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J. Villena-Vargas

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    MA13 - Modern Technologies and Biological Factors in Radiotherapy (ID 395)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Radiotherapy
    • Presentations: 1
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      MA13.07 - Tumor-Targeted Radiation Promotes Abscopal Efficacy of Regionally Administered CAR T Cells: A Rationale for Clinical Trial (ID 5456)

      16:00 - 17:30  |  Author(s): J. Villena-Vargas

      • Abstract
      • Presentation
      • Slides

      Our laboratory has demonstrated the augmented anti-tumor efficacy of intrapleurally administered cancer-antigen mesothelin (MSLN)-targeted chimeric antigen receptor (CAR) T cells (Sci Transl Med 2014), and translated the approach to a clinical trial (NCT02414269) for thoracic malignancies. We hypothesized that regionally administered MSLN CAR T cells can circulate systemically to achieve abscopal anti-tumor efficacy in an antigen-specific manner, and the abscopal efficacy can further be promoted by tumor-targeted radiation therapy (RT).

      Using optimized protocols that would permit non-necrotic, well-vascularized tumor growth in pleura, chest wall, peritoneum and flank, tumors were established in immunodeficient (NOD/SCID gamma) mice using mesothelioma or lung adenocarcinoma (LAC) cells. Tumor burden progression, MSLN-targeted CAR T-Cell accumulation at primary and distant tumors was monitored by noninvasive bioluminescence imaging (BLI) and tumor volume measurements.

      A single dose of MSLN CAR T cells administered intrapleurally proliferated (Figure 1A left panel), circulated extrapleurally and accumulated at abscopal sites, including the lymph nodes, chest wall, peritoneum, and flank within 3-5 days, with subsequent T-cell proliferation at abscopal sites (Figure 1A right panel). Primary tumor-targeted, single-dose, thoracic RT prior to T-cell administration augmented T-cell accumulation as demonstrated by BLI (Figure 1B) and tumor T-cell quantification (p<0.01). In a mouse model of primary pleural, abscopal antigen-expressing and non-expressing flank tumors (Figure 1C), a single, low-dose, non-cytotoxic thoracic RT enhanced abscopal site CAR T-cell accumulation that resulted in tumor regression (p=0.01; Figure 1D). Figure 1

      Regionally administered mesothelin-targeted CAR T cells proliferate and eradicate the primary tumor, accumulate and demonstrate anti-tumor efficacy at abscopal sites prior to eradication of the primary tumor in an antigen-specific manner. A single low-dose primary tumor-targeted radiation therapy promotes scopal and abscopal anti-tumor efficacy. These results provide rationale to initiate a clinical trial of combination regional therapies with radiation therapy and CAR T cells.

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