Side Effects Of Immune Checkpoint Inhibitors Research Articles

Immunotherapy for endocrine tumours: a clinician's perspective.

Immunotherapy has revolutionised the treatment of oncological patients, but its application in various endocrine tumours is rather limited and is mainly used when conventional therapies have failed. Immune checkpoint inhibitors (ICIs) have been employed in progressive adrenocortical carcinoma, primarily utilizing the anti-PD-L1 agent pembrolizumab, obtaining overall response rates ranging between 14% and 23%. In contrast, the response rate in phaeochromocytoma/paraganglioma was substantially less at 9%, considering the small number of patients treated. Similarly, the response rate in advanced differentiated thyroid carcinomas treated with pembrolizumab was also low at 9%, although the combination of ICIs with tyrosine kinase inhibitors showed higher efficacy. Low response rates to ICIs have also been observed in progressive medullary thyroid cancer, except in tumours with a high mutation burden (TMB). Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates, particularly in patients with high PD-L1 expression. Immunotherapy has also been used in a few cases of parathyroid carcinoma, showing limited antitumour effect. Pituitary carcinomas may exhibit a more favourable response to ICIs compared to aggressive pituitary tumours, particularly corticotroph tumours. Patients with advanced neuroendocrine tumours achieve an overall response rate of 15%, which varies according to the primary tumour site of origin, degree of differentiation, and therapeutic regimen utilised. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as programmed death 1/programmed death ligand 1 and TMB, as predictors for the response to immunotherapy. Furthermore, randomised prospective studies could provide more robust data on the efficacy and side effects of ICIs.

Immune-Related Adverse Events and Clinical Outcomes in Advanced Urothelial Cancer Patients Treated With Immune Checkpoint Inhibitors.

In advanced urothelial cancers (UC), immune checkpoint inhibitors (ICI) show promise as a durable therapy. Immune-related adverse events (irAEs), a side effect of ICIs, may serve as an indicator of beneficial response. We investigated the relationship between irAEs and clinical outcomes in patients with advanced UC who received ICI. In this retrospective study, we investigated 70 patients with advanced UC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on patients were collected through chart review. Cox's proportional hazard model and logistic regression were applied to estimate the association with overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). The possible lead-time bias was handled in extended Cox regression models. The median age of the cohort was 68. Over one-third (35%) of patients experienced an irAE, with skin being the most frequent organ involved (12.9%). Patients that experienced at least one irAE had significantly enhanced OS (HR: 0.38, 95% CI, 0.18-0.79, P = .009), PFS (HR: 0.27, 95% CI, 0.14-0.53, P < .001), and CB (OR: 4.20, 95% CI, 1.35-13.06, P = .013). Patients who experienced dermatologic irAEs also had significantly greater OS, PFS, and CB. Of patients with advanced UC that had undergone ICI therapy, those who had irAEs, especially dermatologic irAEs, had significantly greater OS, PFS, and CB. These results may suggest that irAE's may serve as an important marker of durable response to ICI therapy in urothelial cancer. The findings of this study need to be validated with larger cohort studies in the future.

Endocrine side effects of immune-checkpoint inhibitors in patients with malignant melanoma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma

ABSTRACT Glioblastoma (GB) is the most common primary brain tumor, which is characterized by low immunogenicity of tumor cells and prevalent immunosuppression in the tumor microenvironment (TME). Targeted local combination immunotherapy is a promising strategy to overcome these obstacles. Here, we evaluated tumor-cell specific delivery of an anti-PD-1 immunoadhesin (aPD-1) via a targeted adeno-associated viral vector (AAV) as well as HER2-specific NK-92/5.28.z (anti-HER2.CAR/NK-92) cells as components for a combination immunotherapy. In co-culture experiments, target-activated anti-HER2.CAR/NK-92 cells modified surrounding tumor cells and bystander immune cells by triggering the release of inflammatory cytokines and upregulation of PD-L1. Tumor cell-specific delivery of aPD-1 was achieved by displaying a HER2-specific designed ankyrin repeat protein (DARPin) on the AAV surface. HER2-AAV mediated gene transfer into GB cells correlated with HER2 expression levels, without inducing anti-viral responses in transduced cells. Furthermore, AAV-transduction did not interfere with anti-HER2.CAR/NK-92 cell-mediated tumor cell lysis. After selective transduction of HER2+ cells, aPD-1 expression was detected at the mRNA and protein level. The aPD-1 immunoadhesin was secreted in a time-dependent manner, bound its target on PD-1-expressing cells and was able to re-activate T cells by efficiently disrupting the PD-1/PD-L1 axis. Moreover, high intratumoral and low systemic aPD-1 concentrations were achieved following local injection of HER2-AAV into orthotopic tumor grafts in vivo. aPD-1 was selectively produced in tumor tissue and could be detected up to 10 days after a single HER2-AAV injection. In subcutaneous GL261-HER2 and Tu2449-HER2 immunocompetent mouse models, administration of the combination therapy significantly prolonged survival, including complete tumor control in several animals in the GL261-HER2 model. In summary, local therapy with aPD-1 encoding HER2-AAVs in combination with anti-HER2.CAR/NK-92 cells may be a promising novel strategy for GB immunotherapy with the potential to enhance efficacy and reduce systemic side effects of immune-checkpoint inhibitors.

S88 Immune Checkpoint-Inhibitors Are Associated With a Higher Risk of Cholangitis: A Nationwide Population-Wide Study

Introduction: Immune checkpoint-inhibitors (ICIs) improve the survival in certain cancers. However, side effects of ICIs might limit its use. Little is known about their biliary toxicity. Accordingly, we used a large database to investigate the epidemiology of ICI-induced cholangitis and describe underlying associations. Methods: A multi-institutional database (Explorys Inc, Cleveland, OH, USA), an aggregate of electronic health record data from 26 US healthcare systems was surveyed. A cohort of patients who were on ICIs (nivolumab, pembrolizumab, ipilimumab and atezolizumab) between 2011 and 2022 was identified. Subsequently, patients who developed new Systematized Nomenclature of Medicine-Clinical Terms diagnosis of cholangitis after taking ICIs were selected. The prevalence of ICI-induced cholangitis as calculated, and underlying associations were described. Results: There were 70,398,640 in the database of which 417,390 patients had a diagnosis of cholangitis. Among these patients, 260 patients had a prior history of ICI use. Compared to patients with history of ICI use who didn’t develop cholangitis (n=19,940), patients with ICI and cholangitis were more likely to be female [OR: 1.38; 95% CI 1.08–1.76]. There were no statistically significant age or race-based differences. Overall, patients who received any ICI had a significantly higher risk of cholangitis compared to the general population [OR: 1.28; 95% CI 1.13–1.45]. Patients who received Ipilimumab had the highest odds of developing ICI-induced cholangitis (Figure). Conclusion: In this large retrospective study, we found that patients taking ICI have a higher risk of cholangitis compared to the general population. Ipilimumab poses the greatest risk for ICI-induced for cholangitis. The risk of cholangitis should be discussed with all patients prior to initiating an ICI, as it may be a factor in choosing among ICIs.Figure 1.: Odds Ratio with 95% Confidence Interval of Immune Checkpoint Inhibitor-Induced Cholangitis Table 1. - Baseline Characteristics of Patients Receiving ICIs Variable Patients who received ICI Patients with Cholangitis who did not receive ICI ICI without Cholangitis ICI-Induced Cholangitis Age18 -65>65 7190 (37%)12,250 (63%) 90 (35%)160 (62%) 417,140 (59%)288,960 (41%) Female 8,130 (42%) 130 (50%) 475,350 (67%) RaceCaucasianOthers 16,150 (84%)3180 (16%) 220 (85%)40 (15%) Co-morbiditiesHypertensionT2DMHyperlipidemiaObesityCADCholedocholithiasis 19,330 (71%)5,560 (29%)11,830 (62%)4,510 (23%)5,720 (30%)1,570 (8%) 200 (77%)90 (35%)160 (62%)90 (35%)90 (35%)170 (65%) 382,890 (54%)176,910 (25%)329,520 (47%)236,120 (33%)130,060 (18%)532,590 (75%)

Management of Immune-Related Adverse Events from Immune-Checkpoint Inhibitors in Advanced or Metastatic Renal Cell Carcinoma.

Simple SummaryToday, most patients with metastatic renal cancer receive systemic treatment with so-called immune-checkpoint inhibitors that shall activate a patient’s immune system. For patients without prior therapy, these therapeutic agents are combined with a second immunotherapeutic drug or with a therapeutic agent intended to reduce the tumour’s blood supply, namely tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR-TKI). Both parts of the combination therapy cause side effects that need to be treated and handled differently depending on the therapeutic agent responsible for the complaints. Therefore, it is of crucial importance to recognize the side effects and relate them to the right therapeutic agent. Within this review we describe the most frequent immune-related side effects of immune-checkpoint inhibitors, especially focusing on their distinction from side effects caused by VEGFR-TKI. Additionally, we explain the management of these complaints as well as their impact on the therapy.Immune checkpoint inhibitors (ICI) are now, among other cancers, routinely used for the treatment of advanced or metastatic renal cell carcinoma (mRCC). In mRCC various combinations of ICIs and inhibitors of the vascular epidermal growth factor receptor tyrosine kinase (VEGFR-TKIs) as well as dual checkpoint inhibition (nivolumab + ipilimumab), the latter for patients with intermediate and poor risk according to IMDC only (international metastatic renal cell carcinoma database consortium), are now standard of care in the first line setting. Therefore, a profound understanding of immune-related adverse events (irAE) and the differential diagnosis of adverse reactions caused by other therapeutic agents in combination therapies is of paramount importance. Here we describe prevention, early diagnosis and clinical management of the most relevant irAE derived from ICI treatment focusing on the new VEGFR-TKI/ICI combinations.

Small bowel hemorrhage from check point inhibitor enteritis: a case report

BackgroundThere is rising utilization of immune checkpoint inhibitors (ICI) for a growing number of metastatic malignancies. While gastrointestinal side effects of ICI are common, isolated ICI-induced enteritis leading to small bowel hemorrhage is rare.Case presentationA 71-year-old man with a previously resected right colon adenocarcinoma on atezolizumab and recently treated Clostridioides difficile presented with acute on chronic abdominal pain and non-bloody diarrhea. A CT scan revealed enteritis of the duodenum and jejunum without colitis. Initial endoscopic work-up revealed many clean-based non-bleeding duodenal ulcers to the third portion of the duodenum and normal rectosigmoid mucosa. The patient initially improved on steroids but was readmitted on day after discharge with hematochezia and hemorrhagic shock. Repeat CT showed improvement in enteritis; however, repeat push enteroscopy revealed multiple duodenal and jejunal ulcers, two with visible vessels requiring endoscopic intervention. He continued to have significant hemorrhage requiring transfusions despite IV methylprednisolone. Conventional angiogram revealed multiple sites of active extravasation, and he underwent small bowel resection and subsequent IR embolization due to persistent bleeding. He was then started on infliximab 10 mg/kg with resolution of his small bowel hemorrhage and diarrhea.ConclusionsSevere isolated ICI-enteritis is rare and can lead to clinically significant gastrointestinal hemorrhage. Patients with severe ICI-enteritis on endoscopy should be carefully monitored for steroid refractory disease for consideration of step-up therapy such as infliximab.

Effect of dermatological consultation on survival in patients with checkpoint inhibitor-associated cutaneous toxicity.

Cutaneous immune-related adverse events (cirAEs) are a common side-effect of immune checkpoint inhibitors (ICIs). However, prior work examining these toxicities in detail has considered only the fraction of events evaluated by dermatologists. Associations between dermatology referral, cirAE treatment and survival outcomes remain underexplored across care settings. To comprehensively categorize cirAE patterns among all patients treated with immunotherapy at our institution, and to evaluate: (i) the effect of dermatology referral on cirAE treatment and (ii) the impact of cirAE treatment on survival. This was a retrospective cohort analysis of patients with cancer who initiated ICI therapy between 1 January 2016 and 8 March 2019 and developed one or more cirAEs, as screened for using International Classification of Diseases 10th revision codes and confirmed via manual chart review (n=358). All relevant information documented prior to 31 March 2020 was included. CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred (odds ratio 6·08, P<0·001). Patients who received any cirAE treatment had improved progression-free survival [hazard ratio (HR) 0·59, P=0·001] and overall survival (HR 0·58, P=0·007) compared with those who did not. CirAEs evaluated by dermatologists were significantly more likely to be treated than cirAEs that were not referred, and patients who received any treatment for a cirAE had improved survival outcomes.

PD-L1 siRNA Theranostics With a Dextran Nanoparticle Highlights the Importance of Nanoparticle Delivery for Effective Tumor PD-L1 Downregulation.

PurposeThe inhibition of immune checkpoints such as programmed cell death ligand-1 (PD-L1/CD274) with antibodies is providing novel opportunities to expose cancer cells to the immune system. Antibody based checkpoint blockade can, however, result in serious autoimmune complications because normal tissues also express immune checkpoints. As sequence-specific gene-silencing agents, the availability of siRNA has significantly expanded the specificity and range of “druggable” targets making them promising agents for precision medicine in cancer. Here, we have demonstrated the ability of a novel biodegradable dextran based theranostic nanoparticle (NP) to deliver siRNA downregulating PD-L1 in tumors. Optical imaging highlighted the importance of NP delivery and accumulation in tumors to achieve effective downregulation with siRNA NPs, and demonstrated low delivery and accumulation in several PD-L1 expressing normal tissues.MethodsThe dextran scaffold was functionalized with small molecules containing amine groups through acetal bonds. The NP was decorated with a Cy5.5 NIR probe allowing visualization of NP delivery, accumulation, and biodistribution. MDA-MB-231 triple negative human breast cancer cells were inoculated orthotopically or subcutaneously to achieve differences in vascular delivery in the tumors. Molecular characterization of PD-L1 mRNA and protein expression in cancer cells and tumors was performed with qRT-PCR and immunoblot analysis.ResultsThe PD-L1 siRNA dextran NPs effectively downregulated PD-L1 in MDA-MB-231 cells. We identified a significant correlation between NP delivery and accumulation, and the extent of PD-L1 downregulation, with in vivo imaging. The size of the NP of ~ 20 nm allowed delivery through leaky tumor vasculature but not through the vasculature of high PD-L1 expressing normal tissue such as the spleen and lungs.ConclusionsHere we have demonstrated, for the first time, the feasibility of downregulating PD-L1 in tumors using siRNA delivered with a biodegradable dextran polymer that was decorated with an imaging reporter. Our data demonstrate the importance of tumor NP delivery and accumulation in achieving effective downregulation, highlighting the importance of imaging in siRNA NP delivery. Effective delivery of these siRNA carrying NPs in the tumor but not in normal tissues may mitigate some of the side-effects of immune checkpoint inhibitors by sparing PD-L1 inhibition in these tissues.

Awareness of immune-related adverse events among medical residents in a community hospital.

e15154 Background: Immunotherapy has paved the way for new frontiers in the management of certain advanced cancers. Immune checkpoint inhibitors (ICI) have substantially improved prognosis in patients with advanced malignancy. Primary targets for ICIs include programmed cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1) and Cytotoxic T-lymphocyte-associated antigen 4(CTLA-4). These treatments have a wide range of adverse effects distinct from traditional chemotherapy regimens. We conducted a survey to assess the awareness of immune-related adverse events (IRAE) among medical residents in a community hospital. Methods: Internal medicine residents in a community hospital were given a survey of 10 questions related to IRAEs. A total of 40 responses were collected and analyzed. Results: 22.50% respondents were aware that nephrotoxicity is not a common side effect of immunotherapy. 35% were aware that cutaneous toxicities are the most common IRAEs. 42.50% were aware that hair loss is not a common side effect of ICIs. 42.50% were aware that patients do not need pretreatment with anti-emetics before immunotherapy. 45% were aware that the onset of hepatotoxicity is usually not seen within the first week of starting immunotherapy. 50% were aware that immunotherapy is associated with the development of pneumonitis. 62.5% were aware that steroids formed mainstay of treatment in IRAEs. 65% were aware that immunotherapy is associated with thyroid-related side effects. 67.5% were aware that patients with pre-existing autoimmune conditions are at greater risk for immune-related adverse effects. 70% were aware that immune related colitis was not treated with antibiotics. Conclusions: With the rapid advancement and use of immunotherapy the incidence of IRAEs is increasing. Involvement of single or multiple organ systems as well as flare of previously well controlled autoimmune disease can add to the challenge. As we gain more experience, long term data will emerge to help predict at-risk patients. This is a dynamic area of research and new treatments are under development. 6/10 questions were answered correctly by less than 50% respondents and 4/10 were answered correctly by 50-70% respondents. At present no data is available to gauge awareness regarding IRAEs among internists. Our survey suggests a lack of awareness among medical residents on many fronts. Lack of awareness leads to inappropriate treatment and prolonged hospital stay. Active efforts need to be taken to educate residents regarding immunotherapy and IRAEs to achieve better patient outcomes.

Abstract 2338: Checkpoint inhibitor-induced colitis shares mucosal histopathological features with inflammatory bowel and graft-versus-host disease

Abstract Background: Checkpoint inhibitor-induced colitis (CIC) is a severe side-effect of immune-checkpoint inhibitors (ICI). Its pathophysiology is poorly understood, impairing improvement of prevention and treatment strategies. CD4+ and CD8+ T cells and CD68+ macrophages are thought to be critical in colitis development. Studies suggest that CIC is histopathologically similar to inflammatory bowel disease (IBD) and acute graft-versus-host disease (aGVHD) colitis. However, the histopathology of these entities has not been directly compared. We aimed to improve knowledge on CIC by performing a direct immunohistochemical comparison of CIC, IBD and aGVHD. Methods: Archival formalin fixed paraffin-embedded colon biopsies obtained during routine diagnostic procedures from consecutive, eligible, treatment-naïve patients with CIC, IBD and aGVHD (all n=20) were studied. Biopsies from patients without histopathological abnormalities served as controls (n=20). Immunohistochemical staining was performed for CD4+ and CD8+ T cells and CD68+ macrophages. In each biopsy 3 mucosal areas with highest immune cell density were selected for cell counting. The number of cells/hotspot were classified as 0-10, 10-50, 50-100, 100-150 and &amp;gt;150. Next, the distribution of these cells was studied and compared between patient groups. We used descriptive statistics to depict and compare cell counts and infiltration patterns among patient groups. Results: In CIC higher CD4+ and CD8+ T cell density (100-150 cells/hotspot in most patients) was observed compared to IBD, aGVHD and controls (50-100 cells/hotspot in most patients in each group). In contrast to controls, some IBD (12%) and aGVHD (15%) patients had a CD4+ T cell count of 100-150 cells/hotspot and some IBD (20%) and aGVHD (21%) patients had a CD8+ T cell count of 100-150 cells/hotspot. CIC, IBD aGVHD and controls shared a similar CD68+ macrophage count (50-100 cells/hotspot in most patients in each group). During cell counting we noted that cells infiltrated the superficial (subepithelium) and deep (lamina propria and muscularis mucosae) layers of the mucosa with either a scattered or patchy distribution. We recognized 4 distribution patterns: A) superficial diffuse, deep scattered/patchy; B) superficial scattered/patchy, deep diffuse; C) superficial and deep diffuse; D) superficial and deep scattered/patchy. The most prevalent infiltration pattern of CD4+ T cells was D in CIC patients (74%), C in IBD patients (47%), B in aGVHD patients (54%) and A in control patients (83%). The most prevalent infiltration pattern of CD8+ T cells was D in CIC (45%), and A in IBD (85%), aGVHD (63%) and all control patients. In most patients, CD68+ macrophages occurred in pattern A (56% of CIC, 58% of IBD, 59% of aGVHD, 100% of controls). Conclusion: CIC has a distinct immunohistopathological pattern that shares key elements with both IBD and aGVHD. Citation Format: Sara Hone Lopez, Gursah Kats-Ugurlu, Liesbeth De Vries, Marco De Groot, Marijn Visschedijk, Mathilde Jalving, Jacco de Haan. Checkpoint inhibitor-induced colitis shares mucosal histopathological features with inflammatory bowel and graft-versus-host disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2338.

The characteristics of nivolumab-induced colitis: an evaluation of three cases and a literature review

BackgroundThe use of immune-checkpoint inhibitors in cancer treatment has become increasingly common, resulting in an increase in the incidence of related side effects. Diarrhoea and colitis have been previously documented as gastrointestinal tract-related side effects of immune-checkpoint inhibitors. Although PD-1/PD-L1 inhibitors produce fewer side effects than CTLA-4 inhibitors, diarrhoea and colitis continue to be reported. However, little is known about the endoscopic features associated with PD-1/PD-L1 inhibitors. In this report, we describe three cases of colitis induced by a PD-1 inhibitor nivolumab. These cases showed endoscopic findings characteristic of ulcerative colitis (UC). Treatment was in accordance with UC therapy, which resulted in beneficial outcomes.Case presentationThree patients with lung cancer treated with nivolumab presented with diarrhoea with (case 2) or without haematochezia (cases 1 and 3). Treatment with nivolumab was ceased and colonoscopy was performed, revealing endoscopic features similar to those of UC. These patients were diagnosed with nivolumab-induced colitis. Case 1 was treated with mesalazine, whereas cases 2 and 3 were treated with corticosteroids. Subsequently, their symptoms improved.ConclusionsNivolumab-induced colitis exhibited similar characteristics to UC. Treatment was similar to that for UC and was successful.

Endocrinological side-effects of immune checkpoint inhibitors.

Three mAbs targeting immune checkpoint proteins are available for the treatment of patients with melanoma, lung, and kidney cancer, and their use will likely expand in the future to additional tumor types. We here update the literature on the incidence and pathophysiology of endocrine toxicities induced by these agents, and discuss management guidance. Immune checkpoint inhibition may trigger autoimmune syndromes involving different organs, including several endocrine glands (pituitary, thyroid, adrenals, and endocrine pancreas). Hypophysitis is more frequently associated with ipilimumab, whereas the incidence of thyroid dysfunction is higher with nivolumab/pembrolizumab. Primary adrenal insufficiency can rarely occur with either treatment. Autoimmune diabetes is very rare. As hypophysitis and adrenalitis may be life-threatening, endocrinological evaluation is essential particularly in patients developing fatigue and other symptoms consistent with adrenal insufficiency. Corticosteroids should be promptly used when hypophysitis-induced adrenal insufficiency or adrenalitis are diagnosed, but not in thyroiditis or diabetes. No impact of corticosteroids on the efficacy/activity of immune checkpoint-inhibiting drugs is reported. Hormonal deficiencies are often permanent. In absence of predicting factors, accurate information to patients provided by the oncology care team is essential for early diagnosis and to limit the consequences of checkpoint inhibition-related endocrine toxicity.