Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells.

Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these products are generally safe, efficacy is limited. Therefore, we generated and characterized a potent, fully human anti-MSLN CAR. In a phase 1 dose-escalation study of patients with solid tumors, we observed two cases of severe pulmonary toxicity following intravenous infusion of this product in the high-dose cohort (1-3 × 108 T cells per m2). Both patients demonstrated progressive hypoxemia within 48 h of infusion with clinical and laboratory findings consistent with cytokine release syndrome. One patient ultimately progressed to grade 5 respiratory failure. An autopsy revealed acute lung injury, extensive T cell infiltration, and accumulation of CAR T cells in the lungs. RNA and protein detection techniques confirmed low levels of MSLN expression by benign pulmonary epithelial cells in affected lung and lung samples obtained from other inflammatory or fibrotic conditions, indicating that pulmonary pneumocyte and not pleural expression of mesothelin may lead to dose-limiting toxicity. We suggest patient enrollment criteria and dosing regimens of MSLN-directed therapies consider the possibility of dynamic expression of mesothelin in benign lung with a special concern for patients with underlying inflammatory or fibrotic conditions.

Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy.

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)-negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment. SIGNIFICANCE: CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy. This article is highlighted in the In This Issue feature, p. 101.

A Guide for Intentional Home Telehealth Assessment: Patient and Caregiver Perceptions.

Telehealth can provide expanded access to healthcare. The Comprehensive Patient Assessment for Using Telehealth at Home is a comprehensive approach for an intentional remote patient meeting that provides a high-quality patient encounter when using technology. In this study, we describe the perspectives of seriously ill older adults and their caregivers on the usability of the Comprehensive Patient Assessment for Using Telehealth at Home using technology to meet remotely and assess patients in their own homes. This study used qualitative description with semistructured interviews to explore participants' user experience of the telehealth visit using the Comprehensive Patient Assessment for Using Telehealth at Home. The overarching theme of participants' experiences with the Comprehensive Patient Assessment for Using Telehealth at Home intervention was of a continuum of acceptance of technology use. Participants felt that a combination of in-person and telehealth visits was ideal, and telehealth visits were appropriate for routine visits. In-person assessments would be necessary if the communication was not adequately received through remote technology. Other themes were satisfaction and detractors, usability of the technology, privacy and confidentiality, and timing of the telehealth visit. Telehealth presents new opportunities for patients to engage and connect with providers, allowing them to seek care in the comfort of their own home. In some circumstances, telehealth is appropriate but is not a permanent replacement for in-person visits.

"Tipping point" concept analysis in the family caregiving context.

AIM: Analyze the concept "tipping point" in the older adult family caregiving context to further knowledge about caregiving families, enhancing transdisciplinary theory, research, and practice. BACKGROUND: While used commonly in some disciplines, how "tipping point" has been used in health care, generally, and in relation to caregiving families, specifically, is less clear. This project was conducted to offer conceptual clarity to tipping point. DESIGN: Walker and Avant's framework. DATA SOURCE: Searches of scholarly literature in PsycINFO, CINAHL, and PubMed using the search term "tipping point" in either title or abstract. REVIEW METHODS: Definitions used were extracted; instances when the concept was implied but the actual term "tipping point" was not used and contexts where the term was used or implied were identified. RESULTS: The composite definition of a caregiving tipping point is a seemingly abrupt, severe, and absolute change event involving either the older adult or caregiver(s), or both that indicates a breakdown in the status quo of the caregiving system. CONCLUSIONS: Transdisciplinary research, care, and policy should treat caregiving families as complex systems, use longitudinal assessments, and include colloquial communication. Early detection of impending tipping points will provide family-centered decisional support and enhance families' quality of life and safety.