Immunotherapy for Thymomas and Thymic Carcinomas: Current Status and Future Directions.

Thymic epithelial tumors are a histologically diverse group of cancers arising from the epithelial compartment of the thymus. These tumors are characterized by a low tumor mutation burden, a lack of actionable genomic changes, and, especially with thymomas, defects in immune tolerance. Surgery is the mainstay of the management of resectable disease, whereas advanced, unresectable tumors are treated with platinum-based chemotherapy. Disease recurrence can occur months to years after frontline treatment. Although several options are available for conventional treatment of recurrent thymic tumors, response rates are generally low, and treatment-related toxicity can affect quality of life. A subset of patients benefit from biologic therapies, but there remains an unmet need for the development of new treatments. Immune checkpoint inhibitors are safe, clinically active, and have contributed to an improvement in survival for patients with a wide variety of cancers. However, the application of these revolutionary treatments for thymic cancers is limited to their use for the management of recurrent thymic carcinoma because of the risk of immune toxicity. In this paper, we review the current uses of immunotherapy for the management of thymic epithelial tumors and highlight potential strategies to improve safety and broaden the application of these treatments for patients with thymic cancers.

Immunotherapy for Management of Thymic Epithelial Tumors: A Double-Edged Sword.

Thymic epithelial tumors (TETs) are rare thoracic cancers that are broadly classified as thymomas and thymic carcinomas. Surgery is the cornerstone of management for early-stage disease. There are a limited number of effective treatment options for patients with advanced or recurrent disease. The occurrence of paraneoplastic autoimmune disorders in patients with TETs, especially thymomas, creates significant challenges for the development of immunotherapy, including immune checkpoint inhibitors, as a feasible treatment option. In addition, patients with TETs are at increased risk for the development of immune-mediated toxicity with a predilection for musculoskeletal and neuromuscular adverse events upon treatment with immunotherapy. The identification of biomarkers of response and toxicity is expected to play a key role in harnessing the benefits of immunotherapy for patients with TETs. In this paper we review the biology of TETs and the potential effects on the tolerability of immunotherapy. The results of clinical trials of immune checkpoint inhibitors for the treatment of advanced TETs are described to understand the potential risks and benefits of immunotherapy. We also provide an overview of future avenues for treatment with novel immunotherapeutic modalities and opportunities to develop biomarkers to improve the safety and tolerability of immunomodulatory treatments in patients with TETs.

Joint-Predominant Rheumatic Complications of Immune Checkpoint Inhibitor Therapy in Patients with Thymic Epithelial Tumors.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a significant concern for patients with thymic epithelial tumors (TETs) due to defects in immune tolerance. An increased risk of skeletal and cardiac muscle inflammation following treatment with ICIs is well recognized in patients with advanced TETs. However, uncommon musculoskeletal and rheumatic complications can also occur. The cases presented in this report highlight the spectrum of presentation of immune-mediated, joint-predominant musculoskeletal adverse events in patients with advanced TETs treated with ICIs, including polymyalgia rheumatica-like illness and inflammatory arthritis.

Tolerability of Coronavirus Disease 2019 Vaccines, BNT162b2 and mRNA-1273, in Patients With Thymic Epithelial Tumors.

INTRODUCTION: Defects in immunologic self-tolerance result in an increased risk for development of paraneoplastic autoimmune diseases (ADs) and immune-mediated toxicity in response to immune stimulation in individuals with thymic epithelial tumors (TETs). We conducted a survey to evaluate the tolerability of coronavirus disease 2019 (COVID-19) mRNA vaccines in patients with TETs, including individuals with preexisting AD. METHODS: After reviewing published data on adverse events associated with the BNT162b2 (Pfizer, Inc., and BioNTech) and mRNA-1273 (ModernaTX, Inc.) mRNA vaccines, we designed and administered a questionnaire to participants at the following three time points: after each dose of vaccination and 1 month after the final dose. Questions related to AD and use of immunosuppressive drugs were included. Descriptive statistics were used to analyze data, and results were compared with previously described results related to the BNT162b2 and mRNA-1273 vaccines. RESULTS: From February 26 to June 1, 2021, we administered the survey to 54 participants (median age = 58 y, thymoma = 33, preexisting AD = 19). Common adverse events included injection site pain, fatigue, and headaches. There were no vaccination-related hospitalizations or deaths. Autoimmune flares occurred in three patients (16%) after the first dose and three patients (17%) after the second dose. Most AD flares were mild and self-limited. One patient (2%) was diagnosed with having a new AD after vaccination. CONCLUSIONS: Tolerability of COVID-19 mRNA vaccines in patients with TETs is comparable to the general population. Most patients with preexisting AD did not experience disease flares, and the development of new AD was rare. Patients with TETs should be encouraged to get vaccinated against COVID-19 owing to the documented benefits of vaccination and manageable risk profile.

Caregiver-assisted coping skills training for patients with COPD: background, design, and methodological issues for the INSPIRE-II study.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a progressive illness characterized by airflow obstruction and dyspnea that afflicts over 12 million people and represents a leading cause of death in the United States. Not surprisingly, COPD is often associated with emotional distress and reduced psychosocial adjustment, which can negatively impact physical functioning and impair quality of life. However, the psychosocial consequences of COPD remain largely untreated. A previous randomized trial from our research team demonstrated that coping skills training (CST) can improve pulmonary-specific quality of life among pulmonary patients awaiting lung transplant (the INSPIRE study). To date, however, no studies have examined the effects of a caregiver-assisted CST intervention in patients with COPD with less severe disease. PURPOSE: INSPIRE II is a randomized clinical trial (RCT) funded by the NHLBI to evaluate the effects of telephone-based enhanced CST for patients with COPD and their caregivers compared to standardized medical care (SMC) including COPD education and symptom monitoring on medical outcomes, physical functioning, and quality of life. METHODS: Six hundred COPD patients and their respective caregivers recruited from Duke University and Ohio State University will be evaluated and randomized (in a 1:1 ratio) to enhanced CST (including sessions promoting physical activity, relaxation, cognitive restructuring, communication skills, and problem solving) or to SMC. The primary outcomes include all-cause mortality, COPD-related hospitalizations/ physician visits, and quality of life. These endpoints will be measured through self-report questionnaires, behavioral measures of functional capacity (i.e., accelerometer and six minute walk test) and pulmonary function tests (e.g., FEV(1)). RESULTS: This article reviews prior studies in the area and describes the design of INSPIRE-II. Several key methodological issues are discussed including the delivery of CST over the telephone, encouraging physical activity, and inclusion of caregivers as patient coaches to enhance the effectiveness of the intervention. LIMITATIONS: We recognize that SMC does not adequately control for attention, support, and non-specific factors, and that, in theory, non-specific effects of the intervention could account for some, or all, of the observed benefits. However, our fundamental question is whether the telephone intervention produces benefits over-and-above the usual care that patients typically receive. The SMC condition will provide education and additional weekly telephone contact, albeit less than the attention received by the CST group. We recognize that this attention control condition may not provide equivalent patient contact, but it will minimize group differences due to attention. We considered several alternative designs including adding a third usual care only arm as well as an education only control arm. However, these alternatives would require more patients, reduce the power to detect significant effects of our primary medical endpoints, and add a significant additional expense to the cost of the study that would make such an undertaking neither scientifically or financially viable. CONCLUSIONS: We believe that this novel approach to patient care in which caregivers are used to assist in the delivery of coping skills training to patients with COPD has the potential to change the way in which COPD patients are routinely managed in order to reduce distress, enhance quality of life, and potentially improve medical outcomes.