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).

Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity.

Immune checkpoint blockade (ICB) therapy frequently induces immune-related adverse events. To elucidate the underlying immunobiology, we performed a deep immune analysis of intestinal, colitis, and tumor tissue from ICB-treated patients with parallel studies in preclinical models. Expression of interleukin-6 (IL-6), neutrophil, and chemotactic markers was higher in colitis than in normal intestinal tissue; T helper 17 (Th17) cells were more prevalent in immune-related enterocolitis (irEC) than T helper 1 (Th1). Anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) induced stronger Th17 memory in colitis than anti-program death 1 (anti-PD-1). In murine models, IL-6 blockade associated with improved tumor control and a higher density of CD4+/CD8+ effector T cells, with reduced Th17, macrophages, and myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) model with tumors, combined IL-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. IL-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.

Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response.

Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer, but the effect of diet and supplements on this interaction is not well studied. We assessed fecal microbiota profiles, dietary habits, and commercially available probiotic supplement use in melanoma patients and performed parallel preclinical studies. Higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti­programmed cell death 1 (anti­PD-1)­based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-γ­positive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for patients receiving ICB for cancer.

Corrections to: Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature.

Following publication of the original article [1], the authors reported an error in the Acknowledgments section. It should be read: 'We are grateful to Mohsin Shah from the Department of Emergency Medicine at The University of Texas MD Anderson Cancer Center for assisting in study selection, and to Gregory F. Pratt from the Research Medical Library and Erica Goodoff, from the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for their valuable contributions.

Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature.

BACKGROUND: Checkpoint inhibitors (CPIs) have revolutionized the treatment of cancer, but their use remains limited by off-target inflammatory and immune-related adverse events. Solid organ transplantation (SOT) recipients have been excluded from clinical trials owing to concerns about alloimmunity, organ rejection, and immunosuppressive therapy. Thus, we conducted a retrospective study and literature review to evaluate the safety of CPIs in patients with cancer and prior SOT. METHODS: Data were collected from the medical records of patients with cancer and prior SOT who received CPIs at The University of Texas MD Anderson Cancer Center from January 1, 2004, through March 31, 2018. Additionally, we systematically reviewed five databases through April 2018 to identify studies reporting CPIs to treat cancer in SOT recipients. We evaluated the safety of CPIs in terms of alloimmunity, immune-related adverse events, and mortality. We also evaluated tumor response to CPIs. RESULTS: Thirty-nine patients with allograft transplantation were identified. The median age was 63 years (range 14-79 years), 74% were male, 62% had metastatic melanoma, 77% received anti-PD-1 agents, and 59% had prior renal transplantation, 28% hepatic transplantation, and 13% cardiac transplantation. Median time to CPI initiation after SOT was 9 years (range 0.92-32 years). Allograft rejection occurred in 41% of patients (11/23 renal, 4/11 hepatic, and 1/5 cardiac transplantations), at similar rates for anti-CTLA-4 and anti-PD-1 therapy. The median time to rejection was 21 days (95% confidence interval 19.3-22.8 days). There were no associations between time since SOT and frequency, timing, or type of rejection. Overall, 31% of patients permanently discontinued CPIs because of allograft rejection. Graft loss occurred in 81%, and death was reported in 46%. Of the 12 patients with transplantation biopsies, nine (75%) had acute rejection, and five of these rejections were T cell-mediated. In melanoma patients, 36% responded to CPIs. CONCLUSIONS: SOT recipients had a high allograft rejection rate that was observed shortly after CPI initiation, with high mortality rates. Further studies are needed to optimize the anticancer treatment approach in these patients.

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.

Olaratumab in the management of advanced soft tissue sarcoma.

Olaratumab, the first-in-class anti-PDGFRα monoclonal antibody, has been contingently approved in combination with doxorubicin to treat adult patients with advanced soft tissue sarcoma for improving progression-free and overall survival. Olaratumab-doxorubicin combination has tolerable safety profile, which mimics that of doxorubicin monotherapy, with the exception of infusion-related reactions. Survival data of an ongoing confirmatory phase 3 trial are forthcoming to ascertain the optimal role of this product in the management algorithm of advanced soft tissue sarcoma. Active research is ongoing to identify biomarkers predictive of clinical benefit to olaratumab, to expand its utility to the pediatric population, and to explore its safety and efficacy in combination with other active regimens.

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.

Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis.

Background: Diarrhea and colitis are the second most common immune checkpoint inhibitor (ICPI)-induced adverse events. However, a comprehensive characterization of the endoscopic and histologic features of ICPI-induced diarrhea and colitis is lacking. Therefore, we aimed to describe endoscopic and histologic features of ICPI-induced gastrointestinal toxicities and to assess their association with patients' clinical characteristics and outcomes. Methods: We retrospectively reviewed records of 53 patients with ICPI-related diarrhea/colitis between 2011 and 2017. We collected data on demographics, diarrhea/colitis grade, treatment, and endoscopic and histologic findings. Long-term follow-up included repeat endoscopy findings, diarrhea recurrence, and overall survival. We compared groups by treatment, endoscopic and histologic findings, and constructed Kaplan-Meier survival curves. Results: Most patients had grade 2 or higher diarrhea (87%) and colitis (60%). Thirty-one patients were successfully treated with corticosteroids, and 22 additionally required infliximab. On endoscopy, 21 (40%) patients had ulcerations and 22 (42%) had nonulcerative inflammation. Patients with ulcerations had more steroid-refractory disease (P = 0.044) and high-grade diarrhea (P = 0.033). Histology showed mostly acute (23%) or chronic (60%) inflammation. During mean follow-up duration of 18.9 months, 19 (36%) developed recurrent diarrhea. Most patients had persistent endoscopic (8/13, 62%) and histologic (9/11, 82%) inflammation. Patients with higher-grade adverse events had improved survival. Higher-grade colitis was associated with endoscopic inflammation (P = 0.039), but grade of diarrhea was not associated with endoscopic inflammation or grade of colitis. Conclusion: 10.1093/ibd/izy104_video1izy104.video15808053084001.

Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma.

OBJECTIVE: To summarize the clinical development of avelumab and its clinical relevance in metastatic Merkel cell carcinoma (MCC). DATA SOURCES: An English-language literature search using PubMed was performed using the terms avelumab, anti-PD-1, anti-PD-L1, and MCC from January of 1950 to March 2018. Data were also obtained from package inserts, meeting abstracts, and clinical registries. STUDY SELECTION/DATA EXTRACTION: All relevant published articles of avelumab were reviewed. Clinical trial registries and meeting abstracts were used for information about ongoing trials. DATA SYNTHESIS: Avelumab is a fully human monoclonal antibody that inhibits programmed death ligand-1, which reverses T-cell exhaustion and induces antitumor responses. Avelumab is safe and effective in previously treated metastatic MCC based on a phase II trial of previously treated patients with objective response rates in 28 of 88 patients, including 10 complete responses and 19 partial responses. Median overall survival (OS) was 12.9 months, and 1-year progression-free survival and OS were 30% and 52%, respectively. Grade 3 treatment-related side effects included lymphopenia (2 patients), serum creatine phosphokinase increase (1 patient), aminotransferase elevation (1 patient), and serum cholesterol increase (1 patient). Relevance to Patient Care and Clinical Practice: This review outlines the pharmacology and clinical trial data for avelumab in metastatic MCC and guides clinicians on avelumab's place in therapy. CONCLUSIONS: Avelumab is the first Food and Drug Administration-approved medication for metastatic MCC and provides an advantage of durable responses and possibly improved tolerability compared with traditional platinum-based chemotherapy. Clinical trials are under way to expand its utility into the adjuvant and frontline settings.

Treatment patterns, efficacy and toxicity of regorafenib in gastrointestinal stromal tumour patients.

Regorafenib was approved as third-line therapy for advanced Gastrointestinal Stromal Tumour (GIST) at a starting dose of 160 mg daily 3 weeks on, 1 week off, based on improvement in progression free survival over placebo (4.8 vs. 0.9 months), but the response rate was low at 4.5%. Given the high toxicity rate in GIST patients, there is variability in the post-marketing dosing of regorafenib. We aimed to summarize our experience regarding prescribing patterns, efficacy and toxicity of regorafenib and determine the role of response assessment by Choi criteria in GIST patients. We included 28 patients who received regorafenib from our pharmacy. Baseline patient characteristics and treatment outcomes were recorded and an independent radiologist assessed response using Choi and RECIST. Seventy-nine percent of patients started at a 120 mg continuous daily dosing schedule, different from the standard intermittent dosing schedule. Grade 3/4 adverse events were experienced by 43% of patients. Median progression-free survival was 8.7 months. Continuous dosing with regorafenib at 120 mg daily is the preferred prescribing pattern and appears to be better tolerated and with comparable efficacy to the current standard dose. Similar to imatinib, the partial response rate for regorafenib by Choi (29%) was higher compared to RECIST (4%).

The efficacy and safety of adjuvant interferon-alfa therapy in the evolving treatment landscape for resected high-risk melanoma.

INTRODUCTION: Patients with resected stage II or III melanoma are at high risk of recurrence, with 5-year mortality rate of 40-60%. Adjuvant interferon-alfa has demonstrated a small RFS and OS benefit versus observation in this patient population. However, the adjuvant treatment landscape is evolving rapidly. Areas covered: This review aims to summarize the safety and efficacy profiles of adjuvant IFNα/PEG-IFNα, revisit the controversy surrounding its application, and reappraise its position in the rapidly changing treatment landscape of resected melanoma. A literature search using PubMed database was undertaken using search words melanoma, interferon-alfa, pegylated interferon-alfa, adjuvant therapy. Expert opinion: Currently, there is no international consensus regarding the optimal dosing schedule for adjuvant IFNα, but HD IFNα-2b remains the most widely used regimen. The AEs of HD IFNα-2b are substantial; however, toxicity management experience amassed over the past 2 decades has significantly improved safety. Many exciting studies are ongoing to examine the roles of immune checkpoint inhibitors and BRAF-targeted therapies in the adjuvant setting and will further delineate the role of adjuvant IFNα.

An Unusual Case of Central Retinal Vein Occlusion and Review of the Toxicity Profile of Regorafenib in GIST Patients.

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract with around 5000 new cases per year. Outcomes for patients with GIST dramatically improved after the development of tyrosine kinase inhibitors targeted against the aberrant signaling pathways that drive GIST oncogenesis. Majority of patients derive benefit from first-line imatinib, and the type of driver mutation is predictive of response. However, almost half of the patients eventually develop resistance to initial targeted therapy and further lines of treatment do not have the same impact. Regorafenib is an oral multi-kinase inhibitor approved as a third-line therapy for advanced GIST and though its efficacy is limited in comparison to imatinib, it has activity across the various driver mutation categories in GIST even in the setting of imatinib resistance. Herein, we describe a case of central retinal vein occlusion (CRVO) secondary to regorafenib and review regorafenib's efficacy and toxicity profile.

Managing Adverse Events With Immune Checkpoint Agents.

Immune checkpoint inhibitors (anti-cytotoxic T-lymphocyte antigen 4 and anti programmed cell death 1/programmed cell death 1 ligand antibodies) have shown impressive clinical activity in multiple cancer types. Despite achieving great clinical success, challenges and limitations of these drugs as monotherapy or various combinational strategies include the development of a unique set of immune-related adverse events (irAEs) that can be severe and even fatal. Therefore, identification of patients at risk, prevention, consistent communication between patients and medical team, rapid recognition, and treatment of irAEs are critical in optimizing treatment outcomes. This review focuses on the description of more common irAEs and provides a suggested approach for management of specific irAEs.

Clinical use of abiraterone in the treatment of metastatic castration-resistant prostate cancer.

Prostate cancer remains the most common type of cancer among men in the United States. Treatment for metastatic prostate cancer has improved significantly over the years with more and more agents improving overall survival. This review will address the pathophysiology of prostate cancer followed by the mechanism of action and the pharmacokinetic properties of abiraterone. The review will also discuss the role of abiraterone in the treatment of metastatic castrate-resistant prostate cancer.

Bortezomib-induced Sweet's syndrome confirmed by rechallenge.

Sweet's syndrome, also known as acute febrile neutrophilic dermatosis, is characterized predominantly by fever, elevated neutrophil count, and erythematous skin lesions composed of plaques and nodules that appear on upper extremities, face, or neck. The incidence of Sweet's syndrome in the general population is unknown due to the rarity of the condition and potential lack of reporting. Bortezomib, an antineoplastic agent that is the standard of care in patients with multiple myeloma, has been reported to be associated with Sweet's syndrome. We describe a 69-year-old man who developed Sweet's syndrome during his initial course (after cycle 4) of bortezomib for treatment of multiple myeloma; he again experienced Sweet's syndrome 3.5 years later when rechallenged with bortezomib (after cycle 5) for treatment of relapsed multiple myeloma. The patient's signs, symptoms, and biopsy results were identical during both presentations of Sweet's syndrome. In both instances, the syndrome spontaneously resolved without incident and without supportive treatment with corticosteroids or antihistamines. To our knowledge, this is the first case report of a patient who developed Sweet's syndrome during an initial course of treatment with bortezomib and after rechallenge with bortezomib for relapsed disease. As proteasome inhibitors continue to be a mainstay of therapy for both treatment and salvage therapy for multiple myeloma, this case demonstrates that rechallenge with bortezomib is an option for patients who develop Sweet's syndrome.