Chimeric Antigen Receptor (CAR) T Cell Therapy for Malignant Pleural Mesothelioma (MPM)

Cancer immunotherapy has now become a recognized approach to treating cancers. In addition to checkpoint blockade, adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. CARs are engineered receptors, stably or transiently transduced into T cells, that aim to enhance T cell effector function by recognizing and binding to a specific tumor-associated antigen. In this review, we provide a summary of CAR T cell preclinical studies and clinical trials for malignant pleural mesothelioma (MPM), a rare, locally invasive pleural cancer with poor prognosis. We list other attractive potential targets for CAR T cell therapy for MPM, and discuss augmentation strategies of CAR T cell therapy with other forms of immunotherapy in this disease

Overcoming tumor antigen heterogeneity in CAR-T cell therapy for malignant mesothelioma (MM)

Malignant mesothelioma (MM) is a rare, aggressive solid tumor with limited therapeutic options and poor therapeutic response. The role of immunotherapy in MM is now well established and therapeutic options, such as checkpoint inhibitors, are increasingly being approved. Chimeric antigen receptor (CAR)-T cell therapy is successfully implemented in several hematologic cancers, but currently has inadequate effect in solid tumors, owing to several limitations, such as trafficking and infiltration, limited T cell persistence and exhaustion, the immunosuppressive TME and tumor antigen heterogeneity. The lack of uniform and universal expression of tumor-associated antigens (TAAs) on tumor cells, as well as TAA heterogeneity following tumor editing post-therapy, are issues of significant importance to CAR-T cell and associated antigen-targeting therapies. Our review discusses the concept of tumor antigen heterogeneity in MM, the consequences for CAR-T cell therapies and the strategies to overcome it

Transcriptomic analysis-guided assessment of precision-cut tumor slices (PCTS) as an ex-vivo tool in cancer research

Abstract With cancer immunotherapy and precision medicine dynamically evolving, there is greater need for pre-clinical models that can better replicate the intact tumor and its complex tumor microenvironment (TME). Precision-cut tumor slices (PCTS) have recently emerged as an ex vivo human tumor model, offering the opportunity to study individual patient responses to targeted therapies, including immunotherapies. However, little is known about the physiologic status of PCTS and how culture conditions alter gene expression. In this study, we generated PCTS from head and neck cancers (HNC) and mesothelioma tumors (Meso) and undertook transcriptomic analyses to understand the changes that occur in the timeframe between PCTS generation and up to 72 h (hrs) in culture. Our findings showed major changes occurring during the first 24 h culture period of PCTS, involving genes related to wound healing, extracellular matrix, hypoxia, and IFNγ-dependent pathways in both tumor types, as well as tumor-specific changes. Collectively, our data provides an insight into PCTS physiology, which should be taken into consideration when designing PCTS studies, especially in the context of immunology and immunotherapy

FIGURE 2 from Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy

Optical properties, Photofrin content, and oxygenation are similar at the time of illumination in PDT- and TI/PDT-treated tumors. A, Tumor optical properties were measured prior to and immediately after TI exposure. After TI, tumors showed no difference in the mean of the average absorption (μa, P = 0.690), effective coefficient (μeff, P = 0.826), or reduced scattering coefficient (μs’, P = 0.283). n = 6–7 mice per group. B, Spectrofluorometric analysis of tumors showed equivalent Photofrin uptake in TI-exposed and untreated tumors. n = 4–5 mice per group. C, Tumor oxygenation was measured using phosphorescence lifetime imaging via intratumoral injection of PdG4. Oxygenation levels are plotted relative to the pre-TI level in each mouse. The resulting curve demonstrated a transient decrease in tumor oxygenation 30 minutes after administration of TI which returned to a mean of 100% or 89.4% of the pre-TI level external to the incision and along the incision, respectively. n = 4 mice.</p

Supplementary Figure 2 from Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy

Supplemental Figure 2. TI promotes acute inflammation</p

Supplementary Figure 5 from Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy

Supplemental Figure 5. Gating Scheme for Splenocyte Immunophenotyping</p