted] DisclosuresSmith:Celgene: Other: DSMB member; Jazz: Membership on an entity's Board of Directors or advisory committees. Zeidner:Tolero Pharmaceuticals: Honoraria; Agios: Honoraria; Tolero Pharmaceuticals: Research Funding; Takeda: Research Funding; Merck: Research Funding; Celgene: Honoraria. Frattini:Astellas: Honoraria; Lin Bioscience: Consultancy. Levy:Actinium Pharmaceuticals: Equity Ownership; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Takeda: Consultancy, Speakers Bureau. Zeidan:AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Takeda: Speakers Bureau; Otsuka: Consultancy.

Sarcoid-like reaction in a BRAF V600E-mutated metastatic melanoma patient during treatment with BRAF/MEK-targeted therapy.

Treatment with combined BRAF and MEK inhibition is widely accepted as a first-line treatment option for patients with advanced BRAF V600E mutant melanoma. It is generally well-tolerated and has limited side-effects. However, we report a case of a sarcoid-like syndrome induced by treatment with dabrafenib/trametinib (D/T) in a patient with stage IV-M1d melanoma. Sarcoid-like syndrome is a known side-effect of immune checkpoint-inhibition therapy but has only rarely been described in BRAF/MEK inhibition. However, recognizing this side-effect is important because of potential misinterpretation as progressive disease and influence on treatment. We describe a 48-year-old female patient who initially presented with solitary brain metastasis and diffuse lung lesions. She was treated with D/T to which she had an initial response in all lesions. One year later, new hilar and mediastinal lymphadenopathies were detected. Imaging was suggestive of the sarcoid-like syndrome. An endoscopic biopsy of the enlarged lymph node showed no melanoma cells. Treatment was continued. Three months later, the patient experienced a drop in hemoglobin, which prompted further investigations into possible occult intestinal metastasis. Video capsule examination revealed a metastatic lesion in the small intestine. A treatment switch to the combination of checkpoint inhibitors nivolumab and ipilimumab successfully treated both lung and small intestine lesions. After the third dose of this combination therapy, she developed an immune-related pneumonitis. Treatment with corticosteroids resolved the pneumonitis and decreased metabolism in the sarcoid-like syndrome. The treatment was not restarted afterward. She remains free of the disease up to today, 2.5 years after diagnosis.

MO363CHECKPOINT-INHIBITOR-ASSOCIATED ACUTE KIDNEY INJURY AND MORTALITY: AN OBSERVATIONAL STUDY

Abstract Background and Aims Immune checkpoint inhibitors, approved for the treatment of various types of cancer, are known to cause a unique spectrum of autoimmune-related side effects, including acute kidney injury (AKI). The aim of this study was to describe the incidence, risk factors, renal outcomes, and mortality of AKI in patients receiving checkpoint inhibitors. Method Patients receiving checkpoint inhibitors between January 2013 and May 2020 were identified using the Utrecht Patient Oriented Database. AKI was defined as an increase in creatinine of ≥1.5 times the baseline value. Cox proportional hazard regression analysis was used to assess risk factors for AKI and to evaluate the relationship between AKI and mortality. Persistent kidney injury was diagnosed in AKI patients with a final creatinine measurement of >1.3 times the baseline value. Results Out of 676 patients receiving checkpoint inhibitors, AKI occurred in 96 (14.2%) patients. Chart review showed that AKI was checkpoint inhibitor-associated in 32 (4.7%) patients. Baseline variables associated with AKI were a primary gynecological malignancy (HR 3.91, 95% CI 1.55 to 9.85), treatment with checkpoint inhibitor ipilimumab (HR 2.31, 95% CI 1.03 to 5.20), and pre-existent use of a diuretic (HR 2.61, 95% CI 1.21 to 5.60), an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker (HR 2.49, 95% CI 1.10 to 5.60), and a proton pump inhibitor (HR 1.69, 95% CI 1.04 to 2.75). In 35.4% of the patients who had developed AKI, persistent kidney dysfunction was observed at the end of follow-up. Patients who developed AKI had a 2.13-fold (95% CI 1.58 to 2.87) increased mortality risk compared to patients who did not develop AKI. Mortality risk was not increased by checkpoint inhibitor-associated AKI (HR 1.11, 95% CI 0.64 to 1.92), but only by AKI related to other causes (HR 2.87, 95% CI 2.04 to 4.04). Conclusion Patients receiving checkpoint inhibitors frequently develop AKI, however, checkpoint inhibitor-associated AKI does not seem to increase mortality.

A phase 2 study using ipilimumab, nivolumab, and trabectedin for previously untreated metastatic soft tissue sarcoma.

11562 Background: Sarcoma cells are most immunogenic earlier in the disease course and before treatment when the immune system can recognize and destroy them. Hypothesis: Immune checkpoint inhibitors would be most effective when given to previously untreated patients with metastatic soft tissue sarcoma. Methods: Eligible patients for this Phase 2 study are previously untreated patients ≥ 18 years of age with unresectable or metastatic soft tissue sarcoma, with measurable disease by RECIST v1.1. Immune checkpoint inhibitors Ipilimumab (I) and Nivolumab (N) were given with Trabectedin (T), a marine derived alkaloid with defined doses of I (1 mg/kg i.v. q 12 weeks), N (3 mg/kg i.v. q 2 weeks), and T (1.2 mg/m2 i.v. q 3 weeks). Primary endpoints: (1) Objective response rate by RECIST v1.1 via CT scan or MRI, (2) Progression-free survival (PFS): from first day of treatment to disease progression or death due to any cause; otherwise, it is censored at the time of last follow-up, and (3) Overall survival: from first day of treatment to death due to any cause; otherwise, it is censored at the time of last follow-up. Results: There were eighty-two evaluable subjects, having completed the first cycle of I, N, and T and have had a CT or MRI scan at the 6-week follow-up period. Best Overall Response by RECIST v1.1 = 7 CR (2 surgical CR), 9 PR, 54 SD, and 12 PD. Disease control rate was 85.4%. The median PFS was >6.4 (range: 0-32) months; 6-month PFS rate: 57.3%. The median OS was >12.0 (0-38) months; 6-month OS rate: 78.8%. Safety analysis: The most common Grade 3 TRAEs include increased ALT (26), anemia (11), increased AST (9), and fatigue (8). Common Grade 4 TRAEs include thrombocytopenia (2), increased AST (2), increased ALT (2), and increased CPK (2). There was one Grade 5 TRAE of rhabdomyolysis (1). Conclusions: Taken together, these results suggest that first-line combinatorial therapy with I, N, and T are (1) synergistic, and (2) may be equal or superior to, and safer than, standard first line therapy for advanced/metastatic soft tissue sarcoma. Clinical trial information: NCT03138161.

Nivolumab plus ipilimumab for the first-line treatment of metastatic NSCLC

ABSTRACT Introduction In the last decade, immune checkpoint inhibitors have revolutionized the treatment of several malignancies including non-small cell lung cancer (NSCLC). The inhibition of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed death receptor 1 (PD-1) pathways leads to an activation of the immune response against tumor cells. Thanks to a synergistic effect, the combination of the checkpoint inhibitors nivolumab and ipilimumab has the potential to improve outcomes of NSCLC patients. Areas covered We provide an overview of clinical trials evaluating the combination of nivolumab and ipilimumab in the first-line treatment of advanced NSCLC patients. Expert opinion The combination of nivolumab and ipilimumab, alone or with a few cycles of chemotherapy, was demonstrated to be a valid option for first-line treatment of metastatic NSCLC patients without EGFR mutation and ALK rearrangement. However, a better understanding of patients who can benefit from this approach is required.

Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

Adjuvant immunotherapy for melanoma

Surgical resection is the treatment for early cutaneous melanoma and is often curative. Some patients, however, will subsequently relapse. High-risk features in the primary tumor and regional lymph node metastasis highlight patient subsets that are at increased risk for recurrent disease. Immunotherapy in the form of checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab have been shown to improve recurrence-free survival for node-positive melanoma in the adjuvant setting and will be the focus of this review.

Psoriasis and psoriasiform reactions secondary to immune checkpoint inhibitors.

The advent of Immune Checkpoint Inhibitors (ICIs) as a standard of care for several cancers, including melanoma and head/neck squamous cell carcinoma has changed the therapeutic approach to these conditions, drawing at the same time the attention on some safety issues related to their use. To assess the incidence of psoriasis as a specific immune-related cutaneous adverse event attributing to ICIs using the Eudravigilance reporting system. All reports of adverse drug reactions (ADRs) concerning either exacerbation of psoriasis or de novo onset of psoriasis/psoriasiform reactions associated to the use of Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) inhibitors ipilimumab and tremelimumab, and the Programmed cell Death protein 1/Programmed Death-Ligand 1 (PD-1/PD-L1) inhibitors nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab were identified and extracted from the Eudravigilance reporting system, during the period between the date of market licensing (for each study drug) and 30 October 2020. 8213 reports of cutaneous ADRs associated with at least one of study drug have been recorded, of which 315 (3.8%) reporting psoriasis and/or psoriasiform reactions as ADR. In 70.8% of reports patients had pre-existing disease. ICIs-related skin toxicity is a well-established phenomenon, presenting with several conditions, sustained by an immune background based on the activity of some cells (CD4+/CD8+ T-cells, neutrophils, eosinophils, and plasmocytes), inflammatory mediators, chemokines, and tumor-specific antibodies. In this setting, psoriasis represents probably the most paradigmatic model of these reactions, thus requiring adequate recognition as no guidelines on management are now available.

Развитие деструктивного тиреоидита и сахарного диабета после трех введений пембролизумаба по поводу меланомы кожи

The exponential rise in the use of immune checkpoint inhibitors (Ipilimumab, Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, and Avelumab) as the new standard for cancer treatment increase the incidence the immune-related adverse events due to immune activation. Endocrine immune-related adverse events are the third most commonly reported. Thyroid gland is most susceptible to autoimmune dysfunctions from immune checkpoint inhibitors and associated with the use of anti-PD-1 monoclonal antibodies. Hypophysitis develops more often during therapy with anti-CTLA-4 monoclonal antibodies. But such immune-related adverse events as diabetes mellitus, hypoparathyroidism are rare (about 1% of cases). We present a clinical case of the patient with skin melanoma who was prescribed therapy with immune checkpoints inhibitors (Pembrolizumab). Immune-related adverse events developed with damage to the endocrine organs after 3 Pembrolizumab injections. Of greatest interest is the development of two endocrine immune-related adverse events at once: destructive thyroiditis (with a short phase of thyrotoxicosis and subsequent persistent hypothyroidism) and diabetes mellitus. We tried to reflect the chronology of diseases and their features as fully as possible for endocrinologists, oncologists, therapists, family doctors and other medical doctors of related specialties.

Abstract PO030: A Novel T-cell Population Expressing the Ectoenzymes CD38 and CD39 is Associated with Melanoma Patient Non-Response to Immunotherapy

Abstract Cancer immunotherapy has emerged as one of the most potent therapeutic tools in treating melanoma and a variety of other malignancies. Immunotherapy includes inhibition of the modulators of T cell antitumor function, the immune checkpoints, by using antibodies against them. In advanced melanoma patients, immune checkpoint inhibitors ipilimumab (IPI) and nivolumab (NIVO) have had unprecedented efficacy. Although many patients respond well to this therapy, many patients remain unresponsive. The mechanism underlying treatment failures remains poorly understood. Using a novel high-dimensional flow cytometry analysis methodology, CytoBrute, we found that in the cohort of advanced melanoma patients receiving sequential NIVO-IPI, high baseline levels of a novel immunophenotype, CD4+CD38+CD39+CD127-GARP- T-cells (median frequency 0.3%), was associated with poor outcomes (disease progression p=0.008, and decreased overall survival p<0.0001 HR = 6.8). Both CD38 and CD39 are ectoenzymes with CD38 hydrolyzing NAD+ to cyclic-ADP ribose and CD39 converting extracellular ATP to immunosuppressive adenosine nucleosides. Both of these proteins are being evaluated as targets to increase the efficacy of immunotherapies. The association of this novel phenotype, which we have termed T-cells expressing ectoenzymes (Tee), was validated in two independent cohorts of melanoma patients treated with NIVO monotherapy, with progressors showing a higher frequency of this immunophenotype at baseline (p=0.047). In IPI+NIVO adjuvant treated melanoma patients, an increase in this population of cells was observed during treatment in relapsing patients, leading to a higher frequency of these cells in relapsing patients relative to patients with no evidence of disease (p=002). Preliminary data obtained from single cell RNA sequencing from the ectoenzyme expressing peripheral blood T cell population, demonstrated predominant expression of IL-32 and CD99 (a membrane glycoprotein associated with lymphocyte diapedesis) in this population, along with several additional clusters distinguished by expression of specific TcR V beta genes. Collectively, we have identified a novel population of ectoenzyme expressing T-cells (CD3+CD4+CD38+CD39+CD127-GARP-) associated with poor melanoma patient outcomes in response to checkpoint immunotherapy. Further investigation of the mechanisms by which this novel T-cell phenotype is associated with poor patient outcomes is under way. Citation Format: Ankita Mitra, David M. Woods, Anjali Rao, Andressa S. Laino, Aidan Winters, Itai Yanai, Pratip K. Chattopadhyay, Jeffrey S. Weber. A Novel T-cell Population Expressing the Ectoenzymes CD38 and CD39 is Associated with Melanoma Patient Non-Response to Immunotherapy [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO030.

Immune-Related Oral, Otologic, and Ocular Adverse Events.

Emerging immunotherapeutic agents, including immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death protein ligand 1 (PD-L1), have revolutionized cancer treatment. The first immune checkpoint inhibitor (ICI) ipilimumab, an anti-CTLA-4, was approved in 2011. Since then, the US Food and Drug Administration (FDA) has approved more than half a dozen immune checkpoint inhibitors to treat various malignancies. These agents are part of a broader class of chemotherapy agents termed immunotherapy, which selectively target different steps in the immune response cascade to upregulate the body's normal response to cancer. While the effects of traditional chemotherapy are well known, the toxicity profile of emerging immune therapies is not fully elucidated. They have been associated with atypical side effects labeled collectively as immune-related adverse events (irAEs).

Prospects of application of inhibitors of PD-1/PD-L1 checkpoints in malignant tumors of the stomach and esophagogastric junction

Malignant tumors of the stomach and esophagogastric junction in advanced stages progress quite aggressively, and the prospects for treatment of these patients remain unpromising. The use of checkpoint-inhibitors has proven to be an advanced treatment method for various types of cancer around the world. In theRussian Federation, nivolumab has been successfully registered as a monotherapy for common or recurrent stomach or esophagogastric junction cancer after two or more lines of systemic antitumor drug therapy. This literature review focuses on the use of registered checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab) as mono- and/or combined therapy in tumors of the stomach and esophagogastric junction, including tumors with high microsat- ellite instability (MSI-high). This review includes a description of the main therapeutic approaches using checkpoint inhibitors: prescription in mono-mode, in combination with other checkpoint inhibitors (ipilimumab) and cytotoxic drugs, and in combination with tyrosine kinase inhibitors (regorafenib). Issues of efficiency and tolerability of these combinations in patients in different therapeutic lines are considered. The role of possible predictors of therapy response is analyzed: biomarkers such as PD-Ll, MSI, dMMR and TMB expression in tumor tissues as well as immunofenotyping in fresh biopsy samples are evaluated. This article reviews and evaluates the strengths and weaknesses of checkpoint inhibitors and their possible uses.

Immune Activation in Patients with Locally Advanced Cervical Cancer Treated with Ipilimumab Following Definitive Chemoradiation (GOG-9929).

A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti-CTL antigen-4 (anti-CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment. Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot. Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16+ patients and in 2 of 3 HPV18+ patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival. Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response.

Checkpoint Inhibitor Colitis Masked by Multi-drug Effect

Abstract Casestudy: The utilization of checkpoint inhibitors such as programmed cell death protein 1 (PD-1/PD-L1) inhibitors (nivolumab) and cytotoxic T-lymphocyte antigen 4 inhibitors (ipilimumab) for treatment of certain malignancies has steadily gained popularity. Medication related colitis is uncommon, with a reported incidence of 1–9% depending on the checkpoint inhibitor used, and the histologic features have been characterized in recent literature. Because of the immunomodulating effect of these drugs, infectious colitis is in the differential diagnosis of enteritis. Multi-drug therapy in many of these patients further complicates identification of the culprit drug. We present the case of a 63-year-old male with metastatic renal cell carcinoma being treated with both nivolumab and ipilimumab who presented with acute on chronic non-bloody diarrhea. His clinical course was complicated by hypotension, acidosis and coagulopathy. The clinical differential for his colitis was cytomegalovirus infection versus a checkpoint inhibitor colitis. Colonoscopy revealed continuous circumferential loss of vascularity and diffuse erythema throughout the colon. Histology showed acute colitis with prominent apoptosis, cryptitis, crypt abscesses, and rare ringed mitotic figures, but without architectural distortion. Occasional smooth purple crystals consistent with pill material were present in the mucosa, but without significant tissue reaction. No pathogenic organisms were identified, and a cytomegalovirus immunostain was negative. These histologic findings in concert with the clinical history are consistent with checkpoint inhibitor colitis and multi-drug effect. A review of the patient’s chart showed cholestyramine was added to the patient’s regimen during hospitalization, which was consistent with the morphologic appearance of the crystals. Given the acute complications of checkpoint inhibitor induced enterocolitis and potential for increased morbidity (rare cases of bowel perforation and subsequent resection), accurate diagnosis is imperative. Management of checkpoint inhibitor associated colitis ranges from initiation of immunosuppression to checkpoint inhibitor cessation. When these findings are masked by multi-drug effect, accurate diagnosis can be difficult.

Neuro-Ophthalmic Complications in Patients Treated With CTLA-4 and PD-1/PD-L1 Checkpoint Blockade.

In recent years, CTLA-4 and PD-1/PD-L1 checkpoint inhibitors have proven to be effective and have become increasingly popular treatment options for metastatic melanoma and other cancers. These agents work by enhancing autologous antitumor immune responses. Immune-related ophthalmologic complications have been reported in association with checkpoint inhibitor use but remain incompletely characterized. This study seeks to investigate and further characterize the neuro-ophthalmic and ocular complications of immune checkpoint blockade treatment. A survey was distributed through the secure electronic data collection tool REDCap to neuro-ophthalmology specialists in the North American Neuro-Ophthalmology Society listserv. The study received human subjects approval through the University of California at Los Angeles Institutional Review Board. The survey identified patients sent for neuro-ophthalmic consultation while receiving one or more of a PD-1 inhibitor (pembrolizumab, nivolumab, or cemiplimab); PD-L1 inhibitor (atezolizumab, avelumab, or durvalumab); or the CTLA-4 inhibitor ipilimumab. Thirty-one patients from 14 institutions were identified. Patient demographics, neuro-ophthalmic diagnosis, diagnostic testing, severity, treatment, clinical response, checkpoint inhibitor drug used, and cancer diagnosis was obtained. The checkpoint inhibitors used in these patients included pembrolizumab (12/31), nivolumab (6/31), combined ipilimumab with nivolumab (7/31, one of whom also received pembrolizumab during their course of treatment), durvalumab (3/31), ipilimumab (2/31), and cemiplimab (1/31). Malignant melanoma (16/31) or nonsmall cell lung carcinoma (6/31) were the most common malignancies. The median time between first drug administration and the time of ophthalmological symptom onset was 14.5 weeks. Eleven patients had involvement of the optic nerve, 7 patients had inflammatory orbital or extraocular muscle involvement, 6 patients had ocular involvement from neuromuscular junction dysfunction, 4 patients had cranial nerve palsy, and 4 patients had non neuro-ophthalmic complications. Use of systemic corticosteroids with or without stopping the checkpoint inhibitor resulted in improvement of most patients with optic neuropathy, and variable improvement for the other ophthalmic conditions. This study describes the variable neuro-ophthalmic adverse events associated with use of immune checkpoint inhibitors and contributes a more thorough understanding of their clinical presentations and treatment outcomes. We expect this will increase awareness of these drug complications and guide specialists in the care of these patients.

Stereotactic Radiosurgery With Concurrent Immunotherapy in Melanoma Brain Metastases Is Feasible and Effective.

Objective: Stereotactic radiosurgery (SRS) is an established treatment for brain metastases in the management of metastasized melanoma. The increasing use of checkpoint inhibitors in melanoma therapy leads to combined treatment schemes consisting of immunotherapy and SRS that need to be evaluated regarding safety and feasibility.Methods: We retrospectively analyzed 36 patients suffering from cerebral metastasized melanoma. Between November 2011 and May 2016, altogether 66 brain metastases were treated with single-fraction SRS (18–20 Gy prescribed to the 80% isodose) in combination with a checkpoint inhibitor (ipilimumab: 82%, pembrolizumab: 14% or nivolumab: 4%), administered within 3 months before or after SRS. Toxicity was evaluated with focus on the incidence of central nervous system (CNS) radiation necrosis (CRN). Overall survival (OS), freedom from local progression (FFLP), freedom from central nervous system radiation necrosis (FFCRN), and freedom from distant intracranial progression (FFDIP) were analyzed using the Kaplan-Meier method.Results: The median follow-up was 25 months (range: 2–115 months). Two patients (6%) presented with cerebral edema CTCAE °III and another two patients (6%) presented with one-sided muscle weakness CTCAE °III after SRS. One of these four symptomatic cases correlated with an observed CRN, the other three symptomatic cases were related to local tumor progression (n = 2) or related to the performance of additional whole brain radiotherapy (WBRT). No further CTCAE °III or °IV toxicity was seen. During follow-up, seven of the growing contrast-enhanced lesions were resected, revealing two cases of CRN and five cases of local tumor progression. Altogether, the observed CRN rate of the irradiated metastases was 6–17% at the time of analysis, ranging due to the radiologically challenging differentiation between CRN and local tumor progression. The observed ranges of the 1- and 2-years FFLP rates were 82–85% and 73–80%, respectively. The median FFDIP was 6.1 months, the median OS was 22.2 months.Conclusion: In the presented cohort, the combination of SRS and checkpoint inhibitors in the management of cerebral metastasized melanoma was safe and effective. Compared to historic data on SRS only, the observed CRN rate was acceptable. To gain resilient data on the incidence of CRN after combined treatment schemes, prospective trials are needed.

Finding the hot spot: identifying immune sensitive gastrointestinal tumors.

Although researchers have been trying to harness the immune system for over 100 years, the advent of immune checkpoint blockers (ICB) marks an era of significant clinical outcomes in various metastatic solid tumors, characterized by complete and durable responses. ICBs are monoclonal antibodies that target either of a pair of transmembrane molecules in tumors or T-cells involved in immune evasion. Currently 2 ICBs targeting the checkpoint program death 1 (PD-1), nivolumab and pembrolizumab, and one cytotoxic lymphocyte antigen-4 (CTLA-4) inhibitor (ipilimumab) are approved in gastrointestinal malignancies. We review herein the current evidence on predictive biomarkers for ICB response in gastrointestinal tumors. A review of literature based on the National Cancer Institute list of FDA-approved drugs for neoplasms and FDA-approved therapies at the FDA website was performed. An initial literature review was based on the American Association for Clinical Research meeting 2019, the American Society of Clinical Oncology meeting 2019 and the European Society of Medical Oncology 2019 proceedings. A systematic search of PubMed was performed involving MeSH browser terms such as biomarkers, immunotherapy, gastrointestinal diseases and neoplasms. When appropriate, American and British terms were used in the search. The most relevant predictor of response to ICBs is microsatellite instability (MSI) and the data is strongest for colorectal cancer. At least 3 prospective trials show evidence of PD-L1 as a predictive biomarker for ICB response in gastroesophageal malignancies. At least one prospective trial has described tumor mutational burden high (TMB-H), independent of MSI, as predictive of response in anal and biliary tract carcinomas. DNA Polymerase Epsilon (POLE) or delta (POL-D) mutations have been implicated in a subset of MSS colorectal cancer with TMB-H but this biomarker requires prospective validation. There is evolving data based on retrospective observations that gene alterations predicting acquired resistance and hyper-progression. Ongoing clinical research is assessing the role of the human microbiome and RNA-editing complex mutations as predictive biomarkers of response to ICBs. MSI has the strongest predictive power among current biomarkers for ICB response in gastrointestinal cancers. Data continue to accumulate from ongoing clinical trials and new biomarkers are emerging from pre-clinical studies, suggesting that drug combinations targeting pathways complimentary to the PD-1/PD-L1 axis inhibition will define a robust field of clinical research.

The current state of adjuvant therapy of melanoma.

Melanoma adjuvant therapy targets residual micrometastatic disease destined for future recurrence. In patients with resected stage III or IV melanoma, adjuvant therapy was shown to reduce the risk of recurrence, death, or both, leading to the regulatory approval of several agents since 1995: IFNα, pegylated-IFNα, checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab, and BRAF and MEK inhibitors dabrafenib and trametinib. 1 Kirkwood JM Manola J Ibrahim J et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004; 10: 1670-1677 Crossref PubMed Scopus (456) Google Scholar , 2 Kirkwood JM Ibrahim JG Sosman JA et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001; 19: 2370-2380 Crossref PubMed Scopus (783) Google Scholar , 3 Eggermont AM Suciu S Testori A et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012; 30: 3810-3818 Crossref PubMed Scopus (208) Google Scholar , 4 Eggermont AM Chiarion-Sileni V Grob JJ et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015; 16: 522-530 Summary Full Text Full Text PDF PubMed Scopus (856) Google Scholar , 5 Tarhini AA Lee SJ Hodi FS et al. Phase III study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma: North American Intergroup E1609. J Clin Oncol. 2020; 38: 567-575 Crossref PubMed Scopus (51) Google Scholar , 6 Eggermont AMM Blank CU Mandala M et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018; 378: 1789-1801 Crossref PubMed Scopus (929) Google Scholar , 7 Long GV Hauschild A Santinami M et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017; 377: 1813-1823 Crossref PubMed Scopus (799) Google Scholar Key adjuvant trials, their outcomes, and current standard of care status are summarised in the appendix. Adjuvant nivolumab versus ipilimumab in resected stage IIIB–C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trialAt a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB–C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab. Full-Text PDF