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.

Decreasing use of epidural analgesia with increasing minimally invasive lobectomy: Impact on postoperative morbidity.

OBJECTIVE: The goal of this study is to investigate the use of EA and its impact on the postoperative short-term outcomes of patients with non-small cell lung cancer (NSCLC) who received a lobectomy by either minimally invasive surgery (MIS) or thoracotomy. MATERIALS AND METHODS: We investigated 793 patients who underwent lobectomy for pathological stage I-III NSCLC without induction therapy during two time periods, an early-time period (2009-2010: MIS, n = 204 [53%]; and thoracotomy, n = 182 [47%]) and a late-period (2014-2015: MIS, n = 308 [76%]; and thoracotomy, n = 99 [24%]). Patient characteristics, including pulmonary function tests, comorbidities, and use of EA, as well as short-term outcomes, including length of stay, morbidity, and mortality were assessed and compared between early-and late-time periods. We also compared patients who received EA (n = 150) with patients who did not receive EA (n = 158) following MIS lobectomy in the late-time period. RESULTS: The use of MIS lobectomy increased during the late-time period compared to the early-time period (p < 0.001). In patients who underwent MIS lobectomy, the use of EA significantly decreased in the late-time period compared to the early-time period (2009-2010 vs. 2014-2015, 95% vs. 51%; p < 0.001). There was no difference in postoperative morbidity and mortality between the two time periods in both MIS and thoracotomy. In the late-time period MIS group, the length of stay in the no EA group (n = 150) was shorter than that in the EA group (n = 158) (3 vs. 4 days, p = 0.038). There was no difference in morbidity and mortality between the EA and no EA groups. CONCLUSION: In our study cohort, the observed decrease in the use of EA with the increasing rate of MIS lobectomy did not negatively affect postoperative short-term outcomes.

CAR T-cell therapy for lung cancer and malignant pleural mesothelioma.

Immunotherapy is a promising field that harnesses the power of the immune system as a therapeutic agent for cancer treatment. Beneficial outcomes shown in patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM) with relatively higher tumor-infiltrating T cells, combined with impressive responses obtained in a cohort of patients with NSCLC following checkpoint blockade therapy, lays a strong foundation to promote effector immune responses in these patients. One such approach being investigated is administration of tumor antigen-targeted T cells with transduction of a chimeric antigen receptor (CAR). CARs are synthetic receptors that enhance T-cell antitumor effector function and have gained momentum to investigate in solid tumors based on recent successes of clinical trials treating patients with B-cell hematologic malignancies. This review summarizes target antigens for CAR T-cell therapy that are being investigated in preclinical studies and clinical trials for both NSCLC and MPM patients. We discuss the rationale for combination immunotherapies for NSCLC and MPM patients. Additionally, we have highlighted the challenges and strategies for overcoming the obstacles facing translation of CAR T-cell therapy to solid tumors.

Chemotherapy-induced immunomodulation in non-small-cell lung cancer: a rationale for combination chemoimmunotherapy.

Spurred by the survival benefits seen with the use of checkpoint blockade in non-small-cell lung cancer (NSCLC), there has been a growing interest in the potential applications of immunotherapy. Despite this, the objective response rate for single-agent immunotherapy remains ≤20% in patients with advanced NSCLC. A combinatorial approach that utilizes both chemotherapy and immunotherapy is a potential strategy to increase antitumor efficacy. Accumulating evidence has shown that the immunomodulatory effects of chemotherapeutic agents can be exploited in a combinational approach. Herein, we review the influence of specific chemotherapeutic agents on the tumor immune microenvironment in preclinical and clinical studies, and establish the rationale for combination chemoimmunotherapy for the treatment of NSCLC.

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.