Immune-related adverse events caused by combined immune checkpoint inhibitor therapy with nivolumab and ipilimumab for lung cancer

It has been less than a decade since immune checkpoint inhibitors became the mainstay of lung cancer treatment, and 2020 saw the advent of the era of complex immune checkpoint inhibitors. Although clinical trials have shown that the therapeutic effects of complex immune checkpoint inhibitors are favorable, they are associated with an increase in adverse events. The use of combined immune checkpoint inhibitors in clinical practice has progressed slowly, and the frequency and types of adverse events they cause remain unclear. Here we report the adverse events of six patients with lung cancer treated with regimens containing nivolumab and ipilimumab in 2021. Four of the six patients had grade 3 or higher adverse events, including one patient with lung injury and one patient with skin injury, both of whom died. The timing and nature of the adverse events were difficult to predict.

Scar Sarcoidosis as Presenting Finding in Pembrolizumab Induced Systemic Sarcoidosis in Stage III Melanoma: A Case Report

Immune checkpoint blockade using inhibition of Programmed Cell Death-1 (PD-1) improves both progression-free and overall survival in patients with advanced melanoma, but is associated with a unique set of toxicities termed immune-related Adverse Events (irAEs). We present a case of a man with stage IIIc melanoma who was treated with pembrolizumab (anti PD-1). Two months after initiation of the therapy, the patient developed subcutaneous nodules on his upper lip and right knee, both in a pre-existing scar. Histological examination showed non-necrotising granuloma, most consistent with sarcoidosis. PET-CT showed hypermetabolic mediastinal and hilar adenopathies as well as lung lesions and some cutaneous and subcutaneous metabolic hot spots. Bronchoscopy with biopsy of a lymph node confirmed the diagnosis of sarcoidosis. Pembrolizumab was withheld, whereby a gradual decrease and near spontaneous resolution of all lesions was seen over a period of approximately 6 months. The patient is currently in follow up with no evidence of disease recurrence.Our case shows a unique presentation of sarcoidosis in old scar tissue as presenting symptom of pembrolizumab-related systemic sarcoidosis and demonstrates the importance of histological examination of new lesions occurring during checkpoint inhibitor therapy in order to avoid misdiagnosis of melanoma progression.

Il-2 in combination with immune checkpoints inhibitors as a promising approach for cancer immunotherapy: A literature review

Relevance: Interleukin-2 (IL-2) alone has been shown to induce tumor regression and approved to treat metastatic renal cancer and melanoma. Checkpoint inhibitors realize their therapeutic effect through stimulation of immune system effectors; one of such mechanisms is the enhancement of IL-2 production by T-helpers. The purpose of the study was to determine the effectiveness of IL-2 administration as a component of combined immunotherapy with immune checkpoint inhibitors and to suggest the mechanisms by which IL-2 can reduce the frequency and severity of side effects during checkpoint inhibitor therapy without reducing their effectiveness. Methods: The literature search was performed in the PubMed, SCOPUS, and Web of Science databases by the keywords in article titles: “immunotherapy,” “checkpoint inhibitors,” “interleukin-2,” and “combination therapy” for the period 2011-2021. A total of 248 relevant articles were found. The review’s inclusion criteria were: clinical cases; data of clinical research methods; data on humans/body fluids from humans; literature reviews and meta-analyses. The selected 24 articles met the search criteria and were included in the review. Results: The combined action of IL-2 and сheckpoint inhibitors increases the proliferative and killer activity of the antitumor immunity effectors compared to the action of the same drugs in mono-mode at a level exceeding the summation effect. Conclusion: The combination of IL-2 and сheckpoint inhibitors can increase the effectiveness of anticancer treatment and is a promising area of immunotherapy

Immune Checkpoint Inhibitor Therapy for Recurrent Meningiomas: A Retrospective Chart Review

Introduction: Meningiomas that progress after surgery and radiotherapy represent an unmet medical need. Expression of PD-1 and PDL-1 has been demonstrated in meningiomas and is proportional to tumor grade, suggesting a potential role for anti-PD-1/anti-PDL-1 inhibitor therapy. We explored the efficacy of immune checkpoint inhibitor therapy for recurrent meningiomas with primary endpoints of progression-free survival (PFS) and overall survival (OS).Methods: This is a retrospective chart review of patients with meningioma who were treated with PD-1 inhibitors at UPMC Hillman Cancer Center. Any patient over age 18 who received immunotherapy was included in this study. Patients received treatment until development of disease progression, intolerable toxicities or adverse events, death, or oncologist decision. Serial radiographic assessments were made every 3-6 months.Results: Between January 2015 and November 2021, eight patients received anti-PD-1 therapy. All patients underwent tumor resection and radiosurgery, and four patients received prior systemic therapy. Six out of eight patients experienced symptomatic perilesional edema and three patients experienced exacerbation of seizures. Median PFS was 7 months (95% CI 1-24) and median OS was 1.75 years (95% CI 1.5-4.0). In patients with positive PD-1 or PD-L1 expression, median PFS was 2 years and median OS was 3 years.Conclusion: Anti-PD-1 therapy was associated with a manageable safety profile in patients with recurrent meningiomas. Patients with WHO Grade III tumors and positive PD-1/PD-L1 expression were noted to have increased PFS and OS, suggesting a potential role for immunotherapy in this specific subset of patients. Further studies are needed to investigate this in a larger patient population.

Nivolumab-induced exocrine pancreatic insufficiency

Immune checkpoint inhibition is the standard-of-care for many advanced cancers. Side effects of therapy may prevent optimal treatment of the cancer. Management of side effects is dominated by recommendations derived from oncological, not gastroenterological practice. We report a patient who developed pancreatic insufficiency during checkpoint inhibitor therapy with a programmed cell death receptor 1 inhibitor, nivolumab, which if not diagnosed would have prevented ongoing treatment. This is a problem which affects approximately 1 in 100 patients treated with this agent but is rarely recognised. Gastroenterologists need to be aware of the spectrum of gastrointestinal disorders which occur after immunotherapy to treat cancer.

MIRS: an AI scoring system for predicting the prognosis and therapy of breast cancer

Current scoring systems for prognosis of breast cancer are available but usually consider only one prognostic feature. We aim to develop a novel prognostic scoring system based on both immune-infiltration and metastatic features to not only assess the patient prognoses more accurately but also guide therapy for patients with breast cancer. Computational immune-infiltration and gene profiling analysis identified a 12-gene panel firstly characterizing immune-infiltrating and metastatic features. Neural network model yielded a precise prognostic scoring system called metastatic and immunogenomic risk score (MIRS). The influence of MIRS on the prognosis and therapy of breast cancer was then comprehensively investigated. MIRS significantly stratifies patients into high risk-group (MIRShigh) and low risk-group (MIRSlow) in both training and test cohorts. The MIRSlow patients exhibit significantly improved survival rate compared with MIRShigh patients. A series of analyses demonstrates that MIRS can well characterize the metastatic and immune landscape of breast cancer. Further analysis on the usage of MIRS in chemotherapy suggests that MIRShigh patients may benefit from three chemotherapeutic drugs (Cisplatin, Tamoxifen and Vincristine). Higher immune infiltration and significantly prolonged survival are observed in MIRSlow patients, indicating a better response in immune checkpoint inhibitor therapy. Our analysis demonstrates that MIRS could effectively improve the accuracy of prognosis for patients with breast cancer. Also, MIRS is a useful webtool, which is deposited at https://lva85.github.io/MIRS/, to help clinicians in designing personalized therapies for patients with breast cancer.

Deep Learning-Based Body Composition Analysis Predicts Outcome in Melanoma Patients Treated with Immune Checkpoint Inhibitors

Previous studies suggest an impact of body composition on outcome in melanoma patients. We aimed to determine the prognostic value of CT-based body composition assessment in patients receiving immune checkpoint inhibitor therapy for treatment of metastatic disease using a deep learning approach. One hundred seven patients with staging CT examinations prior to initiation of checkpoint inhibition between January 2013 and August 2019 were retrospectively evaluated. Using an automated deep learning-based body composition analysis pipeline, parameters for estimation of skeletal muscle mass (skeletal muscle index, SMI) and adipose tissue compartments (visceral adipose tissue index, VAI; subcutaneous adipose tissue index, SAI) were derived from staging CT. The cohort was binarized according to gender-specific median cut-off values. Patients below the median were defined as having low SMI, VAI, or SAI, respectively. The impact on outcome was assessed using the Kaplan–Meier method with log-rank tests. A multivariable logistic regression model was built to test the impact of body composition parameters on 3-year mortality. Patients with low SMI displayed significantly increased 1-year (25% versus 9%, p = 0.035), 2-year (32% versus 13%, p = 0.017), and 3-year mortality (38% versus 19%, p = 0.016). No significant differences with regard to adipose tissue compartments were observed (3-year mortality: VAI, p = 0.448; SAI, p = 0.731). On multivariable analysis, low SMI (hazard ratio (HR), 2.245; 95% confidence interval (CI), 1.005–5.017; p = 0.049), neutrophil-to-lymphocyte ratio (HR, 1.170; 95% CI, 1.076–1.273; p < 0.001), and Karnofsky index (HR, 0.965; 95% CI, 0.945–0.985; p = 0.001) remained as significant predictors of 3-year mortality. Lowered skeletal muscle index as an indicator of sarcopenia was associated with worse outcome in patients with metastatic melanoma receiving immune checkpoint inhibitor therapy.