The objective of this study was to conduct a systematic review of case reports documenting the development of antiphospholipid syndrome or antiphospholipid syndrome-related features after an infection.
TPS9600 Background: Immune checkpoint inhibitors (ICIs) are approved for multiple malignancies, however, durable remission rates with ICI monotherapy remains low. Combined treatment with anti-CTLA-4 and anti-PD1 has shown higher response rates in several cancers but is associated with up to 60% grade 3/4 immune-related adverse events (irAEs) leading to frequent treatment discontinuation. The need for corticosteroids to control irAEs may further diminish anti-tumor activity. A multi-disciplinary approach using clinical, preclinical, and translational analyses implicated the IL-6/Th17 axis in both ICI-related autoimmunity and resistance. Further, preliminary data showed that targeting interleukin 6 (IL-6) could be an effective approach to reduce irAEs while maintaining and possibly boosting the antitumor immune response. Methods: We are conducting a phase II, open-label, single center study to evaluate the use of combination treatment with tocilizumab (toci; anti-IL6), ipilimumab (ipi; anti-CTLA4) and nivolumab (nivo; anti-PD1) as a front-line therapy for patients (pts) with treatment-naïve advanced cutaneous melanoma (cohort 1), urothelial carcinoma (cohort 2), and EGFR mutant non-small cell lung cancer after tyrosine kinase inhibitors failure (cohort 3) (NCT04940299). Ten pts per disease site will be enrolled, plus an additional 25 melanoma pts in an expansion cohort. Key inclusion criteria are age ≥18 years (yrs) and histologically confirmed locally advanced or metastatic disease, with specific eligibility criteria defined for each cohort. Patients with interstitial lung diseases, autoimmune diseases, infection, or conditions requiring immunosuppressive therapies are not eligible, but stable asymptomatic brain mets are allowed. Ipi/Nivo dosing is as per approved disease indications: in cohort 1 &2, ipi 3 mg/kg + nivo 1 mg/kg is administered intravenously (IV) every 3 weeks (wks) for 4 doses then nivo 480 mg/4 wks up to 2 yrs. In cohort 3, IV ipi 1 mg/kg/6 wks + nivo 3 mg/kg/2 wks is administered up to 2 yrs. In all 3 cohorts, subcutaneous (SQ) toci 162 mg/2wks is administered up to 12 wks. Imaging is every 12 wks up to 2 yrs or until dose-limiting toxicities or progression. The primary outcome is safety/tolerability of the triple therapy. The secondary outcomes are antitumor efficacy and overall survival. Additionally, tumor and blood samples are being collected for longitudinal immune analysis, including gene expression and multiplex histochemistry to identify predictive biomarkers of response, resistance, and toxicity. The trial opened in October 2021 and has enrolled 14 patients to date. Clinical trial information: NCT04940299.
A decrease in bone mass has been described in a high percentage with increased risk of osteoporosis in JIA subtypes. The pathogenesis of bone loss in active JIA is complex, and results in reduced bone mineral density. Recent data have indicated an overlapping pathway between bone biology and biology of inflammation giving impression that inflammation may have a role in pathology of osteoporosis. Understanding the role of OPG/RANK/RANKL modulation in pathogenesis of bone loss among JIA subtypes will hold the key for identification of patients at risk and for management of osteoporosis.
Objectives
To evaluate the role of receptor activation of nuclear factor kB (RANK)/receptor activator of nuclear factor kB ligand (RANKL)/osteoprotegerin (OPG) modulation in juvenile idiopathic arthritis (JIA) subtypes with and without bone erosions.
Methods
Seventy children presenting JIA subtypes were recruited for the study and were chosen according to ILAR, 2001 criteria. They were compared with thirty healthy controls of matched age, sex, and ethnicity. Both groups had the average dietary intake of calcium products and sun exposure. Clinical presentations, laboratory investigations, and treatments used especially corticosteroids were recorded. JIA subtypes were oligo articular, polyarticular RF negative, RF positive, systemic onset JIA (SOJIA), enthesitis related arthritis (ERA) and psoriatic (PsA). All involved articulations were assessed by plain radiography for juxtaarticular osteoporosis and bone erosions. Disease activity was measured by Juvenile Arthritis Disease Activity Score (JADAS-27). Serum levels of OPG, RANK and RANKL were measured with estimation of OPG/RANKL ratio, using an enzyme-linked immunosorbent assay (ELISA).
Results
A significant low serum concentration of OPG was found in all JIA subgroups. There was a significant increase in serum level of RANKL, and a significant decrease of OPG/RANKL ratio. OPG/RANKL ratio was significantly lower in SOJIA, active polyarticular JIA and ERA than other groups within the subtypes. A significant low OPG/RANKL ratio was found in patients with prolonged steroid use and those with erosions. To our knowledge, this research is the first one studied these biomarkers in JIA subtypes, including ERA.
Conclusions
OPG/RANKL ratio can be an early predictor of increased bone resorption, and may be a valuable biomarker for bone damage in JIA subtypes. Systemic onset juvenile idiopathic arthritis, active polyarticular juvenile idiopathic arthritis and enthesitis related arthritis are at higher risk for osteoporosis.
This review summarizes the current evidence on inflammatory arthritis following cancer treatment with immune checkpoint inhibitors (ICI), and the effects of these therapies in patients with preexisting autoimmune arthritis.As the use of ICI for cancer therapy continues to expand, a myriad of immune-related adverse events (irAE) caused by these therapies are being recognized. Arthritis has been increasingly reported as a de novo irAE, presenting sometimes as a well defined disorder, such as rheumatoid arthritis or psoriatic arthritis, and in other occasions as undifferentiated monoarthritis, oligoarthritis, or polyarthritis. Remitting seronegative symmetric synovitis with pitting edema (RS3PE) and tenosynovitis have also been reported. Most published cases are reported as mild to moderate in severity. The most common treatment for arthritis has been systemic corticosteroids, although several patients have been treated with traditional disease-modifying antirheumatic drugs (DMARD), and a few, with biologic DMARD.Arthritis following ICI therapy is pleomorphic. Prompt identification and treatment are imperative to achieve optimal outcomes. Management should be multidisciplinary, including rheumatologists and oncologists, to ensure prompt symptomatic and functional management and continuation of cancer therapy as appropriate.
Immune checkpoint blockade (ICB) for cancer is associated with high response rates but also high rates of adverse events. To elucidate the underlying immunobiology, we profiled gene expression in intestinal, colitis, and tumor tissue from ICB-treated patients, with parallel studies in preclinical models, and validated our findings in a review of clinical cohort treated with interleukin-6 blockade. Expression of interleukin-6, neutrophil and chemotactic markers was higher in colitis than in normal intestinal tissue. The genes upregulated in colitis were not upregulated in responding tumors from patients receiving ICB. In murine models, interleukin-6 blockade was associated with improved tumor control and a higher density of CD4/CD8 effector T-cells, with reduced Th17, macrophages, and myeloid cells. In an experimental autoimmune encephalomyelitis (EAE) model with tumors, combined interleukin-6 blockade and ICB enhanced tumor rejection while simultaneously mitigating EAE symptoms versus ICB alone. Interleukin-6 blockade with ICB could de-couple autoimmunity from antitumor immunity.
Immune checkpoint inhibitors (ICIs) have resulted in unprecedented advances in the treatment of cancer. By disinhibiting the immune system, they enhance anti-tumor immunity, but provoke off-target inflammatory and immune-related adverse events (irAEs) which can seriously impact morbidity and mortality. The exact immunobiology of irAEs is not completely understood, but may involve specific immune pathways. To date, there is no validated biomarker test to predict the development of irAEs in patients treated with ICIs.
Methods
To identify possible biomarkers of irAEs, we performed in-depth proteomic profiling of blood samples obtained from cancer patients receiving ICIs. The plasmas were processed with Hu-14 immuno-depletion column (Agilent Technologies) and the samples were labeled with TMT (Thermo Scientific). The proteins were next pre-fractionated with HPLC, trypsin digested and analyzed by nanoAQUITY LC coupled Synapt G2-Si ion-mobility mass spectrometry (WATERS).
Results
A total of 12 patients were enrolled in the study; all were receiving anti-programmed cell death-1 (PD-1) agents. Cancer types included melanoma (n=9), renal cell carcinoma (n=2), and non-small cell lung cancer (n=1). Eight patients had irAEs with active toxicity symptoms at blood draw (4 with pneumonitis-irAE and 4 with arthritis-irAE); 6 of those patients were receiving corticosteroids (ranging from 5 to 60 mg/d), and 1 was receiving tocilizumab (an anti-IL-6 receptor antibody). Four patients who completed a minimum of one year of anti-PD1 treatments without irAEs were enrolled as control group. Median time from ICI initiation until blood draw was 16 months (range, 4–31) among patients with irAEs and 23 months (range, 17–28) among controls.We identified 925 protein gene products from 2.5 million mass spectra that can cover 107 dynamic range of plasma proteins. Among them, 19 proteins showed statistically significant differences between patients with and without irAEs (P<0.05) (figure 1). Nine proteins including CFB, CLEC3B, ITIH4, HPX, RARRES2, TF, OAF, MYL12A, and MYL12B were significantly upregulated in patients with irAEs; MYL12A and MYL12B are known to be elevated in airway inflammation of lung tissues. While, 10 other proteins including APOC4, AVPR2, B9D1, DPEP2, JCHAIN, LINC00238, PLG, RAB40C, TCF4, and ZFP30 were significantly downregulated in patients with irAEs (figure 2).
Conclusions
In-depth plasma proteome analysis identified possible biomarkers of adverse events modulated by ICI treatment. We plan a prospective validation cohort study of melanoma patients initiating treatment with ICIs to further evaluate the potential clinical utility of the identified biomarkers and their association with immune toxicity, and tumor response to ICI therapy.
Ethics Approval
The study was approved by The Institutional Review Board at The University of Texas MD Anderson Cancer Center, approval number PA16-0928
Consent
Written informed consent was obtained from all patients who agreed to participate in the study
