Rheumatic Immune-Related Adverse Events due to Immune Checkpoint Inhibitors-A 2023 Update.

With the aging of the population, malignancies are becoming common complications in patients with rheumatoid arthritis (RA), particularly in elderly patients. Such malignancies often interfere with RA treatment. Among several therapeutic agents, immune checkpoint inhibitors (ICIs) which antagonize immunological brakes on T lymphocytes have emerged as a promising treatment option for a variety of malignancies. In parallel, evidence has accumulated that ICIs are associated with numerous immune-related adverse events (irAEs), such as hypophysitis, myocarditis, pneumonitis, and colitis. Moreover, ICIs not only exacerbate pre-existing autoimmune diseases, but also cause de novo rheumatic disease-like symptoms, such as arthritis, myositis, and vasculitis, which are currently termed rheumatic irAEs. Rheumatic irAEs differ from classical rheumatic diseases in multiple aspects, and treatment should be individualized based on the severity. Close collaboration with oncologists is critical for preventing irreversible organ damage. This review summarizes the current evidence regarding the mechanisms and management of rheumatic irAEs with focus on arthritis, myositis, and vasculitis. Based on these findings, potential therapeutic strategies against rheumatic irAEs are discussed.

The effect of hormone therapy on physiological uptake of the endometrium on [18F]F-FDG PET in postmenopausal women.

OBJECTIVE: The effects of hormonal therapy, estrogen-based hormone replacement therapy (HRT), and anti-tumor hormone therapy, such as tamoxifen, on the physiological uptake of the endometrium on 2-deoxy-2[18F]fluoro-D-glucose ([18F]F-FDG) positron emission tomography (PET) in postmenopausal women have not been determined. We explored the effect of hormone therapy, particularly HRT, on physiological uptake in the endometrium of postmenopausal women. MATERIALS AND METHODS: Postmenopausal women receiving hormone therapy who underwent cancer screening using PET/computed tomography (CT) between June 2016 and April 2023 were included in the hormone therapy group (n = 21). Postmenopausal women with no history of hormone therapy were included in the control group (n = 49). First, the physiological endometrial uptake at menopausal age and at least 1 year thereafter was compared quantitatively (SUVmax) and qualitatively (4-point scale) in the control group, to assess when the endometrium ceased to show significant physiological [18F]F-FDG uptake after menopause. Endometrial uptake was compared between the hormone therapy and control groups. The association between HRT duration (months) and endometrial uptake (SUVmax) was evaluated. Endometrial thickness, measured using transvaginal ultrasonography, was also compared between the two groups. RESULTS: Endometrial uptake was significantly reduced both qualitatively and quantitatively (P < 0.05) at least 1 year after menopause in control patients, by which time most women (89.8%) no longer had significant endometrial uptake. The hormone therapy group (n = 21) showed higher FDG uptake in the endometrium compared to the control group (median SUVmax: 2.3 vs 1.9, P = 0.0011), as well as a higher visual score (P < 0.0001). HRT duration did not correlate with endometrial uptake (P = 0.097). Endometrial thickness in the hormone therapy group was significantly thicker than in the control group (median: 3.9 mm vs 1.8 mm, P = 0.002). CONCLUSION: Hormone therapy may affect physiological uptake in the endometrium in postmenopausal women.

Novel Artificial Intelligence-based Technology for Chest Computed Tomography Analysis of Idiopathic Pulmonary Fibrosis.

Rationale: There is a growing need to accurately estimate the prognosis of idiopathic pulmonary fibrosis (IPF) in clinical practice, given the development of effective drugs for treating IPF. Objectives: To develop artificial intelligence-based image analysis software to detect parenchymal and airway abnormalities on computed tomographic (CT) imaging of the chest and to explore their prognostic importance in patients with IPF. Methods: A novel artificial intelligence-based quantitative CT image analysis software (AIQCT) was developed by applying 304 high-resolution CT (HRCT) scans from patients with diffuse lung diseases as the training set. AIQCT automatically categorized and quantified 10 types of parenchymal patterns as well as airways, expressing the volumes as percentages of the total lung volume. To validate the software, the area percentages of each lesion quantified by AIQCT were compared with those of the visual scores using 30 plain high-resolution CT images with lung diseases. In addition, three-dimensional analysis for similarity with ground truth was performed using HRCT images from 10 patients with IPF. AIQCT was then applied to 120 patients with IPF who underwent HRCT scanning of the chest at our institute. Associations between the measured volumes and survival were analyzed. Results: The correlations between AIQCT and the visual scores were moderate to strong (correlation coefficient 0.44-0.95) depending on the parenchymal pattern. The Dice indices for similarity between AIQCT data and ground truth were 0.67, 0.76, and 0.64 for reticulation, honeycombing, and bronchi, respectively. During a median follow-up period of 2,184 days, 66 patients died, and 1 underwent lung transplantation. In multivariable Cox regression analysis, bronchial volumes (adjusted hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.16-1.53) and normal lung volumes (adjusted HR, 0.97; 95% CI, 0.94-0.99) were independently associated with survival after adjusting for the gender-age-lung physiology stage of IPF. Conclusions: Our newly developed artificial intelligence-based image analysis software successfully quantified parenchymal lesions and airway volumes. Bronchial and normal lung volumes on HRCT imaging of the chest may provide additional prognostic information on the gender-age-lung physiology stage of IPF.

Whole-body PET Imaging of T-cell Response to Glioblastoma.

PURPOSE: Immunotherapy is a promising approach for many oncological malignancies, including glioblastoma, however, there are currently no available tools or biomarkers to accurately assess whole-body immune responses in patients with glioblastoma treated with immunotherapy. Here, the utility of OX40, a costimulatory molecule mainly expressed on activated effector T cells known to play an important role in eliminating cancer cells, was evaluated as a PET imaging biomarker to quantify and track response to immunotherapy. EXPERIMENTAL DESIGN: A subcutaneous vaccination approach of CpG oligodeoxynucleotide, OX40 mAb, and tumor lysate at a remote site in a murine orthotopic glioma model was developed to induce activation of T cells distantly while monitoring their distribution in stimulated lymphoid organs with respect to observed therapeutic effects. To detect OX40-positive T cells, we utilized our in-house-developed 89Zr-DFO-OX40 mAb and in vivo PET/CT imaging. RESULTS: ImmunoPET with 89Zr-DFO-OX40 mAb revealed strong OX40-positive responses with high specificity, not only in the nearest lymph node from vaccinated area (mean, 20.8%ID/cc) but also in the spleen (16.7%ID/cc) and the tumor draining lymph node (11.4%ID/cc). When the tumor was small (<106 p/sec/cm2/sr in bioluminescence imaging), a high number of responders and percentage shrinkage in tumor signal was indicated after only a single cycle of vaccination. CONCLUSIONS: The results highlight the promise of clinically translating cancer vaccination as a potential glioma therapy, as well as the benefits of monitoring efficacy of these treatments using immunoPET imaging of T-cell activation.

Imaging alloreactive T cells provides early warning of organ transplant rejection.

Diagnosis of organ transplant rejection relies upon biopsy approaches to confirm alloreactive T cell infiltration in the graft. Immune molecular monitoring is under investigation to screen for rejection, though these techniques have suffered from low specificity and lack of spatial information. ImmunoPET utilizing antibodies conjugated to radioisotopes has the potential to improve early and accurate detection of graft rejection. ImmunoPET is capable of noninvasively visualizing the dynamic distribution of cells expressing specific immune markers in the entire body over time. In this work, we identify and characterize OX40 as a surrogate biomarker for alloreactive T cells in organ transplant rejection and monitor its expression by utilizing immunoPET. In a dual murine heart transplant model that has both syngeneic and allogeneic hearts engrafted in bilateral ear pinna on the recipients, OX40 immunoPET clearly depicted alloreactive T cells in the allograft and draining lymph node that were not observed in their respective isograft counterparts. OX40 immunoPET signals also reflected the subject's immunosuppression level with tacrolimus in this study. OX40 immunoPET is a promising approach that may bridge molecular monitoring and morphological assessment for improved transplant rejection diagnosis.

ICOS Is an Indicator of T-cell-Mediated Response to Cancer Immunotherapy.

Immunotherapy is innovating clinical cancer management. Nevertheless, only a small fraction of patient's benefit from current immunotherapies. To improve clinical management of cancer immunotherapy, it is critical to develop strategies for response monitoring and prediction. In this study, we describe inducible T-cell costimulator (ICOS) as a conserved mediator of immune response across multiple therapy strategies. ICOS expression was evaluated by flow cytometry, 89Zr-DFO-ICOS mAb PET/CT imaging was performed on Lewis lung cancer models treated with different immunotherapy strategies, and the change in tumor volume was used as a read-out for therapeutic response. ImmunoPET imaging of ICOS enabled sensitive and specific detection of activated T cells and early benchmarking of immune response. A STING (stimulator of interferon genes) agonist was identified as a promising therapeutic approach in this manner. The STING agonist generated significantly stronger immune responses as measured by ICOS ImmunoPET and delayed tumor growth compared with programmed death-1 checkpoint blockade. More importantly, ICOS ImmunoPET enabled early and robust prediction of therapeutic response across multiple treatment regimens. These data show that ICOS is an indicator of T-cell-mediated immune response and suggests ICOS ImmunoPET as a promising strategy for monitoring, comparing, and predicting immunotherapy success in cancer. SIGNIFICANCE: ICOS ImmunoPET is a promising strategy to noninvasively predict and monitor immunotherapy response.See related commentary by Choyke, p. 2975.

Visualization of Activated T Cells by OX40-ImmunoPET as a Strategy for Diagnosis of Acute Graft-versus-Host Disease.

Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT), mediated primarily by donor T cells that become activated and attack host tissues. Noninvasive strategies detecting T-cell activation would allow for early diagnosis and possibly more effective management of HCT recipients. PET imaging is a sensitive and clinically relevant modality ideal for GvHD diagnosis, and there is a strong rationale for the use of PET tracers that can monitor T-cell activation and expansion with high specificity. The TNF receptor superfamily member OX40 (CD134) is a cell surface marker that is highly specific for activated T cells, is upregulated during GvHD, and mediates disease pathogenesis. We recently reported the development of an antibody-based activated T-cell imaging agent targeting OX40. In the present study, we visualize the dynamics of OX40 expression in an MHC-mismatch mouse model of acute GvHD using OX40-immunoPET. This approach enabled visualization of T-cell activation at early stages of disease, prior to overt clinical symptoms with high sensitivity and specificity. This study highlights the potential utility of the OX40 PET imaging as a new strategy for GvHD diagnosis and therapy monitoring. SIGNIFICANCE: OX40-immunoPET imaging is a promising noninvasive strategy for early detection of GvHD, capable of detecting signs of GvHD pathology even prior to the development of overt clinical symptoms.

Clinical and radiological features of immune checkpoint inhibitor-related pneumonitis in lung cancer and non-lung cancers.

OBJECTIVE: To investigate the clinical and radiological features of immune checkpoint inhibitor-related pneumonitis (ICI-P), a rare but serious pulmonary complication of cancer immunotherapy and to evaluate key differences between lung cancer (LC) and non-LC patients. METHODS: 247 patients (LC, n = 151) treated with ICI for malignancies were retrospectively screened in a single institute. The number of patients, history of other immune-related adverse events (irAE), the onset, serum KL-6 levels, and chest CT features (types of pneumonitis, symmetry, laterality, location) were recorded for the ICI-P population and compared for LC and non-LC groups. RESULTS: ICI-P was identified in 26 patients in total (LC, n = 19; non-LC, n = 7). The incidence of other irAE was significantly higher in ICI-P group (63%) compared with patients without ICI-P (34%) (p = 0.0056). An earlier onset of ICI-P was recorded in LC (78 days) compared to non-LC patients (186 days) (p = 0.0034). Serum KL-6 was significantly elevated only in the non-LC group when ICI-P was noticed (p = 0.029). Major CT findings of ICI-P, irrespective of primary disease, were organizing pneumonia pattern and ground glass opacities. LC patients commonly exhibited consolidation and traction bronchiectasis and were prone to asymmetrical shadows (p < 0.001). Non-LC patients were more likely to exhibit symmetrical infiltrations. A small fraction of both groups experienced relapse or moving patterns of ICI-P. CONCLUSION: ICI-P patients more often experienced other irAE prior to the development of ICI-P. The characteristics of ICI-P can differ in terms of the onset, KL-6 reliability, and chest CT findings between LC and non-LC patients. ADVANCES IN KNOWLEDGE: In ICI-P patients, a history of other irAE can be more frequently observed. Differences in disease onset and radiological patterns between LC and non-LC patients might be helpful to make a diagnosis of ICI-P; however, longitudinal observation of chest CT scans is advised to observe the pneumonitis activity irrespective of cancer types.