Tumor-Targeted Nonablative Radiation Promotes Solid Tumor CAR T-cell Therapy Efficacy.

Infiltration of tumor by T cells is a prerequisite for successful immunotherapy of solid tumors. In this study, we investigate the influence of tumor-targeted radiation on chimeric antigen receptor (CAR) T-cell therapy tumor infiltration, accumulation, and efficacy in clinically relevant models of pleural mesothelioma and non-small cell lung cancers. We use a nonablative dose of tumor-targeted radiation prior to systemic administration of mesothelin-targeted CAR T cells to assess infiltration, proliferation, antitumor efficacy, and functional persistence of CAR T cells at primary and distant sites of tumor. A tumor-targeted, nonablative dose of radiation promotes early and high infiltration, proliferation, and functional persistence of CAR T cells. Tumor-targeted radiation promotes tumor-chemokine expression and chemokine-receptor expression in infiltrating T cells and results in a subpopulation of higher-intensity CAR-expressing T cells with high coexpression of chemokine receptors that further infiltrate distant sites of disease, enhancing CAR T-cell antitumor efficacy. Enhanced CAR T-cell efficacy is evident in models of both high-mesothelin-expressing mesothelioma and mixed-mesothelin-expressing lung cancer-two thoracic cancers for which radiotherapy is part of the standard of care. Our results strongly suggest that the use of tumor-targeted radiation prior to systemic administration of CAR T cells may substantially improve CAR T-cell therapy efficacy for solid tumors. Building on our observations, we describe a translational strategy of "sandwich" cell therapy for solid tumors that combines sequential metastatic site-targeted radiation and CAR T cells-a regional solution to overcome barriers to systemic delivery of CAR T cells.

Implementing a thoracic enhanced recovery with ambulation after surgery program: key aspects and challenges.

Enhanced recovery after surgery (ERAS) protocols aim to improve operative outcomes by focusing on perioperative care, including early mobilization, limitation of narcotics, and maintenance of fluid balance. We implemented a T-ERAAS (Thoracic-Early Recovery with Ambulation After Surgery) protocol which focused on early ambulation, with the rationale that a patient's mobility may be a reproducible and measurable metric for their overall status-pain control, respiratory function, cardiac function, and patient satisfaction. We set a benchmark distance of 250 feet for our early ambulation goal and redefined "early" as within the first hour post extubation. We describe some of the major aspects to our program as well as some of the challenges and successes during our 8-year experience following the implementation of this program.

Endoluminal Approaches to Gastroesophageal Reflux Disease.

Endoluminal antireflux procedures were pioneered in the 1980s as an alternative to the more invasive Nissen fundoplication. Recent advances in device design and technique have generated renewed interest. Herein we review available data for currently available devices used for endoluminal therapy for GERD.

Cancer antigen profiling for malignant pleural mesothelioma immunotherapy: expression and coexpression of mesothelin, cancer antigen 125, and Wilms tumor 1.

BACKGROUND: To develop cancer antigen-targeted immunotherapeutic strategies for malignant pleural mesothelioma (MPM), we investigated the individual and coexpressions of the cancer-associated antigens mesothelin (MSLN), cancer antigen 125 (CA125), and Wilms tumor 1 (WT1) in both epithelioid and non-epithelioid MPM. METHODS: All available hematoxylin and eosin-stained slides from patients who were diagnosed with MPM (1989-2010) were reviewed. We constructed tissue microarrays from 283 patients (epithelioid = 234; non-epithelioid = 49). Intensity and distribution for each antigen were assessed by immunohistochemistry. RESULTS: Positive expression of MSLN, CA125, and WT1 were demonstrated in 93%, 75%, and 97% of epithelioid MPM cases, and 57%, 33%, and 98% of non-epithelioid MPM cases, respectively. Triple- and double-positive antigen coexpressions were demonstrated in 72% and 23% of epithelioid MPM cases and 29% and 33% of non-epithelioid MPM cases, respectively. Complete absence of expression for all three antigens was demonstrated in <2% of MPM cases. More than two-thirds of MPM cases had ≥50% distribution of MSLN-positive cells and, among the remaining third, half had ≥50% distribution of WT1-positive cells. CA125/MSLN coexpression was observed in more than two-thirds of epithelioid MPM cases and one-third of non-epithelioid MPM cases. CONCLUSION: A limited number of cancer-associated antigens can target almost all MPM tumors for immunotherapy.

Surgical immune interventions for solid malignancies.

BACKGROUND: The purpose of this study was to systematically review clinically translatable immunotherapeutic agents that are delivered regionally for solid malignancies. DATA SOURCES: PubMed and ClinicalTrials.gov were searched for published and registered clinical trials, respectively. The search yielded 334 relevant publications, of which 116 articles were included for review after exclusion criteria were applied. CONCLUSIONS: There has been an increase in the regional administration of cell-based and viral vector-based clinical trials over the last 5 years. Surgical interventions have been developed for intrapleural, intracranial, intraperitoneal, and intratumoral routes of access to enhance the local delivery of these therapies. Multimodality therapies that combine regional immunotherapy with other local and systemic therapies are demonstrating continued growth as the field of immunotherapy continues to expand.

Immunotherapy for non-small cell lung cancer: current concepts and clinical trials.

Recent successes in immunotherapeutic strategies are being investigated to combat cancers that have less than ideal responses to standard of care treatment, such as non-small-cell lung cancer. In this paper, we summarize concepts and the current status of immunotherapy for non-small cell lung cancer, including salient features of the major categories of immunotherapy-monoclonal antibody therapy, immune checkpoint blockade, immunotoxins, anticancer vaccines, and adoptive cell therapy.