Immune checkpoint therapy-current perspectives and future directions.

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients. Varying response rates across tumor types and the need for predictive biomarkers to optimize patient selection to maximize efficacy and minimize toxicities prompted efforts to unravel immune and non-immune factors regulating the responses to ICT. This review highlights the biology of anti-tumor immunity underlying response and resistance to ICT, discusses efforts to address the current challenges with ICT, and outlines strategies to guide the development of subsequent clinical trials and combinatorial efforts with ICT.

Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy.

Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.

A review of cancer immunotherapy toxicity.

Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune-modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.

Post-immunotherapy CTLA-4 Ig treatment improves antitumor efficacy.

Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether CTLA-4 or PD-1 blockade. The frequency of Tregs was significantly decreased with CTLA-4 Ig. The resulting increased CD8/Treg ratio potentially underlies the enhanced efficacy of ICT followed by CTLA-4 Ig. This paradoxical mechanism shows that a CTLA-4 Ig regimen shown to reduce irAE severity does not compromise antitumor efficacy.

Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses.

Immune checkpoint inhibitors (ICIs) are potentially life-saving cancer therapies that can trigger immune-related adverse events (irAEs). irAEs can impact any organ and range in their presentation from mild side effects to life-threatening complications. The relationship between irAEs and antitumor immune responses is nuanced and may depend on the irAE organ, the tumor histology, and the patient. While some irAEs likely represent an immune response against antigens shared between tumor cells and healthy tissues, other irAEs may be entirely unrelated to antitumor immune responses. Clinical observations suggest that low-grade irAEs have a positive association with responses to ICIs, but the correlation between severe irAEs and clinical benefit is less clear. Currently, severe irAEs are typically treated by interrupting or permanently discontinuing ICI treatment and administering empirically selected systemic immunosuppressive agents. However, these interventions could potentially diminish the antitumor effects of ICIs. Efforts to understand the mechanistic relationship between irAEs and the tumor microenvironment have yielded meaningful insights and nominated therapeutic targets for irAE management that may preserve or even boost ICI efficacy. We explore the clinical and molecular relationship between irAEs and antitumor immunity as well as the role that irAE treatments may play in shaping antitumor immune responses.

CD4 T cells and toxicity from immune checkpoint blockade.

Immune-related toxicities, otherwise known as immune-related adverse events (irAEs), occur in a substantial fraction of cancer patients treated with immune checkpoint inhibitors (ICIs). Ranging from asymptomatic to life-threatening, ICI-induced irAEs can result in hospital admission, high-dose corticosteroid treatment, ICI discontinuation, and in some cases, death. A deeper understanding of the factors underpinning severe irAE development will be essential for improved irAE prediction and prevention, toward maximizing the benefits and safety profiles of ICIs. In recent work, we applied mass cytometry, single-cell RNA sequencing, single-cell V(D)J sequencing, bulk RNA sequencing, and bulk T-cell receptor (TCR) sequencing to identify pretreatment determinants of severe irAE development in patients with advanced melanoma. Across 71 patients separated into three cohorts, we found that two baseline features in circulation-elevated activated CD4 effector memory T-cell abundance and TCR diversity-are associated with severe irAE development, independent of the affected organ system within 3 months of ICI treatment initiation. Here, we provide an extended perspective on this work, synthesize and discuss related literature, and summarize practical considerations for clinical translation. Collectively, these findings lay a foundation for data-driven and mechanistic insights into irAE development, with the potential to reduce ICI morbidity and mortality in the future.

Tissue-resident memory T cells in immunotherapy and immune-related adverse events by immune checkpoint inhibitor.

Tissue-resident memory T cells (TRM) are a specialized subset of T cells that reside in tissues and provide long-term protective immunity against pathogens that enter the body through that specific tissue. TRM cells have specific phenotype and reside preferentially in barrier tissues. Recent studies have revealed that TRM cells are the main target of immune checkpoint inhibitor immunotherapy since their role in cancer immunosurveillance. Furthermore, TRM cells also play a crucial part in pathogenesis of immune-related adverse events (irAEs). Here, we provide a concise review of biological characteristics of TRM cells, and the major advances and recent findings regarding their involvement in immune checkpoint inhibitor immunotherapy and the corresponding irAEs.

Immune-related adverse events requiring hospitalization in patients with lung cancer: implications and insights.

BACKGROUND: Immune checkpoint inhibitors (ICI) are associated with a distinct spectrum of toxicities. Data on irAE hospitalization rates and clinical course of patients with thoracic malignancies are lacking. METHODS: Patients with advanced thoracic malignancy treated with ICI (2/2016 to 6/2021) were retrospectively identified. Demographic and clinical data of confirmed irAE hospitalizations were extracted from the medical record and a descriptive analysis was performed. RESULTS: From February 2016 to June 2021, 1312 patients with thoracic malignancy received ICI (monotherapy, combination with 2nd ICI or other agents) with 102 patients (7.7%) hospitalized for irAEs. Treatment intent was first-line therapy in most patients (N = 50, 49%) with 9% (n = 9) receiving adjuvant ICI (N = 9). Sixty patients (59%) received ICI alone, 32% (N = 33) chemo plus immunotherapy, and 7% (N = 7) dual ICI. The median age on admission was 68 years. The median time between ICI initiation and admission was 64 days (1-935 days). Pneumonitis (32.3%; 33/102) was the most frequent indication for admission followed by gastroenterocolitis (19.6%; 20/102), hepatitis (12.7%; 13/102), myo/pericarditis (9.8%; 10/102), and endocrinopathies (9.8%; 10/102). Multi-organ toxicity occurred in 36% (N = 37) of patients. Overall, 85.2% (87/102) of patients received systemic corticosteroids and 17.6% (18/102) required additional lines of immunosuppression. The median length of hospitalization stay was 7 days (2-28 days) with a 25.5% (n = 26) readmission rate within 60 days and an 11.8% (n = 12) in house mortality rate. CONCLUSIONS: Severe irAE requiring inpatient admission, although infrequent, results in considerable morbidity, mortality, and healthcare utilization. Pneumonitis was the most common irAE requiring inpatient management in our patient population with a significant risk of mortality despite the use of guideline-directed systemic immunosuppression. This study highlights the continued need for collaborative efforts amongst medical specialties for improving the diagnostic and therapeutic management of patients with irAEs.

Tocilizumab provides dual benefits in treating immune checkpoint inhibitor-associated arthritis and preventing relapse during ICI rechallenge: the TAPIR study.

BACKGROUND: The aim of this retrospective study was to evaluate the dual efficacy of tocilizumab (TCZ) in the treatment of immune checkpoint inhibitor (ICI)-associated arthritis (ICI-AR) and the prevention of relapses after rechallenge. PATIENTS AND METHODS: We identified 26 patients with ICI-AR. The primary objectives were to evaluate TCZ efficacy in ICI-AR treatment and as secondary prophylaxis during ICI rechallenge in 11 of them. Patients received prednisone (CS) at 0.3 mg/kg tapered at 0.05 mg/kg weekly for six weeks. TCZ was administered at a dose of 8 mg/kg every 2 weeks. In the subgroup receiving secondary prophylaxis (rechallenge n = 11), TCZ was reintroduced with the same regimen concurrently with ICI rechallenge, and without the addition of CS. A control group of patients (rechallenge n = 5) was rechallenged without TCZ. Secondary endpoints included post-rechallenge evaluation of ICI duration, reintroduction of CS >0.1 mg/kg/day, ICI-AR flares, and disease control rate. RESULTS: The median age of the patients was 70 years. The median follow-up from ICI initiation was 864 days. Among the 20 patients treated with TCZ for ICI-AR, all (100%) achieved an ACR70 response rate, defined as greater than 70% improvement, at 10 weeks. Some 81% of these patients achieved steroid-free remission after 24 weeks on TCZ. The median follow-up period was 552 days in rechallenged patients. The results demonstrated a reduction in ICI-AR relapses upon ICI rechallenge in patients receiving TCZ prophylaxis compared with patients who did not receive prophylaxis (17% versus 40%). The requirement for CS was completely abolished with prophylaxis (0% versus 20%), and the mean duration of ICI treatment was notably extended from 113 to 206 days. The 12-month post-rechallenge outcomes showed a disease control rate of 77%. During TCZ prophylaxis, CXCL9 remained elevated, showing no decline from their concentrations at the onset of ICI-AR. CONCLUSIONS: In addition to treating ICI-AR, TCZ demonstrated efficacy as a secondary prophylactic agent, preventing the recurrence of symptoms and lengthening ICI treatment duration after ICI rechallenge.

Peripheral blood immune parameters, response, and adverse events after neoadjuvant chemotherapy plus durvalumab in early-stage triple-negative breast cancer.

PURPOSE: We evaluated T- and B-cell receptor (TCR and BCR) repertoire diversity and 38 serum cytokines in pre- and post-treatment peripheral blood of 66 patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy plus durvalumab and assessed associations with pathologic response and immune-related adverse events (irAEs) during treatment. METHODS: Genomic DNA was isolated from buffy coat for TCR and BCR clonotype profiling using the Immunoseq platform and diversity was quantified with Pielou's evenness index. MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel was used to measure serum cytokine levels, which were compared between groups using moderated t-statistic with Benjamini-Hochberg correction for multiple testing. RESULTS: TCR and BCR diversity was high (Pielou's index > 0.75) in all samples. Baseline receptor diversities and change in diversity pre- and post-treatment were not associated with pathologic response or irAE status, except for BCR diversity that was significantly lower post-treatment in patients who developed irAE (unadjusted p = 0.0321). Five cytokines increased after treatment in patients with pathologic complete response (pCR) but decreased in patients with RD, most prominently IL-8. IFNγ, IL-7, and GM-CSF levels were higher in pre-treatment than in post-treatment samples of patients who developed irAEs but were lower in those without irAEs. CONCLUSION: Baseline peripheral blood cytokine levels may predict irAEs in patients treated with immune checkpoint inhibitors and chemotherapy, and increased post-treatment B-cell clonal expansion might mediate irAEs.

Comparing anti-tumor and anti-self immunity in a patient with melanoma receiving immune checkpoint blockade.

BACKGROUND: Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. METHODS: Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. RESULTS: While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. CONCLUSIONS: This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

Pituitary-related immune adverse events induced by programmed death Protein-1 inhibitors differ clinically from hypophysitis.

OBJECTIVE: We aimed to elucidate the clinical features of pituitary immune-related adverse events (irAEs) induced by PD-1 inhibitors in a Chinese cohort and the previous literatures. PATIENTS AND DESIGN AND MEASUREMENTS: We retrospectively analysed the clinical manifestations, laboratory examination findings, imaging features and treatments of 14 patients with pituitary irAEs caused by PD-1 inhibitors in our cohort. In addition, we searched PubMed for all English articles on pituitary irAEs induced by PD-1 inhibitors published from 1950 to 2023. A total of 47 articles were included, and the clinical characteristics of 94 patients with pituitary irAEs induced by PD-1 inhibitors in these literatures were compared to the characteristics of our cohort. RESULTS: Among the 14 patients in our cohort with pituitary irAEs induced by PD-1 inhibitors, 12 patients (85.71%, 12/14) exhibited isolated ACTH deficiency (IAD), 100.0% (14/14) of the central adrenocortical insufficiency, and 2 patients showed more than one hypothalamic-pituitary axis injury (14.29%, 2/14). Pituitary magnetic resonance imaging in all the 14 patients showed no pituitary enlargement. In previous studies we reviewed, 82.98% of the total (78/94) presented with pituitary irAEs as IAD, 100.0% (94/94) of the central adrenocortical insufficiency, and 78.33% of the patients showed no abnormality of the pituitary gland (47/60). The pituitary irAEs caused by PD-1 inhibitors did not involve typical manifestations of hypophysitis, such as pituitary enlargement, headache, visual field defects, and multiple pituitary function impairments in our cohort and the previous literatures. CONCLUSION: In our study, pituitary immune-related adverse reactions induced by PD-1 inhibitors mainly manifested isolated ACTH deficiency rather than hypophysitis.

Correlation between immune-related adverse events and efficacy of PD-(L)1 inhibitors in small cell lung cancer: a multi-center retrospective study.

BACKGROUND: Patients receiving PD-(L)1 inhibitors frequently encounter unusual side effects known as immune-related adverse events (irAEs). However, the correlation of irAEs development with clinical response in small cell lung cancer (SCLC) is unknown. METHOD: This retrospective study enrolled 244 stage IV SCLC patients who receiving PD-(L)1 inhibitors from 3 cancer centers. The correlation of irAEs with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: 140 in 244 (57%) patients experienced irAEs, with 122 (87.1%) experiencing one and 18 (12.9%) experiencing two or more. Compared to patient without irAEs, those developing irAEs had higher ORR (73.6% vs. 52.9%, P < 0.001) and DCR (97.9% vs. 79.8%, P < 0.001), as well as prolonged median PFS (8.8 vs. 4.5 months, P < 0.001) and OS (23.2 vs. 21.6 months, P < 0.05). Among the different spectra of irAEs, thyroid dysfunction, rash, and pneumonitis were the most powerful indicator for improved PFS. When analyzed as a time-dependent covariate, the occurrence of irAEs was associated with significant improvement in PFS rather than in OS. Furthermore, patients experiencing multisystem irAEs displayed a longer PFS and OS compared with single-system irAEs and the irAE-free ones. IrAEs grade and steroid use did not impact the predictive value of irAEs on PFS. CONCLUSION: The presence of irAEs predicts superior clinical benefit in SCLC. Patients who develop multi-system irAEs may have an improved survival than those developed single-system irAEs and no-irAEs. This association persists even when systemic corticosteroids were used for irAEs management.

Immune Checkpoint Inhibitors-Associated Diabetes and Ketoacidosis Were Found in FDA Adverse Event Reporting System: A Real-World Evidence Database Study.

OBJECTIVE: To investigate the risk of developing diabetes and ketoacidosis in clinical patients with immune checkpoint inhibitors (ICIs). METHODS: We looked in the FDA Adverse Event Reporting System for reports of ICIs-associated diabetes mellitus (DM) and ketoacidosis between January 2004 and March 2022. We explored the signals using fourfold table-based proportional imbalance algorithms. Patient characteristics, country distribution, and outcomes of adverse reactions were described. Kruskal-Wallis test was used to compare the time of onset and prognosis of adverse reactions. RESULTS: A total of 2110 reports of ICIs-related DM were included in the study. The largest number of reports was from Japan (752, 35.64%), followed by the United States and France (624, 29.57%; 183, 8.67%). Seven drugs detected signals of DM and ketoacidosis according to 4 proportional imbalance algorithms: nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab. Diabetes and ketoacidosis generally occurred early in the course of ICIs treatment, the median time to event onset was 144.5 (interquartile range 27-199) days. ICIs-related diabetes and ketoacidosis events resulted in 934 major medical events (44.3%), 524 hospitalizations (24.8%), 60 life-threatening events (2.8%), 42 deaths (2.0%), and 39 disability events (1.8%). CONCLUSION: The study reveals the risk and characteristics of diabetes and ketoacidosis associated with ICIs, which may provide evidence for postmarketing evaluation. Careful consideration should be given to the possibility of an increased risk of diabetes and ketoacidosis after using ICIs, and careful monitoring for diabetes and ketoacidosis is recommended.

Clinical characteristics and potential biomarkers of thyroid and pituitary immune-related adverse events.

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) in several organs including endocrine glands. Among endocrine irAEs, thyroid and pituitary irAEs are frequently observed, followed by primary adrenal insufficiency, insulin-dependent diabetes mellitus, and hypoparathyroidism. These conditions could lead to life-threatening consequences, such as adrenal crisis and diabetic ketoacidosis. On the other hand, several types of irAEs including thyroid and pituitary irAEs are reported to be associated with better overall survival. Therefore, it is important to understand and manage endocrine irAEs, which differ depending on the ICI regimen used. In this review, we describe the clinical features, potential biomarkers, management strategies, and possible mechanisms of thyroid and pituitary irAEs.

Development of Vogt-Koyanagi-Harada disease-like uveitis during treatment by anti-programmed death-1 antibody: a case report.

BACKGROUND: Several immune checkpoint inhibitors (ICIs) have been linked to the occurrence of Vogt-Koyanagi-Harada disease (VKHD)-like uveitis. Among the ICIs, there has been no report of immune-related adverse events (irAEs) caused by a new programmed death protein-1(PD-1) monoclonal antibody (Toripalimab). CASE PRESENTATION: This paper presents a case of VKHD-like uveitis that arose following Toripalimab therapy for urothelial cancer of the bladder, and the patient experienced symptoms 10 days after the final dosage of 20 months of medication treatment. This patient with bladder uroepithelial carcinoma had severe binocular acute panuveitis with exudative retinal detachment after receiving Toripalimab therapy. Binocular VKHD-like uveitis was suggested as a diagnosis. Both eyes recovered after discontinuing immune checkpoint inhibitors and local and systemic corticosteroid treatment. CONCLUSIONS: This report suggests that VKHD-like uveitis can also occur in patients receiving novel PD-1 antibodies and the importance of paying attention to eye complications in patients receiving treatment over a long period.

Digital ischemia: a rare immune-related adverse event of immune checkpoint inhibitors-case report and review of the literature.

Immune checkpoint inhibitors (ICIs) play a crucial role in treating various cancers. While ICIs are invaluable in the fight against different cancers, they also pose the risk of immune-related adverse events (irAEs), which can range widely in symptoms and severity. Rheumatologic complications, including digital ischemia, are among the irAEs. While rare, they require early detection for effective management. The aim of the study is to present a case report on digital ischemia related to immunotherapy and to conduct a literature review on relevant cases. We present a case involving a patient from our oncology department who developed, pericarditis, digital ischemia and anti-centromere antibodies during immunotherapy with pembrolizumab for non-small cell lung cancer (NSCLC). We collaborated with our rheumatology department to initiate treatment, including corticosteroids, iloprost, and mycophenolate mofetil. Through the follow-up, the patient showed clinical improvement. A literature review identified only 10 relevant articles, highlighting the rarity of digital ischemia as an irAE. Corticosteroids and vasodilators were commonly used treatments, with amputation unavoidable in 40% of cases. IrAEs are becoming more common due to the widespread use of ICIs. For this reason, it is crucial to diagnose and treat rare IrAEs, such as digital ischemia, as early as possible to improve outcomes.

Immune-related adverse effects: Recognition and initiation of appropriate treatment in cancer patients on immunotherapy.

PURPOSE: Delayed or improper identification of immune-related adverse events (IRAEs) during cancer treatment can impact time to receive proper treatment. This study describes rates of IRAE recognition and appropriate treatment in adult patients with cancer at a community teaching hospital. METHODS: This single-center, retrospective, cohort study evaluated rates of proper IRAE treatment in conjunction with National Comprehensive Cancer Network (NCCN) guidelines. Secondary outcomes included time from presentation to IRAE diagnosis and hospital readmissions/repeat emergency department (ED) visits following initial admission for IRAE. Retrospective chart review assessed IRAE presentation including common terminology criteria for adverse event (CTCAE) grading and treatment choices. RESULTS: Fifteen subjects included in this study contributed to 21 encounters with noted IRAE. Over half (52.4%) of the encounters received proper IRAE treatment (e.g. correct drug, dose, route, frequency, or therapy duration). Nearly 22% of total actionable components were improper, occurring more often in patients with colitis, pneumonitis, and hepatitis. Median time to IRAE diagnosis was approximately 3.5 days, with the longest being 24 days. There were eight all-cause rehospitalizations one year after initial IRAE presentation, with four directly IRAE-related. Most (75%) IRAE-related rehospitalizations occurred with colitis. Seven ED return visits were also noted. CONCLUSION: Many IRAEs were misdiagnosed and/or received improper treatment resulting in increased rehospitalization/return ED visit rates. The importance of medical oncology involvement (e.g. medical oncology consult at time of admission and/or notification of primary oncologist) in IRAE management in the hospital or ED was also stressed. Organizations may benefit from systematic improvements and staff education to improve patient outcomes and prevent readmissions.

Balancing Tumor Immunotherapy and Immune-Related Adverse Events: Unveiling the Key Regulators.

Tumor immunotherapy has emerged as a promising approach in cancer treatment in recent years, offering vast potential. This method primarily involves targeting and inhibiting the suppressive checkpoints present in different immune cells to enhance their activation, ultimately leading to tumor regression. However, tumor cells exploit the surrounding immune cells and tissues to establish a tumor microenvironment (TME) that supports their survival and growth. Within the TME, the efficacy of effector immune cells is compromised, as tumor cells exploit inhibitory immune cells to suppress their function. Furthermore, certain immune cells can be co-opted by tumor cells to facilitate tumor growth. While significantly enhancing the body's tumor immunity can lead to tumor regression, it can also result in severe toxic side effects and an inflammatory factor storm. As a consequence, patients often discontinue treatment due to immune-related adverse events (irAEs) or, in extreme cases, succumb to toxic side effects before experiencing tumor regression. In this analysis, we examined several remission regimens for irAEs, each with its own drawbacks, including toxic side effects or suppression of tumor immunotherapy, which is undesirable. A recent research study, specifically aimed at downregulating intestinal epithelial barrier permeability, has shown promising results in reducing the severity of inflammatory bowel disease (IBD) while preserving immune function. This approach effectively reduces the severity of IBD without compromising the levels of TNF-α and IFN-γ, which are crucial for maintaining the efficacy of tumor immunotherapy. Based on the substantial similarities between IBD and ICI colitis (combo immune checkpoint inhibitors-induced colitis), this review proposes that targeting epithelial cells represents a crucial research direction for mitigating irAEs in the future.

Immune checkpoint inhibitors and the orbit; two cases of reactive dacryoadenitis.

Immune checkpoints refer to mechanisms entrusted with the modulation of immune responses in peripheral tissues and are required for minimising collateral damage. Immune checkpoint inhibitors (ICPi) work through numerous pathways, including the anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), anti-PD-1 (programmed cell death protein 1) and the PD-L1 (protein cell death protein-ligand-1) pathways. They are proving to be an exciting therapeutic avenue in the attempt to activate anti-tumour activity. Ipilimumab is a fully human monoclonal antibody working on the anti-CTLA-4 pathway, while nivolumab and pembrolizumab are humanised monoclonal IgG4 antibodies that work on the PD-1 pathway. Despite a growing body of research pertinent to these novel therapies, early indications show that they are limited by their side effect profile. Furthermore, their efficacy appears to be greater in cancers with a high mutational burden. We present two female patients with bilateral reactive dacryoadenitis secondary to ICPi therapy, a finding that to the best of our knowledge was not previously described in the literature.