Atezolizumab (ATZ) plus bevacizumab (BEV) combination therapy has recently been approved for the treatment of unresectable hepatocellular carcinoma. However, immune-related adverse events (irAEs), including peripheral neuropathy, have also been reported. This case report describes a multidisciplinary intervention for a patient who developed peripheral neuropathy as an irAE following ATZ+BEV combination therapy.

The patient was a 60-year-old man with a history of hypertension. ATZ + BEV combination therapy was initiated for unresectable hepatocellular carcinoma on day 0. On day 6, he experienced a grade 2 hypertensive episode with a systolic blood pressure of 160 mmHg, despite being on amlodipine (5 mg) and azilsartan (20 mg). Based on the pharmacist's recommendations, the amlodipine dose was increased to 10 mg. However, as hypertension persisted, an additional 20 mg of azilsartan was prescribed, ultimately stabilizing the patient's blood pressure to approximately 110/60 mmHg. On day 23, the patient reported numbness in his extremities, which was later diagnosed as grade 3 peripheral neuropathy. Notably, data from the IMbrave150 trial indicated that the of peripheral neuropathy as an irAE was 1.5%. This prompted a consultation with a neurologist. Prednisolone (40 mg/day) was initiated on day 26, followed by steroid pulse therapy with methylprednisolone (1000 mg/day for three days) starting on day 37. Despite these interventions, the symptoms did not improve. Rehabilitation therapy was commenced on day 42 after steroid tapering. On day 48, the patient underwent a five-day course of high-dose intravenous immunoglobulin therapy, which also failed to yield improvement. Rehabilitation efforts subsequently shifted to enhancing activities of daily living. Initially, the patient required assistance to stand and faced significant difficulty walking. With consistent strength and mobility training, the patient progressed to walking with crutches and demonstrated increased walking distance.

The pathophysiology of irAE-induced peripheral neuropathy associated with immune checkpoint inhibitors remains poorly understood. This case underscores the challenges of managing irAE-related neuropathy, which may exhibit limited responsiveness to conventional treatments. Early detection, timely intervention, and multidisciplinary approaches are crucial for optimizing patient outcomes and mitigating the impact of severe side effects.

Chemoimmunotherapy is the primary treatment approach for non-small cell lung cancer (NSCLC); however, it is associated with immune-related adverse events (irAEs). Corticosteroids can control irAEs through their anti-inflammatory and immunosuppressive effects. Dexamethasone (DEX) is a potent corticosteroid commonly used to prevent chemotherapy-induced nausea and vomiting (CINV). This study aimed to the association of corticosteroids used to alleviate CINV and irAE occurrence.

This retrospective study included patients with NSCLC who underwent chemoimmunotherapy across eight hospitals. Cases lacking aprepitant use were excluded. All corticosteroids for CINV were standardized to intravenous DEX doses, and cutoff values were calculated using receiver operating characteristic curve analysis. Logistic regression analysis was performed to investigate irAE risk factors.

The cutoff value for DEX was 15.9 mg (area under the curve, 0.58; 95% confidence interval, 0.45-0.70; sensitivity, 0.63; specificity, 0.61), with 99 and 76 patients in the DEX < 15.9 and ≥ 15.9 mg groups, respectively. Patients in the DEX < 15.9 mg group had a significantly higher incidence of irAE than patients in the DEX ≥ 15.9 mg group (P = 0.03). Multivariate analysis identified that DEX < 15.9 mg was a risk factor for irAEs (P = 0.04; odds ratio: 2.51; 95% confidence interval, 1.03-6.09).

Corticosteroids with DEX equivalent doses of < 15.9 mg in combination with aprepitant for CINV may elevate the risk of irAEs. Therefore, diligent monitoring for irAEs occurrence is warranted in regimens utilizing DEX-equivalent corticosteroid doses of < 15.9 mg combined with aprepitant for CINV prevention.

Background/Objectives: Few studies have focused on patients with immune-related adverse events (irAEs) after immune checkpoint inhibitor (ICI) treatment who were cared for primarily by hospitalists. The objective of our study was to describe the patterns and outcomes of adult solid-tumor cancer patients admitted to our onco-hospital medicine service. Methods: We retrospectively reviewed patients with solid tumors who received ICIs and were admitted to our service in 2021-2022 with an irAE and compared them to a control group (IOTOX vs. NO IOTOX, respectively). The primary outcome was the patterns of irAEs requiring hospitalization; secondary outcomes included 30-day emergency room visit, readmission, and 30-day mortality. Results: There were 144 patients in the IOTOX group and 286 controls. The most common tumor type was lung and thoracic malignancies (62, 43.1%). The most common ICI causing the irAEs was pembrolizumab (66, 45.8%). The most common irAEs were pneumonitis (49, 34%), colitis (28, 19.4%), hepatitis (18, 12.5%), and myocarditis (16, 11.1%). Of the 144 patients, eight (6%) died from the hospitalization irAE. Fifteen (15.6%) had an ER visit within 30 days due to the same irAE, and thirteen (13.7%) were readmitted. Survival at 30 days after discharge did not differ significantly between groups. Conclusions: Despite many patients having severe irAEs and irAEs associated with higher mortality, they generally had a favorable outcome compared to the literature.

Although the incidence and outcomes of rituximab-induced interstitial lung disease (RILD) have been partially reported, there are no systematic studies on the characteristics and types of RILD. This study aimed to investigate the clinical characteristics, bronchoalveolar lavage (BAL) findings, and treatment course of RILD in patients with non-Hodgkin lymphoma. We retrospectively analyzed the data from 321 patients with non-Hodgkin lymphoma who developed RILD between 2020 and 2022. The extent, distribution, and radiologic patterns of interstitial lung disease were determined using high-resolution computed tomography of the chest. BAL was performed in 299 (93.1%) patients to determine cellular distribution patterns and identify pathogenic microorganisms using metagenomic next-generation sequencing. All patients received combination therapy, with cyclophosphamide, doxorubicin, vincristine, and prednisone being the most commonly administered regimens. The median time from treatment to RILD development was 1.7 months. In the 217 patients who underwent metagenomic next-generation sequencing, 179 pathogenic microorganisms were detected, including 77 (43.0%) bacteria, 45 (25.1%) viruses, 28 (15.6%) Pneumocystis jirovecii strains, 17 (9.5%) fungi, 6 (3.5%) Mycobacterium tuberculosis, and 6 (3.5%) atypical pathogens. All RILD diagnoses were based on multidisciplinary team discussions and compliance with international standards. In conclusion, RILD exhibits a range of radiological and BAL patterns, reflecting different interstitial lung disease types. The most common patterns of RILD are infectious lung disease, organizing pneumonia, and nonspecific interstitial pneumonia. These findings enhance the understanding of RILD in patients with non-Hodgkin lymphoma and serve as a reference for best management guidelines in these patients.

The third-line treatment for refractory colorectal cancer (CRC) has limited efficacy. This study aimed to evaluate the safety and efficacy of SHR-8068 (an anti-CTLA-4 antibody), combined with adebrelimab (an anti-PD-L1 antibody), and bevacizumab in refractory non-microsatellite instability-high (MSI-H) or proficient mismatch repair (pMMR) CRC.

This study is a prospective, open-label, single-center phase Ib/II clinical trial. Patients with pathologically confirmed pMMR/non-MSI-H metastatic colorectal adenocarcinoma who have failed ≥2 lines prior standard systemic treatments will be enrolled (n=36). The Ib phase will evaluate two dosing regimens of SHR-8068 in combination therapy (n=9 each dosage): SHR-8068 (1 mg per kilogram, every six weeks, intravenously) or SHR-8068 (4 mg per kilogram, every twelve weeks, intravenously) combined with adebrelimab (1200 mg, every three weeks, intravenously) and bevacizumab (7.5 mg per kilogram, every three weeks, intravenously). The efficacy and adverse events (AEs) of these regimens will be assessed to determine the recommended phase II dose (RP2D) of SHR-8068. Those of RP2D group from the phase Ib will be included in the phase II. The study will go to include 18 additional patients according to the one-sample log-rank test design in the phase II. The primary endpoint of the Ib phase is safety, with secondary endpoints including the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and quality of life (QOL). The primary endpoint for phase II was PFS, with secondary endpoints including ORR, OS, DCR, safety, and QOL. Identifying biomarkers to predict the efficacy of this regimen is the exploratory study endpoint.

This proof-of-concept study would provide safety and efficacy signals of this novel combination treatment for the MSS CRCs in the late-line setting. And it may offer new insights on the clinical application of dual immunotherapy combined with anti-angiogenic therapy in the MSS CRC.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet they can induce immune-related adverse events (irAEs), including cutaneous toxicities such as lichenoid eruptions. Pembrolizumab, a PD-1 inhibitor, is known for its association with lichen-planus-like reactions, while the side effect profile of combining immunotherapy with MK-4830, a novel fully human IgG4 monoclonal antibody that targets ILT-4, remains limited.

We present a case of a 47-year-old female with metastatic breast cancer who developed a grade 2 Common Terminology Criteria for Adverse Events (CTCAE) lichenoid reaction after 9 months of MK-4830 and pembrolizumab use. Confluent, erythematous papules with Wickham's striae appeared predominantly on the extremities. Initial therapy with high-potency topical corticosteroids proved insufficient, however prednisone 40 mg daily resulted in satisfactory remission of lichen-planus-like reaction, permitting continued immunotherapy without dosage adjustment.

This case highlights the novel occurrence of lichenoid eruption induced by MK-4830 and pembrolizumab in breast cancer treatment. The patient was successfully treated with oral prednisone, which controlled the skin symptoms without interrupting ICI therapy. We emphasize that early diagnosis and treatment of low-grade lichenoid eruption can prevent the cessation of ICIs, thereby combining the benefits of managing irAEs and avoiding cancer progression, leading to a better long-term prognosis.

Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis.

This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed.

Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis.

Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.

Intratumoral immunotherapies are those that are administered directly into a tumor to remodel the local tumor microenvironment and stimulate systemic anti-tumor immunity. Small molecule Toll-like receptor (TLR) agonists are undergoing development as intratumoral immunotherapies, and here we considered the TLR3 agonist poly(I:C). Because small molecule therapeutics often suffer rapid washout effects and ineffective immune cell uptake, we encapsulated poly(I:C) into nanoparticles derived from cowpea chlorotic mottle virus (CCMV). The particles (but not the separate components) stimulated the activity of macrophages in vitro and were able to reduce tumor growth and prolong survival in mouse models of colon cancer and melanoma. We also combined CCMV-poly(I:C) with oxaliplatin and found the combination therapy to be even more potent, strongly inhibiting tumor growth and increasing survival. The analysis of immune markers revealed that CCMV-poly(I:C) VLPs with oxaliplatin promoted the infiltration and activation of CD4+ and CD8+ cells and the production of IL-4 and IFN-γ, indicating a synergistic immunogenic effect. The combined treatment also enhanced the rate of apoptosis and immunogenic cell death (ICD). Our data support the development of combination therapies involving immunomodulatory plant virus nanoparticles and antineoplastic drugs to attack tumors directly and via the activation of innate and adaptive immune responses.

The immune checkpoint inhibitor pembrolizumab is now considered a first-line treatment for recurrent or metastatic head and neck squamous cell cancer. Pembrolizumab is less toxic than conventional chemotherapy but may result in immune-related adverse events. We report a case in which liver injury occurred just two days after the administration of pembrolizumab plus chemotherapy. A 48-year-old woman achieved a complete response after chemoradiotherapy for cT2N3bM0 squamous cell carcinoma of the oropharynx with multiple lymph node metastases. However, the tumor recurred one year later, and she was started on pembrolizumab plus chemotherapy. On day 3, her alanine aminotransferase and aspartate transaminase concentrations markedly increased. She was initially diagnosed with drug-induced liver injury and all medications were withdrawn. Her liver function recovered within two weeks without intervention. The lymphocyte transformation test was only positive for pembrolizumab. Clinicians should consider pembrolizumab-induced allergic hepatitis as a possible cause of liver injury after excluding liver metastasis and immune-related adverse events.

Immune checkpoint inhibitor-related pancreatic injury (ICI-PI) is a rare occurrence, which has not been reported in detail. We conducted a retrospective multicenter study to determine the clinical characteristics, risk factors, and treatment of ICI-PI.

We reviewed the medical records of patients who received ICIs for malignant tumors between April 2014 and April 2019 at 16 participating hospitals. Patients with elevated pancreatic enzymes or pancreatitis were identified and classified using the Common terminology Criteria for Adverse Events (CTCAE) ver.5.0). The number of patients with pancreatic enzyme elevation was determined and those with pancreatic enzyme elevation of ≥ grade 3 according to CTCAE ver.5.0, or pancreatitis underwent detailed analysis for ICI-PI.

The study enrolled 1069 patients. Nineteen patients (1.8%) had ICI-PI, 5 (0.5%) of whom also had pancreatitis. Four patients had mild pancreatitis, whereas 1 patient had severe pancreatitis, culminating in death. Steroid therapy was administered to 7 of 19 patients, which led to ICI-PI improvement in 5 patients. On the other hand, ICI-PI improved in 9 of 12 patients who were not administered steroid therapy. Six of the 14 patients with ICI-PI improvement were rechallenged with ICI, and ICI-PI relapse occurred in only 1 patient (16.7%), which improved with ICI discontinuation and steroid therapy.

ICI-PI is a rare occurrence, with a low incidence of pancreatitis, which followed a very serious course in one patient. Although the benefit of steroid therapy for ICI-PI is unclear, ICI rechallenge is acceptable after improvement of ICI-PI without pancreatitis.

Advances in cancer immunotherapy over the last decade have led to the development of several agents that affect immune checkpoints. Inhibitory receptors expressed on T cells that negatively regulate the immune response include cytotoxic T‑lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1), which have been studied more than similar receptors. Inhibition of these proteins and other immune checkpoints can stimulate the immune system to attack cancer cells, and prevent the tumor from escaping the immune response. However, the administration of anti-PD1 and anti-CTLA4 antibodies has been associated with adverse inflammatory responses similar to autoimmune diseases. The current review discussed the role of the NF-κB pathway as a tumor promoter, and how it can govern inflammatory responses and affect various immune checkpoints. More precise knowledge about the communication between immune checkpoints and NF-κB pathways could increase the effectiveness of immunotherapy and reduce the adverse effects of checkpoint inhibitor therapy.

The overexpression of the immunoinhibitory receptor programmed death-1 (PD1) on T-cells is involved in immune evasion in cancer. The use of anti-PD-1/PDL-1 strategy has deeply changed the therapies of cancers and patient survival. However, their efficacy diverges greatly along with tumor type and patient populations. Thereby, novel treatments are needed to interfere with the anti-tumoral immune responses and propose an adjunct therapy. In the current study, we found that the antifungal drug Sulconazole (SCZ) inhibits PD-1 expression on activated PBMCs and T cells at the RNA and protein levels. SCZ repressed NF-κB and calcium signaling, both, involved in the induction of PD-1. Further analysis revealed cancer cells treatment with SCZ inhibited their proliferation, and migration and ability to mediate tumor growth in zebrafish embryos. SCZ found also to inhibit calcium mobilization in cancer cells. These results suggest the SCZ therapeutic potential used alone or as adjunct strategy to prevent T-cell exhaustion and promotes cancer cell malignant phenotype repression in order to improve tumor eradication.

Neuro-ophthalmologic diseases include a broad range of disorders affecting the afferent and efferent visual pathways. Recently, monoclonal antibody (mAb) therapies have emerged as a promising targeted approach in the management of several of these complex conditions. Here, we describe the mechanism-specific applications and advancements in neuro-ophthalmologic mAb therapies. The application of mAbs in neuro-ophthalmologic diseases highlights our increasing understanding of disease-specific mechanisms in autoimmune conditions such as neuromyelitis optica, thyroid eye disease, and myasthenia gravis. Due to the specificity of mAb therapies, applications in neuro-ophthalmologic diseases have yielded exceptional clinical outcomes, including both reduced rate of relapse and progression to disability, visual function preservation, and quality of life improvement. These advancements have not only expanded the range of treatable neuro-ophthalmologic diseases but also reduced adverse events and increased the response rate to treatment. Further research into neuro-ophthalmologic disease mechanisms will provide accurate and specific targeting of important disease mediators through applications of future mAbs. As our understanding of these diseases and the relevant therapeutic targets evolve, we will continue to build on our understanding of how mAbs interfere with disease pathogenesis, and how these changes improve clinical outcomes and quality of life for patients.

The immune checkpoint inhibitor (ICI), anti-programmed cell death receptor-1 (PD-1) antibody, has gained widespread approval for treating various malignancies. Among the immune-related adverse reactions (irAEs) during ICI treatment, the lichenoid reaction is noteworthy. Sintilimab, a new PD-1 inhibitor, has secured approval in China for treating refractory non-Hodgkin's lymphoma, and phase I/II clinical trials for other solid tumors are ongoing both domestically and abroad. This paper presents a case of a mucocutaneous lichenoid reaction associated with sintilimab therapy, its diagnosis, and management. Our study, using multiplex immunofluorescence staining, reveals localized infiltration of CD4+ and CD8+ T lymphocytes in the subepithelial lamina propria region with upregulated PD-1 expression, implying an association between PD-1 expression upregulation and lichenoid reactions provoked by PD-1 monoclonal antibody. We provide a summary of clinical characteristics and treatment guidelines for lichenoid reactions induced by ICIs from previous reports, highlighting the success of a combined therapeutic regimen of oral antihistamines and topical corticosteroids in controlling symptoms without interrupting ICI treatment.

Immune-checkpoint inhibitors (ICIs) are effective against various cancers; however, immune-related adverse events (irAEs) have been reported and the timing and risk factors are unknown. Therefore, we examined the incidence and timing of irAE occurrence.

Patients who received ICIs at our hospital between 1 April 2016 and 31 March 2020 were enrolled. Patients were classified into an irAE group or non-irAE group. In addition, we examined the onset time and symptoms of irAEs for each ICI type.

A total of 80 patients received ICIs, of which 27 (33.8%) developed irAEs. The incidence of irAEs was 35.3% for nivolumab, 35.5% for pembrolizumab, and 28.6% for atezolizumab. The incidence of pneumonitis was 12.5%, 8.8% for dermatologic adverse events, and 6.3% for thyroid dysfunction. The earliest case of onset was after the 1st course, and the latest cases occurred after the 66th course. By the sixth course, 69% of the irAEs occurred. The positive rates for anti-thyroid peroxidase and anti-thyroglobulin antibodies were higher in the irAE group compared to the non-irAE group.

Our findings suggest a high probability of irAEs occurring early in ICI treatment, with a diverse range of symptoms. This underscores the need for vigilant monitoring and tailored patient management during the initial courses of ICI therapy.

PD-L1 staining using long-stored paraffin sections may not be consistent with the true PD-L1 expression of patients. Therefore, it is necessary to explore the expression of PD-L1(SP142) in paraffin sections of invasive breast cancer with different storage times and the optimal storage temperature for unstained paraffin sections.

The study included 71 cases of PD-L1(SP142) positive breast cancer. The unstained paraffin sections were stored at room temperature conditions (20-25 °C), 4 °C, -20 °C and - 80 °C, respectively. PD-L1 staining was performed at 1, 2, 3, 4, 8, 12 and 24 weeks of storage. PD-L1 expression was assessed with a continuity score.

The PD-L1 antigen was gradually lost as the storage time of paraffin sections increased. The PD-L1 positivity rate was 97.18% at 1 week for the sections stored at room temperature, and decreased from 83.10 to 71.83% for the sections stored for 2 weeks to 4 weeks, and 61.97%, 54.93%, and 32.93% for 8, 12, and 24 weeks, respectively. When stored at low temperatures of 4 °C, -20 °C and - 80 °C, the positivity rate decreases with the same trend but more slowly compared to room temperature. The mean IC score of PD-L1 also showed a gradual decrease in all cases. In the consistency analysis, PD-L1 expression in slices stored at room temperature for 2 weeks was consistent with PD-L1 expression in fresh slices (ICC ≥ 0.9 for all slices), and PD-L1 expression in slices stored at 4 °C or -20 °C for 4 weeks was consistent with PD-L1 expression in fresh slices (ICC ≥ 0.9 for all slices). When stored under refrigeration at -80 °C, PD-L1 expression in slices stored for 3 weeks was consistent with that in fresh slices (ICC ≥ 0.9).

To our knowledge, this is the first article on the effect of preservation time and preservation temperature of paraffin sections on PD-L1 expression in breast cancer. Long-term storage of paraffin sections of unstained invasive breast cancer can lead to antigen loss of PD-L1 (SP142). Refrigerated storage of paraffin sections can delay antigen loss, with best results at 4 °C or -20 °C, and a storage time of no more than 4 weeks is recommended.

Background and Objectives: One type of immune-related adverse event caused by immune checkpoint inhibitors (ICIs) is pituitary-related adverse events. The management of pituitary-related adverse events is important because they can be fatal if not treated promptly. Therefore, this study was conducted to investigate the onset of pituitary-related adverse events using the Japanese Adverse Drug Report (JADER) database. Materials and Methods: Cases registered in the JADER database from 2004 to 2019 were used. The target drugs were ipilimumab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab, and the target adverse events were the high-level terms "Anterior pituitary hypofunction," "Anterior pituitary hyperfunction," "Posterior pituitary disorder," and "Pituitary neoplasm" in the Medical Dictionary for Regulatory Activities, Japanese version (MedDRA/J). The information component (IC) was used for signal detection and IC delta (ICΔ) was used for women-related signals. Onset timing and patterns were analyzed using the Weibull distribution. Results: Signals were detected with ipilimumab, nivolumab, pembrolizumab, and atezolizumab in "Anterior pituitary hypofunction," with ICs and 95% credible intervals (95%CrI) of 5.53 (5.30-5.69), 4.96 (4.79-5.08), 4.04 (3.76-4.25), and 2.40 (1.53-3.00). Significant signals were detected in women, except for atezolizumab. Additionally, the time of onset was classified as the wear-out failure type. Inverse signals were detected with ipilimumab and nivolumab in "Posterior pituitary disorder," with ICs (95%CrI) of -1.24 (-2.80--0.26), and -0.89 (-1.64--0.37). Conclusions: Anterior pituitary hypofunction is likely to occur with the long-term administration of ipilimumab, nivolumab, and pembrolizumab. Further investigation is needed to determine the differences in the tendencies to detect signals in the anterior and posterior pituitaries between ipilimumab and nivolumab.

Immune checkpoint inhibitors (ICI), pembrolizumab and atezolizumab, were recently approved for treatment-refractory triple-negative breast cancer (TNBC), where those with Programmed death-ligand 1 (PD-L1) positive early-stage disease had improved responses. ICIs are administered systemically in the clinic, however, reaching effective therapeutic dosing is challenging due to severe off-tumor toxicities. As such, intratumoral (IT) injection is increasingly investigated as an alternative delivery approach. However, repeated administration, which sometimes is invasive, is required due to rapid drug clearance from the tumor caused by increased interstitial fluid pressure. To minimize off-target drug biodistribution, we developed the nanofluidic drug-eluting seed (NDES) platform for sustained intratumoral release of therapeutic via molecular diffusion. Here we compared drug biodistribution between the NDES, intraperitoneal (IP) and intratumoral (IT) injection using fluorescently labeled PD-L1 monoclonal antibody (αPD-L1). We used two syngeneic TNBC murine models, EMT6 and 4T1, that differ in PD-L1 expression, immunogenicity, and transport phenotype. We investigated on-target (tumor) and off-target distribution using different treatment approaches. As radiotherapy is increasingly used in combination with immunotherapy, we sought to investigate its effect on αPD-L1 tumor accumulation and systemic distribution. The NDES-treated cohort displayed sustained levels of αPD-L1 in the tumor over the study period of 14 days with significantly lower off-target organ distribution, compared to the IP or IT injection. However, we observed differences in the biodistribution of αPD-L1 across tumor models and with radiation pretreatment. Thus, we sought to extensively characterize the tumor properties via histological analysis, diffusion evaluation and nanoparticles contrast-enhanced CT. Overall, we demonstrate that ICI delivery via NDES is an effective method for sustained on-target tumor delivery across tumor models and combination treatments.

Immune checkpoint inhibitors (ICIs) have revolutionized treatment strategies in the field of oncology. Their favourable outcomes in terms of efficacy and side-effect profile can be thwarted by the development of immune-related adverse events (irAEs). Cutaneous irAEs are relatively common in patients undergoing immunotherapy and include common inflammatory dermatoses (e.g. eczematous, psoriasiform and lichenoid phenotypes), maculopapular eruptions, pruritus and immunobullous disorders. Most of these reactions can be managed without ICIs having to be stopped completely; however, there are some life-threatening toxicities that dermatologists and oncologists should be aware of. In this review, we focus on how to recognize the commonly associated cutaneous irAEs, touching upon rarer reactions and red flags; finally, we provide guidance on their management.

Immune checkpoint inhibitors (ICIs) stimulate antitumor immune responses and, in parallel, they might trigger autoimmune and other immunopathological mechanisms eventually leading to immune-related adverse events (irAE). In our study, we assessed patients with malignancies who underwent anti-PD-1 treatment at the University of Debrecen, Clinical Center.

Between June 2017 and May 2021, 207 patients started ICI treatment at our university. A total of 157 patients received nivolumab and 50 were treated with pembrolizumab. We looked for factors associated with the development of irAEs. In addition to correlation studies, we performed binary logistic regression analysis to determine, which factors were associated with irAEs. We also performed Forward Likelihood Ratio (LR) analysis to determine independent prognostic factors.

At the time of data analysis, the mean duration of treatment was 2.03 ± 0.69 years. ROC analysis determined that 9 or more treatment cycles were associated with a significantly higher risk of irAEs. A total of 125 patients received ≥9 treatment cycles. Three times more patients were treated with nivolumab than pembrolizumab. Of the 207 patients, 66 (32%) developed irAEs. Among the 66 patients who developed irAEs, 36 patients (55%) developed one, 23 (35%) developed two, while 7 (10%) developed three irAEs in the same patient. The most common irAEs were thyroid (33 cases), dermatological (25 cases), pneumonia (14 cases) and gastrointestinal complications (13 cases). Patients who developed irAEs received significantly more treatment cycles (21.8 ± 18.7 versus 15.8 ± 17.4; p=0.002) and were younger at the start of treatment (60.7 ± 10.8 versus 63.4 ± 10.1 years; p=0.042) compared to patients without irAEs. Pembrolizumab-treated patients developed more but less severe irAEs compared to those receiving nivolumab.

ICI treatment is very effective, however, irAEs may develop. These irAEs might be related to the number of treatment cycles and the type of treated malignancy.

Manipulating the immune system by blocking the immune checkpoint receptors is the basis of immunotherapy, a relevant tool in current clinical oncology. The strategy of blocking the immune checkpoints (Immune Checkpoint Inhibitors, ICI) consists of using monoclonal antibodies to inhibit the interaction between ligand and inhibitory receptors from triggering a complete activation of helper and cytotoxic T cells to fight against tumour cells. Immunotherapy has benefited patients with diverse cancers such as stomach, lung, melanoma, and head and neck squamous cell carcinoma, among others. Unfortunately, a growing number of reports have indicated that the ICI treatment also can show a dark side under specific conditions; some of the adverse effects induced by ICI are immunosuppression, opportunistic infections, and organ-specific alterations. This review discusses some immunologic aspects related to these unwanted effects.

Immune checkpoint inhibitors (ICIs) are a class of drug that produces durable and sustained anti-tumour responses in a wide variety of malignancies. The exponential rise in their use has been mirrored by a rise in immune-related adverse events (IrAEs). Knowledge of such toxicities, as well as effective management algorithms for these toxicities, is essential to optimize clinical efficacy and safety. Currently, the guidelines for management of the IrAEs are based largely on retrospective studies and case series. In this article, we review the current landscape of clinical trials investigating the management of IrAEs with an aim to develop standardised, randomised controlled trial-based management algorithms for ICI-related toxicities.

The advent of immune checkpoint inhibitors (ICIs) has led to noteworthy progressions in the management of diverse cancer types, as evidenced by the pioneering "ipilimumab" medication authorized by US FDA in 2011. Importantly, ICIs agents have demonstrated encouraging potential in bringing about transformation across diverse forms of cancer by selectively targeting the immune checkpoint pathways that are exploited by cancerous cells for dodging the immune system, culminating in progressive and favorable health outcomes for patients. The primary mechanism of action (MOA) of ICIs involves blocking inhibitory immune checkpoints. There are three approved categories including Programmed Death (PD-1) inhibitors (cemiplimab, nivolumab, and pembrolizumab), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (Ipilimumab), and Programmed Death-Ligand 1 (PDL-1) (Avelumab). Although ICIs promisingly increase therapeutic response and cancer survival rates, using ICIs has demonstrated some limitations including autoimmune reactions and toxicities, requiring close monitoring. The present review endeavors to explicate the underlying principles of the MOA and pharmacokinetics of the approved ICIs in the realm of cancer induction, including an appraisal of their level of practice-based evidence.

Immune checkpoint inhibitors (ICI) ushered in a new era for the treatment of non-small cell lung cancer (NSCLC). However, they carry the risk of immune-related adverse events (irAEs). Recently, various studies have been conducted on the predictive factors for irAEs, but there are no reports focusing only on ICI plus platinum agents. The present study aimed to identify the risk factors for irAEs due to ICI combined with platinum-based induction immunochemotherapy in NSCLC patients, focusing only on the period of combined therapy and excluding the period of ICI maintenance therapy.

This retrospective study included 315 NSCLC patients who started ICI combined with platinum-based chemotherapy treatment at 14 hospitals between December 2018 and March 2021. A logistic regression analysis was used to explore the predictive factors.

Fifty patients (15.9%) experienced irAEs. A multivariate analysis revealed that squamous cell carcinoma (P = 0.021; odds ratio [OR]: 2.30; 95% confidence interval [Cl]: 1.14-4.65), anti-programmed death 1 antibody (anti-PD-1) plus anti-cytotoxic T-lymphocyte antigen-4 antibody (anti-CTLA-4) regimens (P < 0.01; OR: 22.10; 95% Cl: 5.60-87.20), and neutrophil-to-lymphocyte rate (NLR) < 3 (P < 0.01; OR: 2.91; 95% Cl: 1.35-6.27) were independent predictive factors for irAEs occurrence.

Squamous cell carcinoma, anti-PD-1 plus anti-CTLA-4 regimens, and NLR < 3 may be predictive factors for the occurrence of irAEs due to induction immunochemotherapy in patients with NSCLC. By focusing on the potential risk of irAEs in patients with these factors, irAEs can be appropriately managed from an early stage.

The advent of immunotherapy and targeted therapies in treating dermatological malignancies has dramatically changed the landscape of dermato-oncology in recent years. Their superior efficacy compared to previous therapeutic options, such as chemotherapy, has resulted in their use in treating devastating malignancies, such as melanoma or unresectable/metastatic basal cell and squamous cell carcinoma. Skin toxicity is a critical safety consideration, among other adverse reactions, that can occur under treatment with these agents. This article aims to summarize the cutaneous side effects of immune checkpoint inhibitors and targeted dermato-oncological therapies. Although the skin side effects of these agents are primarily mild, they can occasionally affect the decision for treatment continuation and the quality of life of the affected patients. Therefore, physicians must be acquainted with the specific cutaneous toxicity profile of such treatments to mitigate their impact on the patients and optimize the overall outcome of dermato-oncological therapy.

Immune checkpoint inhibitors have revolutionized management of advanced malignancies. However, their use is frequently complicated by immune related adverse events (irAEs), immune checkpoint inhibitor enterocolitis (IMEC) being the most common toxicity. IMEC is a distinct form of bowel inflammation that is highly reminiscent of idiopathic inflammatory bowel disorders (Crohn's disease, ulcerative colitis, and microscopic colitis). In this review, we highlight the similarities and differences in the pathophysiology, clinical presentation, evaluation, and management of these overlapping immune inflammatory bowel disorders. IMEC is an inflammatory bowel disease-like irAE that occurs as an outcome of disruption of intestinal immune surveillance and gut dysbiosis. Clinical and endoscopic presentation of both entities is strikingly similar, which often guides management. Though well established in inflammatory bowel disease, little is known about the long term outcomes of IMEC.

Immune checkpoint inhibitors (ICIs) have been shown to prolong the survival of patients with non-small cell lung cancer (NSCLC) and have allowed complete resection for advanced lung cancer. However, immune-related adverse events (irAEs) have been recognized as concerning side effects of ICIs.

A 62-year-old man visited our hospital because of fever, dyspnea, and anorexia. A tumor was found in the right hilum of the lung. It compressed the left atrium and was also thought to be invading the esophagus and a vertebral body. A bronchoscopic biopsy revealed squamous cell carcinoma of the lung (cT4N2M0-IIIB). We thought that a complete resection was impossible because of the N2 status of the tumor and because it had invaded several organs. Radiotherapy was thought to be contraindicated because of the patient's marked emphysema. Therefore, we administered 4 courses of pembrolizumab plus carboplatin plus nab-paclitaxel immunochemotherapy. After immunochemotherapy, the tumor was downstaged to ycT2bN0M0-IIA and was determined to be acceptable for salvage surgery. A right lower lobectomy and systematic dissection of the mediastinal lymph nodes were performed. The histopathological examination of the resected specimen found that the proportion of the remaining tumor cells was 5%, indicating achievement of a major pathologic response. On postoperative day 79, the patient visited the emergency room because of anorexia. Blood tests showed hyponatremia, hypoglycemia, and eosinophilia. The serum thyroid hormone and thyroid-stimulating hormone levels were low and high, respectively. A corticotropin-releasing hormone stimulation test revealed levels of adrenocorticotropic hormone and cortisol far below the normal ranges. We speculated that the patient had developed pituitary hypoadrenocorticism and hypothyroidism as irAEs associated with ICI treatment. We administered hydrocortisone and levothyroxine, with improvement in the patient's appetite and normalization of the patient's serum sodium level. The patient has been receiving ongoing supplementation with oral hydrocortisone and levothyroxine and is doing well 11 months after surgery.

The increasing numbers of patients treated with perioperative ICIs might lead to increasing numbers of patients who develop perioperative irAEs. Careful attention should be paid to the possible development of irAEs during the perioperative management of patients undergoing surgery for lung cancer.

Immunotherapy is becoming an advanced clinical management for various cancers. Rebuilding of aberrant immune surveillance on cancers has achieved notable progress in the past years by either in vivo or ex vivo engineering of efficient immune cells. Immune cells can be programmed with several strategies that improves their therapeutic influence and specificity. It has become noticeable that effective immunotherapy must consider the complete complexity of the immune cell function. However, today, almost all immune cells can be transiently or stably reprogrammed against various cancer cells. As a consequence, investigations have interrogated strategies to improve the efficacy of cancer immunotherapies by enhancing T-cell infiltration into tumour tissues. Here, we review the emerging role of furin-like enzymes work related to T-cell reprogramming, their tumour infiltration and cytotoxic function.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block key mediators of tumor-mediated immune evasion. The frequency of its use has increased rapidly and has extended to numerous cancers. ICIs target immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1), and T cell activation, including cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). However, ICI-driven alterations in the immune system can induce various immune-related adverse events (irAEs) that affect multiple organs. Among these, cutaneous irAEs are the most common and often the first to develop. Skin manifestations are characterized by a wide range of phenotypes, including maculopapular rash, psoriasiform eruption, lichen planus-like eruption, pruritus, vitiligo-like depigmentation, bullous diseases, alopecia, and Stevens-Johnson syndrome/toxic epidermal necrolysis. In terms of pathogenesis, the mechanism of cutaneous irAEs remains unclear. Still, several hypotheses have been proposed, including activation of T cells against common antigens in normal tissues and tumor cells, increased release of proinflammatory cytokines associated with immune-related effects in specific tissues/organs, association with specific human leukocyte antigen variants and organ-specific irAEs, and acceleration of concurrent medication-induced drug eruptions. Based on recent literature, this review provides an overview of each ICI-induced skin manifestation and epidemiology and focuses on the mechanisms underlying cutaneous irAEs.

The programmed cell death protein 1 (PD-1) inhibitor, as one of the immune checkpoint inhibitors (ICIs), is the standard treatment for advanced lung cancer. However, immune-related adverse events (irAEs) remain poorly understood toxicities. It is unclear whether frailty plays a role in the occurrence of irAEs. Thus, we assess whether irAEs occur more often in frail patients than in non-frail patients according to the Frailty Index (FI).

A retrospective study was conducted. Medical records from lung cancer patients treated with PD-1 inhibitors (Sintilimab, Camrelizumab, Tislelizumab, and Pembrolizumab) at Peking University First Hospital (May 2018-June 2022). Patients were categorized into non-frail and frail groups according to a cut-point of 0.25 by FI. The FI calculation included 28 baseline variables, all of which were health deficits measured by questionnaires and body measurements.

The statistical analysis included 114 advanced lung cancer patients. The median age was 66 years, and the male/female ratio was 4.7:1 (94/20). Approximately 39 (34%) were classified as frail. PD-1 inhibitor-related adverse events occurred in 17.5% of patients, and 6.1% experienced irAEs of grade ≥3. There was no significant difference in the occurrence of irAEs (14.7% vs. 23.1%, p = 0.26), grade ≥ 3 irAEs (5.3% vs. 7.7%, p = 0.93), and treatment discontinuation due to irAEs (12.0% vs. 17.9%, p = 0.39) between non-frail and frail patients. However, frail patients are more likely to have more than one type of irAEs and are more possibly to have checkpoint inhibitor pneumonitis (CIP) than non-frail patients when they use PD-1 inhibitors (p < 0.05). Frail patients had a longer hospital stay (6 vs. 3 days, p = 0.01).

Frailty is not associated with severe irAEs, but is related to CIP. Meanwhile, it predicts more than one type of irAEs and a longer hospital stay. Frailty screening has added value to the decision-making process for frail patients eligible for PD-1 inhibitors.

Immune checkpoint inhibitors (ICIs) have been established as the cornerstone for advanced non-small cell lung cancer, while thyroid adverse events (AEs) associated with ICIs have not been systematically documented. Therefore, we performed a meta-analysis to evaluate the effect of ICI applications on the thyroid of patients with non-small cell lung cancer. We performed a systematic search of PubMed, the Cochrane Library, Web of Science, and Embase for eligible randomized controlled trials up to December 2021. Clinical trials reporting thyroid AEs including hypothyroidism, hyperthyroidism, and thyroiditis were enrolled. The I²  statistic was also calculated to quantify the heterogeneity. Data were evaluated as risk ratio (RR) and corresponding 95%CIs. A total of 10 randomized clinical trials involving 6154 patients were included in this meta-analysis. ICI application was found to have a statistically significant higher risk of all grade hypothyroidism (RR, 7.03; P < 0.0001), hyperthyroidism (RR, 4.88; P < 0.0001), and thyroiditis (RR, 6.58; P = 0.0014) compared with the chemotherapy group. Moreover, we demonstrated that second-line therapy significantly increased the risk of all-grade hypothyroidism (RR, 7.03 [95%CI, 4.69-10.55]) and hyperthyroidism (RR, 4.88 [95%CI, 3.11-7.65]). Our meta-analysis manifested that regimens with ICIs may significantly increase all grades of hypothyroidism, hyperthyroidism, and thyroiditis. ICIs may induce the occurrence and exacerbation of endocrine AEs compared with chemotherapy.

Immunotherapy, along with chemotherapy, targeted delivery, radiation and surgery has become one of the most common cancer treatments. The aim of cancer immunology is to use the bodys immune system to combat tumors and develop a robust antitumor immune response. In the last few years, immune checkpoint inhibitors and chimeric antigen receptor-modified T cells have made substantial advancements in cancer immunotherapy. By boosting cell type-specific delivery and immunological responses, nanocarriers like liposomes have the ability to enhance greater immune responses. The efficacy of anti-tumor therapeutics is being significantly improved as liposomes can assist in resolving a number of issues that can arise from a variety of cancer immunotherapies. Since, liposomes can be loaded with both hydrophilic and hydrophobic drugs and protect the immunotherapeutic agents loaded inside the core, they offer significant advantages over other nano delivery systems. The use of liposomes for accurate and timely delivery of immunotherapies to particular targeted neoplasms, with little or no injury to healthy cells, maximizes immunotherapy efficacy. Liposomes are also suitable vehicles for delivering medications simultaneously with other therapies such as chemotherapy, radiation, and phototherapy. Liposomal nanoparticles will be introduced and used as an objective immunotherapy delivery system for great precision, making them a viable cancer treatment approach.With an emphasis on dendritic cells, T cells, tumor and natural killer cells, and macrophages; outline of many forms of immune-therapies in oncology and cutting-edge advances in liposomal nanovesicles for cancer immunotherapy are covered in this review.

Non-viral vectors are promising nucleic acid carriers which have been utilized in gene-based cancer immunotherapy. The aim of this study is to compare the transfection efficiency and cytotoxicity of three cationic non-viral vectors namely Polyethylenimine (PEI), Lipofectamine 2000 (LPF) and stable nucleic acid lipid particles (SNALPs) of different lipid compositions, for the delivery of plasmid DNA (pDNA) expressing immunostimulatory molecules, OX40L or 4-1BBL, to cancer cells in vitro. The results indicate that PEI and LPF are efficient vectors for pDNA delivery with high transfection efficiency obtained. However, pDNA-PEI and pDNA-LPF complexes up-regulated the expression of programmed death ligand-1 (PD-L1) and induced significant cytotoxicity in both B16F10 and CT26 cell lines. The up-regulation of PD-L1 expression induced by pDNA-PEI and pDNA-LPF complexes was independent of cancer cell line, nor was it linked to the presence of GpC motifs in the pDNA. In contrast, the use of biocompatible SNALPs (MC3 and KC2 types) resulted in lower pDNA transfection efficiency, however no significant up-regulation of PD-L1 or cytotoxicity was observed. A strong correlation was found between up-regulation of PD-L1 expression and cytotoxicity. Up-regulation of PD-L1 expression could be mitigated with RNAi, maintaining expression at basal levels. Due to the improved biocompatibility and the absence of PD-L1 up-regulation, SNALPs represent a viable non-viral nucleic acid vector for delivery of pDNA encoding immunostimulatory molecules. The results of this study suggest that PD-L1 expression should be monitored when selecting commercial transfection reagents as pDNA vectors for cancer immunotherapy in vitro.

The usefulness of ultrasonography (US) in diseases of the gastrointestinal tract has been reported recently. This prospective study aimed to determine the features of US findings in immune-mediated colitis (IMC), an adverse event induced by immune checkpoint inhibitor, and examine the correlation between US findings, colonoscopy (CS) findings, and severity of colitis.

We studied patients examined using CS and US upon suspicion of IMC in Hokkaido University Hospital between April 2018 and February 2021. Endoscopic findings of IMC were assessed using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). The severity of US findings in IMC was evaluated using US grade, which is the ultrasonographic grading scale in ulcerative colitis. Bowel wall thickness and the intensity of the color Doppler signal were also analyzed. Severity of colitis was evaluated using Common Terminology Criteria for Adverse Events (CTCAE) grade version 5.

Fourteen patients with IMC were enrolled. The US findings were bowel wall thickening, loss of stratification, ulceration and increased blood flow signal. The US grade was moderately correlated with the UCEIS (r=0.687, p=0.009) and CTCAE grade (r=0.628, p=0.035). Bowel wall thickness and UCEIS (r=0.628, p=0.020), as well as color Doppler signal grade and CTCAE grade (r=0.724, p=0.008), were significantly correlated.

US findings in IMC were mainly similar to those of ulcerative colitis, but there were some findings that were characteristic only of IMC. Significant correlation was found between US findings, CS findings, and severity of colitis. Hence, US could be useful for the evaluation of IMC.

Here, we describe a case of temporary severe neutropenia after atezolizumab monotherapy and its treatment course. Atezolizumab monotherapy was introduced as a 6th-line treatment for a man in his late 60s, who was diagnosed with stage Ⅳ lung adenocarcinoma. The first treatment cycle was administered during hospitalization, and the patient presented with a fever of 37.8°C on the first day. The fever resolved after the administration of acetaminophen and naproxen, and the white blood cell count, neutrophil count, and other white blood cell fractions were normal. However, grade 3 leukopenia and grade 4 neutropenia appeared at the beginning of the third cycle, and treatment was discontinued. After treatment, monocyte count in the leukocyte fraction increased from approximately 10% to 25.6%. Lenograstim 100 μg subcutaneous injection and oral levofloxacin 500 mg once daily were started of onset of neutropenia, and he was hospitalized the next day. Laboratory findings upon admission showed a significant improvement to 5,300/µL for leukocytes and 3,376/µL for neutrophils. Lenograstim was discontinued, with no further decrease in the neutrophil count. Atezolizumab therapy was resumed, and there was no further reduction in leukocyte, neutrophil, or leukocyte fractions over about a 2-year period. Concomitant drugs were maintained during the atezolizumab treatment, suggesting that they did not induce neutropenia. In conclusion, we observed temporary severe neutropenia during atezolizumab monotherapy. Neutrophil recovery with cautious monitoring has enabled longer efficacy. We should consider temporary symptom occurrence in cases of haematological immune-related adverse events.

Checkpoint molecules are cell surface receptors on immune cells that mitigate excessive immune responses, but they have increased expression levels in cancer to facilitate immune escape. Checkpoint blockade therapies (e.g., anti-PD-1, anti-CTLA-4, and anti-LAG-3 therapy, among others) have been developed for multiple cancers. Colitis associated with checkpoint blockade therapy has pathophysiological similarities to inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. Current therapeutic guidelines for checkpoint blockade-induced colitis include corticosteroids and, if the patient is refractory to steroids, immunomodulating antibodies, such as anti-TNF and anti-integrin agents. Interestingly, immunomodulatory molecules, such as TNFα, are upregulated in both IBD and checkpoint-mediated colitis. The inflammatory colitis toxicity symptoms from checkpoint blockade are similar to clinical symptoms experienced by patients with IBD. The pathophysiologic, dietary, and genetic factors associated with IBD will be reviewed. We will then explain how the principles developed for the treatment of IBD can be applied to patients experiencing inflammatory bowel toxicity secondary to checkpoint blockade.

Immune checkpoint inhibitors have achieved clinical success in cancer treatment, but this treatment causes immune-related adverse events, including type 1 diabetes (T1D). Our aim was to test whether a JAK1/JAK2 inhibitor, effective at treating spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice, can prevent diabetes secondary to PD-L1 blockade.

Anti-PD-L1 antibody was injected into NOD mice to induce diabetes, and JAK1/JAK2 inhibitor LN3103801 was administered by oral gavage to prevent diabetes. Flow cytometry was used to study T cells and beta cells. Mesothelioma cells were inoculated into BALB/c mice to induce a transplantable tumour model.

Anti-PD-L1-induced diabetes was associated with increased immune cell infiltration in the islets and upregulated MHC class I on islet cells. Anti-PD-L1 administration significantly increased islet T cell proliferation and islet-specific CD8⁺ T cell numbers in peripheral lymphoid organs. JAK1/JAK2 inhibitor treatment blocked IFNγ-mediated MHC class I upregulation on beta cells and T cell proliferation mediated by cytokines that use the common γ chain receptor. As a result, anti-PD-L1-induced diabetes was prevented by JAK1/JAK2 inhibitor administered before or after checkpoint inhibitor therapy. Diabetes was also reversed when the JAK1/JAK2 inhibitor was administered after the onset of anti-PD-L1-induced hyperglycaemia. Furthermore, JAK1/JAK2 inhibitor intervention after checkpoint inhibitors did not reverse or abrogate the antitumour effects in a transplantable tumour model.

A JAK1/JAK2 inhibitor can prevent and reverse anti-PD-L1-induced diabetes by blocking IFNγ and γc cytokine activities. Our study provides preclinical validation of JAK1/JAK2 inhibitor use in checkpoint inhibitor-induced diabetes.