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Jingli Zhang



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    MA12 - New Frontiers from Pathology to Genomics (ID 138)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA12.11 - Anti-Tumor Efficacy of Mesothelin Targeted Immunotoxin LMB-100 Plus Pembrolizumab in Mesothelioma Patients and Mouse Models (Now Available) (ID 2316)

      14:00 - 15:30  |  Author(s): Jingli Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      LMB-100 is an immunotoxin targeting mesothelin (MSLN) that is highly expressed in malignant mesothelioma and lung adenocarcinoma. Given the clinical efficacy of immune checkpoint inhibitors in these cancers, we aimed to evaluate if LMB-100 in combination with αPD-1 antibody will result in greater anti-tumor efficacy.

      Method

      Patients who were treated on a phase I clinical trial of LMB-100 and then received pembrolizumab were evaluated for anti-tumor response and overall survival. We also evaluated LMB-100/αPD-1 combination efficacy in humanized mouse model transplanted with the tumor cells derived from the mesothelioma patient who achieved complete response and healthy donor’s PBMCs. Immune gene expression in pre- and post- LMB-100-treated mesothelioma patient tumor biopsies was detected with NanoString. To further understand the mechanisms of anti-tumor efficacy of LMB-100 plus αPD-1 therapy,we established a human MSLN expressing lung adenocarcinoma syngeneic mouse model with mouse lung adenocarcinoma cell line 531LN2 stably transfected with a vector encoding hMSLN. Using NanoString gene expression assay and flow cytometry, we analyzed drug induced cancer immune responses in 531LN2-hMSLN tumors. Finally, to understand the role of CD8+ T cells in the anti-tumor effects, we depleted CD8+ T cells in LMB-100 plus anti-PD-1 treated 531LN2-hMSLN bearing mice.

      Result

      Nine mesothelioma patients received pembrolizumab, off-protocol, within 3-4 weeks post LMB-100 treatment. Two patients had disease progression before they could be evaluated for tumor response. Out of the 7 patients who were evaluable for response, 4 had durable objective tumor response including 1 complete and 3 partial responses with progression free survival of 104.3+, 49.6, 49.2 and 37.7 weeks. The overall survival of patients with response was 30.2+, 27.7, 23.8+, and 13.8 months from the start of LMB-100 treatments. The immune cell type signature scores including CD45+, CD8+ T cells, exhausted CD8+ T cells, dendritic cells and macrophages were increased in 4 of 6 patients post LMB-100 treatments. The enhanced anti-tumor effects with LMB-100/αPD1 combination were also observed in the PBMC humanized mouse model transplanted with the tumor cells derived the patient with complete response. In the 531LN2-hMSLN mouse syngeneic model, tumor growth was significantly inhibited by LMB-100/αPD-1 treatments than either monotherapy and overall survival was improved in the combination treated mice. The median tumor volume was 865mm3, 420mm3, 277mm3, and 65mm3 in untreated, LMB-100-treated, αPD-1-treated, and combination treated groups respectively on day 34 post tumor inoculation (p<0.001). We observed increased expression of genes related to CD8+T cells and antigen presentation in tumors treated with LMB-100/αPD-1 compared to either agent alone. Flow cytometry confirmed the CD8+T cells increase in LMB-100 /αPD-1 treated 531LN2-hMSLN tumor. Depletion of CD8+T cells significantly negated the anti-tumor benefits in LMB-100/αPD-1-treated mice.

      Conclusion

      Pembrolizumab following LMB-100 is associated with durable tumor response in mesothelioma patients as well as pre-clinical models of mesothelioma and lung cancer. This combination is currently being evaluated in a prospective clinical trial in patients with mesothelioma (clinicaltrials.gov # NCT03644550).

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