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Janna Claire Minehart



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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.03 - Clinical Rationale and Preclinical Evidence for Chimeric Antigen Receptor (CAR) T Cell Therapy Clinical Trial in KRAS-Mutant Lung Cancer (ID 3075)

      11:30 - 13:00  |  Presenting Author(s): Janna Claire Minehart

      • Abstract
      • Slides

      Background

      Chimeric antigen receptor (CAR) T cells are engineered to express a synthetic receptor that redirects specificity to a tumor-associated antigen (TAA). Mesothelin (MSLN) is a TAA expressed by solid tumors, notably in mesothelioma and lung adenocarcinoma (ADC). Our group clinical trial of MSLN-targeted CAR T cells in mesothelioma demonstrated a favorable safety profile and evidence of antitumor activity. In this study, we evaluated the feasibility and utility of MSLN-targeted CAR T cell therapy in advanced, KRAS-mutant lung ADC.

      Method

      Tissue microarray from stage I-III lung ADC tumors (n=1438) were reviewed by two pathologists, then stained for MSLN expression on cell-surface and cytoplasm. Of 327 patients with distant recurrences, adequate tissue was available from 34 autologous metastatic sites for MSLN expression evaluation. Healthy donor T cells were retrovirally transduced with a MSLN-targeted CAR. In vitro function against lung ADC cell lines with heterogenous MSLN expression resembling human tumors was assessed via chromium release assay, ELISA, and flow cytometry. In vivo antitumor efficacy (n=30) was evaluated by median survival and tumor bioluminescence in mice bearing lung ADC tumors.

      Result

      The incidence of cell-surface MSLN expression was higher in metastases than matched primary tumors (65% vs 38%) and higher in KRAS-mutant than wild type tumors (42% vs 32%). CAR T cells secrete cytokines and lyse lung ADC cell lines in proportion to their cell-surface MSLN expression. No activity against MSLN-very low mesothelial or MSLN-negative lung ADC cell lines was observed. In vivo, a single dose of CAR T cells eradicates established primary and metastatic MSLN-high tumors without evidence of on-target off-tumor toxicity.

      Conclusion

      Therapeutically-relevant cell surface MSLN expression is enriched in a population of KRAS-mutant lung ADC patients with poor prognosis and limited treatment options. MSLN-targeted CAR T cells exhibit antigen-specific and antigen density-dependent cytotoxicity against lung ADC cells in vitro and in vivo with no on-target, off-tumor toxicity to normal tissues. These results provide strong rationale for our upcoming MSLN-targeted CAR T cell therapy clinical trial in metastatic, KRAS-mutant lung ADC patients.

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