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MINI 02 - Immunotherapy (ID 92)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P. Forde, S.J. Antonia
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
MINI02.06 - Humanized Immuno-Mouse for Study of Anti-PD-1 Therapy in KRAS-Mutated Lung Cancer Patient Derived Xenotransplant (PDX) (ID 3104)
10:45 - 12:15 | Author(s): L. Shultz
Preclinical modeling of immunotherapeutics in PDX-bearing mice has been limited by the absence of a relevant immune microenvironment, as a highly immunosuppressive environment is often required for the implanted tumor to grow. Checkpoint inhibitors including anti-PD-1 and anti-PD-L1 antibodies (mAbs) are promising new treatments in non-small cell lung cancer (NSCLC). The creation of a PDX model system that supports human tumor growth and recapitulates the relevant genomics in NSCLC while providing the immune microenvironment necessary for anti-PD-1 and anti-PD-L1 mAb activity is critical for validation of combination checkpoint inhibitor strategies in NSCLC.
Hematopoietic CD34+ progenitor stem cells (CD34+ HPC) were engrafted into the tail vein of sublethally irradiated NSG mice. A KRAS G12D PDX was assayed for PD-L1 expression by FACS (Biolegend; clone 29E. 2A3, San Diego CA) and implanted into Hu-CD34 NSG mice with > 25% Hu-CD45+ cells 12 weeks post CD34+ HPC injection. Multilineage engraftment of immune cell subsets was assayed in peripheral blood, spleen and tumor by FACS (CD45, CD3, CD4, CD8, CD19). PDX were treated with vehicle Q5D x 6, pembrolizumab (Merck, Whitehorse Station PA) 5 mg/kg Q5D x 6, and combination pembrolizumab and docetaxel (Hospira, Lake Forest) 10 mg/kg Q7D x4 at the same single agent dosages. Body weight and tumor growth were assessed twice weekly.
Hu-CD45+ cells were detected in peripheral blood, spleen and tumor by flow cytometry on single cell suspension. The majority of Hu-CD45+ cells were T-cells: CD3CD4+ (mean blood 50%, spleen 53%, tumor 52%) and CD3CD8+ (mean blood 14%, spleen 15%, tumor 39%). KRAS G12D tumor had 89% surface expression of PD-L1. No significant change in Hu-CD45+ cell composition was noted between the different treatment groups. Pembrolizumab both alone and in combination with docetaxel showed activity in KRAS G12D PDX with substantial tumor growth inhibition and decreased mean tumor volume at day 24 post-treatment.
Multilineage engraftment of relevant immune cell subsets for PD-1 inhibition is present in the humanized immune-mouse (Hu-CD34 NSG). PD-1 inhibition in a KRAS G12D Hu-CD34 NSG with high PD-L1 expression demonstrated substantial tumor growth inhibition both alone and in combination with chemotherapy. Additional studies are underway exploiting the Hu-CD34 NSG mouse model for study of anti-PD-1/PD-L1 therapies in KRAS mutant and other important molecular subsets of NSCLC.
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