Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events.

BACKGROUND: Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs. METHODS: We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment. RESULTS: We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04). CONCLUSION: Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs (NCT04940299, NCT03999749).

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients with Cancer and Viral Hepatitis: The MD Anderson Cancer Center Experience.

BACKGROUND: Despite the clinical benefit of immune checkpoint inhibitors (ICIs), patients with a viral hepatitis have been excluded from clinical trials because of safety concerns. The purpose of this study was to determine the incidence rate of adverse events (AEs) in patients with viral hepatitis who received ICIs for cancer treatment. MATERIALS AND METHODS: We conducted a retrospective study in patients with cancer and concurrent hepatitis B or C, who had undergone treatment with ICI at MD Anderson Cancer Center from January 1, 2010 to December 31, 2019. RESULTS: Of the 1076 patients screened, we identified 33 with concurrent hepatitis. All 10 patients with HBV underwent concomitant antiviral therapy during ICI treatment. Sixteen of the 23 patients with HCV received it before the initiation of ICI. The median follow-up time was 33 months (95% CI, 23-45) and the median duration of ICI therapy was 3 months (IQR, 1.9-6.6). Of the 33 patients, 12 (39%) experienced irAEs (immune-related adverse events) of any grade, with 2 (6%) having grade 3 or higher. None of the patients developed hepatitis toxicities. CONCLUSION: ICIs may be a therapeutic option with an acceptable safety profile in patients with cancer and advanced liver disease.

Clinical activity of checkpoint inhibitors in angiosarcoma: A retrospective cohort study.

BACKGROUND: Systemic treatments for angiosarcoma remains an area of unmet clinical need. The authors conducted this retrospective study to assess the clinical activity of checkpoint inhibitors in patients with angiosarcoma. The primary objective was to assess the objective response rate, and the secondary objective was to assess the progression-free and overall survival durations and disease control rate. METHODS: Patient data were obtained using The University of Texas MD Anderson Cancer Center Tumor Registry database. The final study population was refined to only include patients who had undergone pembrolizumab monotherapy. The objective response rate was evaluated using RECIST/irRECIST version 1.1. Progression-free survival and overall survival were defined as the time from the initiation of immunotherapy to disease progression or recurrence, death, or last follow-up and to death or last follow-up, respectively. RESULTS: The final cohort comprised 25 patients. Most patients had metastatic disease (72%) and had undergone at least two lines of systemic therapy (80%) before starting pembrolizumab. The objective response rate was 18%, whereas the disease control rate was 59%. The median progression-free survival duration was 6.2 months and was not significantly different between the cutaneous (4.7 months) and visceral angiosarcoma (6.2 months) groups (p = .42). The median overall survival duration was 72.6 months. Toxicities were recorded for eight patients, with fatigue, anemia, constipation, and rash being the most common. CONCLUSIONS: Pembrolizumab shows durable clinical activity in angiosarcoma. These findings suggest that checkpoint inhibition as monotherapy or combination therapy is likely to have a high probability of success.© 2022 American Cancer Society. LAY SUMMARY: This is the largest retrospective study to assess the clinical activity of checkpoint inhibitor monotherapy in angiosarcomas. The study includes an adequate number of patients with visceral angiosarcoma that enabled to obtain meaningful clinical insights that were previously unavailable. Our findings indicate an improvement in progression-free survival with pembrolizumab that is comparable to other active agents in angiosarcoma. Pembrolizumab monotherapy in angiosarcomas also has a favorable tolerability profile. Our findings emphasize the need for prospective studies to evaluate the activity of pembrolizumab monotherapy and combination therapy.

Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have produced significant survival benefit across many tumor types. However, immune-related adverse events are common including autoimmune responses against different endocrine organs. Here, a case of ICI-mediated hypoparathyroidism focusing on long-term follow-up and insights into its etiology is presented. CASE AND METHODS: A 73-year-old man developed severe symptomatic hypocalcemia after the initiation of ipilimumab and nivolumab for the treatment of metastatic melanoma. Hypoparathyroidism was diagnosed with undetectable intact parathyroid hormone (PTH). Immunoprecipitation assays, ELISAs, and cell-based functional assays were used to test the patient for antibodies against the calcium-sensing receptor (CaSR). NACHT leucine-rich repeat protein 5 (NALP5) and cytokine antibodies were measured in radioligand binding assays and ELISAs, respectively. RESULTS: The patient's symptoms improved with aggressive calcium and vitamin D supplementation. At 3 years and 3 months since the diagnosis of hypoparathyroidism, PTH was still inappropriately low at 7.6 pg/mL, and attempted discontinuation of calcium and calcitriol resulted in recurrent symptomatic hypocalcemia. Analysis for an autoimmune etiology of the patient's hypoparathyroidism indicated that CaSR antibodies were negative before treatment and detected at multiple time points afterwards, and corresponded to the patient's clinical course of hypoparathyroidism. CaSR antibodies purified from the patient's serum activated the human CaSR. The patient was seronegative for NALP5 and cytokine antibodies, indicating that their hypoparathyroidism was not a manifestation of autoimmune polyendocrine syndrome type 1. CONCLUSION: The etiology of hypocalcemia is likely autoimmune hypoparathyroidism caused by the development of CaSR-activating antibodies that might prevent PTH release from the parathyroid.

The Role of Pharmacists in Managing Adverse Events Related to Immune Checkpoint Inhibitor Therapy.

OBJECTIVE: To provide an overview of immune checkpoint inhibitor (ICI) therapy-associated immune-related adverse events (irAEs) and their management, focusing on the key responsibilities for pharmacists in recognizing, distinguishing, and treating irAEs and in educating patients about irAEs and their management. DATA SOURCES: Literature published from January 2000 to March 2018 available from online sources. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language studies, guidelines, and articles. DATA SYNTHESIS: ICI therapies have been approved for the treatment of several cancers as single-agent therapies, combined ICI therapies, or in combination with other agents. ICI therapies increase the activity of the immune system and consequently can have autoimmune-like adverse effects that are often termed irAEs. irAE management can be challenging as irAEs can vary in their frequency and severity among patients, according to the specific agent, and can occur at any time during treatment or after therapy discontinuation. Additionally, for patients treated with ICI therapies in combination with other therapies, ICI-associated irAEs must be distinguished from adverse events associated with chemotherapy or targeted therapies, which often require different management. Pharmacists can provide essential support to diagnose and manage irAEs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Early and accurate diagnosis and prompt management of irAEs by pharmacists are critical to reduce the risk of severe or life-threatening complications and prevent premature ICI discontinuation. CONCLUSIONS: Pharmacists have a key role in the recognition, monitoring, and management of irAEs and in educating patients about irAEs associated with ICI therapies and the agents used to manage them.

Correction to: Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis.

Following publication of the original article [1], the authors reported an error in their listed affiliations.

IL17A Blockade Successfully Treated Psoriasiform Dermatologic Toxicity from Immunotherapy.

Dermatologic toxicities are the most common immune-related adverse events (irAE) secondary to immune checkpoint inhibitors (ICI). First-line treatment for grade 3 or 4 skin irAEs is high-dose corticosteroids, which have their own side effects. Prolonged treatment with corticosteroids may abrogate antitumor ICI activity. The cellular causes of these dermatologic toxicities, which can manifest as a variety of clinical presentations, remain unclear. Beyond steroids, recommended treatment options are limited. We report a case of psoriasiform dermatologic toxicity, induced by inhibition of PD-1 with the mAb pembrolizumab, which resolved after treatment with systemic interleukin IL17A blockade. Introduction of IL17A blockade did not alter the patient's melanoma response to pembrolizumab. This case suggests a possible pathogenic role of Th17 cells the irAE of the skin in this metastatic melanoma patient.

Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis.

BACKGROUND: Immune-related enterocolitis (irEC) is the most common serious complication from checkpoint inhibitors (CPIs). The current front-line treatment for irEC, high-dose corticosteroids (CS), have significant side effects and prolonged therapy may reduce CPI-anti-tumor activity. Early addition of TNF-α inhibitors such as infliximab (IFX) may expedite symptom resolution and shorten CS duration. Thus, we conducted the first retrospective study, to our knowledge, evaluating symptom resolution in patients with irEC treated with and without IFX. METHODS: Data were collected from the medical records of patients diagnosed with irEC. The primary endpoint was time to symptom resolution for irEC for cases managed with IFX plus CS (IFX group) versus CS alone (CS group). Duration of CS, overall survival (OS), and time to treatment failure (TTF) were secondary endpoints. RESULTS: Among 75 patients with irEC, 52% received CS alone, and 48% received IFX. Despite higher grade colitis in the IFX group (grade 3/4: 86% vs. 34%; p < 0.001), median times to diarrhea resolution (3 vs. 9 days; p < 0.001) and to steroid titration (4 vs. 13 days; p < 0.001) were shorter in the IFX group than in the CS group without a negative impact on TTF or OS. Total steroid duration (median 35 vs. 51 days; p = 0.150) was numerically lower in the IFX group. CONCLUSIONS: Despite higher incidence of grade 3/4 colitis, IFX added to CS for the treatment of patients with irEC was associated with a significantly shorter time to symptom resolution. The data suggest that early introduction of IFX should be considered for patients with irEC until definitive prospective clinical trials are conducted.

High cytotoxic T-lymphocyte-associated antigen 4 and phospho-Akt expression in tumor samples predicts poor clinical outcomes in ipilimumab-treated melanoma patients.

Ipilimumab, a fully human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), is the first immune checkpoint inhibitor approved for the treatment of unresectable melanoma on the basis of its overall survival (OS) benefit. However, ipilimumab is associated with significant immune-related adverse events. We hypothesized that biomarker exploration of pretreatment tumor samples and correlation with clinical outcome would enable patient selection with an increased benefit/risk ratio for ipilimumab therapy. At the University of Texas MD Anderson Cancer Center, a total of 81 advanced melanoma patients were treated on the Ipilimumab Expanded Access Program from 2007 to 2008. Using immunohistochemistry, we analyzed the expression of immune checkpoint (CTLA-4, PD-1, PD-L1) and Akt-pathway proteins in formalin-fixed tumor tissue. Associations between these biomarkers and progression-free survival (PFS) and OS were analyzed with univariate and multivariate Cox proportional-hazards models. There was a significant correlation between high CTLA-4 protein expression levels in tumor cells and risk of death (P=0.02) and decreased PFS (P=0.023). In addition, high expression of CTLA-4 in peritumoral lymphocytes correlated with poor OS (P=0.023). In multivariate analysis, patients with high CTLA-4 and phospho-Akt (p-Akt) expression correlated with poor OS (log-rank test, P=0.039) and PFS (log-rank test, P=0.014). High levels of CTLA-4 and p-Akt expression in pretreatment tumor cells in melanoma patients were associated with poor clinical outcomes. Immunohistochemistry analysis of CTLA-4 and p-Akt in pretreatment tumor samples provides useful biomarkers that may enable improved patient selection for ipilimumab therapy. Prospective clinical studies are warranted to investigate the predictive value of these biomarkers.

Selective inhibition of autoimmune exacerbation while preserving the anti-tumor clinical benefit using IL-6 blockade in a patient with advanced melanoma and Crohn's disease: a case report.

BACKGROUND: Novel immunotherapies, or checkpoint inhibitors, targeting programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) have significantly improved outcomes for patients with numerous different cancer types. However, owing to their exclusion from clinical trials and risk for autoimmune exacerbation on these treatments, the impact on safety and degree of toxicity of these potentially life-prolonging therapies is not well characterized in patients with an underlying autoimmune disease or previous organ transplant. CASE PRESENTATION: We report a case of a patient with advanced melanoma and refractory Crohn's disease who was treated concurrently with pembrolizumab (anti-PD-1 antibody) and tocilizumab (anti-interluekin-6 receptor antibody). This novel treatment strategy was well tolerated and did not result in Crohn's disease exacerbation for at least 16 weeks. Importantly, this treatment resulted in marked, durable antitumor responses. CONCLUSIONS: This outcome suggests that targeted immunosuppression combined with checkpoint inhibitors may hold promise as a treatment strategy for this unique patient population and may warrant additional study.

Stability study of carboplatin infusion solutions in 0.9% sodium chloride in polyvinyl chloride bags.

BACKGROUND AND PURPOSE: Carboplatin is a platinum-containing compound with efficacy against various malignancies. The physico-chemical stability of carboplatin in dextrose 5% water (D5W) has been thoroughly studied; however, there is a paucity of stability data in clinically relevant 0.9% sodium chloride infusion solutions. The manufacturer's limited stability data in sodium chloride solutions hampers the flexibility of carboplatin usage in oncology patients. Hence, the purpose of this study is to determine the physical and chemical stability of carboplatin-sodium chloride intravenous solutions under different storage conditions. METHODS: The physico-chemical stability of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL carboplatin-sodium chloride solutions prepared in polyvinyl chloride bags was determined following storage at room temperature under ambient fluorescent light and under refrigeration in the dark. Concentrations of carboplatin were measured at predetermined time points up to seven days using a stability-indicating high-performance liquid chromatography method. RESULTS: All tested solutions were found physically stable for at least seven days. The greatest chemical stability was observed under refrigerated storage conditions. At 4℃, all tested solutions were found chemically stable for at least seven days, with nominal losses of ≤6%. Following storage at room temperature exposed to normal fluorescent light, the chemical stability of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL solutions was three days, five days, and seven days, respectively. CONCLUSION: The extended physico-chemical stability of carboplatin prepared in sodium chloride reported herein permits advance preparation of these admixtures, facilitating pharmacy utility and operations. Since no antibacterial preservative is contained within these carboplatin solutions, we recommend storage, when prepared under specified aseptic conditions, no greater than 24 h at room temperature or three days under refrigeration.

Management of melanoma brain metastases.

Relapses in the brain remain a major obstacle to cure in many patients with advanced melanoma. At present, the management of melanoma brain metastases continues to rely heavily on surgical and radiotherapeutic interventions, which have become safer and more effective with modern imaging, surgery and radiation technologies. Additionally, novel targeted and immunotherapeutic agents, shown to generate meaningful intracranial response and survival benefit in patients with melanoma brain metastases when compared with historical controls, expand systemic treatment options for this subset of patients. These systemic therapies become particularly important when intracranial disease burden precludes neuro- or radio-surgery. Considerable multidisciplinary research effort is ongoing to improve outcomes for melanoma patients with brain metastases, a key challenge in the management of advanced melanoma.

Physical and chemical stability of reconstituted and diluted dexrazoxane infusion solutions.

BACKGROUND AND PURPOSE: Dexrazoxane is used clinically to prevent anthracycline-associated cardiotoxicity. Hydrolysis of dexrazoxane prior to reaching the cardiac membranes severely hampers its mode of action; therefore, degradation during the preparation and administration of intravenous dexrazoxane admixtures demands special attention. Moreover, the ongoing national shortage of one dexrazoxane formulation in the United States has forced pharmacies to dispense other commercially available dexrazoxane products. However, the manufacturers' limited stability data restrict the flexibility of dexrazoxane usage in clinical practice. The aims of this study are to determine the physical and chemical stability of reconstituted and diluted solutions of two commercially available dexrazoxane formulations. METHODS: The stability of two dexrazoxane products, brand and generic name, in reconstituted and intravenous solutions stored at room temperature without light protection in polyvinyl chloride bags was determined. The concentrations of dexrazoxane were measured at predetermined time points up to 24 h using a validated reversed phase high-performance liquid chromatography with ultraviolet detection assay. RESULTS: Brand (B-) and generic (G-) dexrazoxane products, reconstituted in either sterile water or 0.167 M sodium lactate (final concentration of 10 mg/mL), were found stable for at least to 8 h. Infusion solutions of B-dexrazoxane, prepared according to each manufacturer's directions, were stable for at least 24 h and 8 h at 1 mg/mL and 3 mg/mL, respectively. Infusion solutions of G-dexrazoxane, prepared in either 5% dextrose or 0.9% sodium chloride following the manufacturer's guidelines, were also stable for at least 24 h and 8 h at 1 mg/mL and 3 mg/mL, respectively. All tested solutions were found physically stable up to 24 h at room temperature. CONCLUSION: The stability of dexrazoxane infusion solutions reported herein permits advance preparation of dexrazoxane intravenous admixtures, facilitating pharmacy workflow and clinical operations. However, due to the potential risks of fluid overload when these intravenous solutions are administered to patients, caution is advised to ensure patient safety.

Ipilimumab in the treatment of melanoma.

INTRODUCTION: Recent advances in the understanding of the complex cellular mechanisms regulating cancer immunity have led to new strategies in the development of cancer immunotherapy. Targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), a key negative regulator of immune activity, with the monoclonal antibody ipilimumab has shown promising clinical benefit in patients with advanced or metastatic melanoma. AREAS COVERED: This review illustrates the pharmacology of ipilimumab and highlights the clinical evidence regarding its efficacy and safety in patients with advanced or metastatic melanoma. The unique clinical response pattern and class-specific immune-related toxicity profile associated with this biologic agent are also characterized. A literature search using PubMed database was undertaken using search words ipilimumab, anti-cytotoxic T-lymphocyte-associated antigen 4, melanoma and tumor immunity barrier. EXPERT OPINION: Ipilimumab, approved by the FDA for patients with advanced or metastatic melanoma based on the overall survival benefit when compared with a peptide vaccine, is a major breakthrough in the treatment of melanoma. While clinicians are embracing this innovative biologic agent, special attentions in patient selection, class-specific immune-related toxicities and their management as well as treatment response evaluation are needed.

Chemoprevention for brain metastases.

With the advent of effective therapies for systemic disease control, the prevalence of brain metastases (BMs) has been increasing. Relapses in the brain are a major barrier to cure in many patients with lung cancer and other malignancies. Effective agents are needed to prophylactically treat micrometastatic disease in patients at high risk for BMs, thereby reducing the incidence. In this report, we review the pathogenesis of and clinical risk factors for BMs, obstacles to BM treatment, and BM chemoprevention in lung cancer, breast cancer, melanoma, and renal cell carcinoma.