MA13.07 Tumor-Targeted Radiation Promotes Abscopal Efficacy of Regionally Administered CAR T Cells: A Rationale for Clinical Trial

Abstract

annotated by The Cancer Genome Atlas lung ACA dataset and all hypermorphic mutations identified were located in the highly conserved kinase domain. The majority of mutations have been known to enhance kinase activity in melanoma in a fashion analogous to the well-known BRAF V600E mutation. In line with these findings, we showed that kinase domain mutations were hypermorphic as measured by MEK and ERK1/2 phosphorylation. We also showed that exposure of wild type BRAF cells to radiation results only in a transient activation of MEK and ERK1/2. The MEK inhibitor selumetinib selectively decreased the growth of cells with kinase domain BRAF mutations and sensitized these cells to radiation. Conclusion: BRAF mutations are associated with radiation resistance in lung ACA. Our data nominates MEK inhibitors, a drug class currently in clinical use, as a targeted therapeutic in select BRAF-mutant lung ACA. Further investigation has the potential to yield an additional genotype-directed therapy that could impact up to 4-6% of patients with lung ACA, a frequency comparable to that of ALK rearrangements (4%) or EGFR mutations (10%).

On target methods to induce abscopal phenomenon for Off‐Target effects: From happenstance to happenings

“…Also, intrapleural delivery of cancer‐antigen mesothelin targeted CAR‐T cells were administered to a murine model with prior focal thoracic XRT which elicited a systemic abscopal response as well. This is yet to see potential in the clinical space at this time 66 …”

“…This is yet to see potential in the clinical space at this time. 66 One of the earliest preclinical studies demonstrated synergy when IL-15 which facilitates release of effector T cells and NK cells, and ionizing radiation potentiated a cellular mediated immune response in the tumor and systemic circulation. Addition of DTA-1 which is a glucocorticoid-induced tumor necrosis factor receptorrelated protein agonist sustained this response longer.…”

Novel immunotherapy clinical trials in malignant pleural mesothelioma

“…Preclinical investigations have demonstrated potential immune responses following radiation therapy and augmentation of these responses by combining with immunotherapeutic agents (62). We have reported that a single dose of thoracic radiation prior to administration of CAR T cells has improved survival outcomes in a preclinical MPM model (63). More mechanistic insights into these combination therapy approaches will help translate benefits to mesothelioma patients.…”

CAR T cell-based immunotherapy and radiation therapy: potential, promises and risks

“…In the RT group, the pleural tumor was irradiated with a single sub-therapeutic RT dose prior to CAR T cells injection. Locally-injected CAR T cells promoted the abscopal effect in distant tumor sites, and this effect was potentiated via RT [98].…”