Immune Checkpoint Inhibitors And Fluorouracil (5FU) As Combination Therapy In Human Colorectal Carcinoma In A Humanized Patient-derived Orthotopic Mouse Model
*Lara McKean Basté, *Xin Zhang, *Grace Maresh, *Neeha Mathew, *Linh Hellmers, *Amita Bhattarai, *Henry Yip, *Heather Green, *Li Li, David Margolin
Ochsner Medical Center, Nova Orleans, LA
The immune checkpoint pathway is an area of increasing research associated with the progression of cancer. Many tumors can stimulate the expression of immune checkpoint molecules, resulting in a phenotype of exhausted T cells that cannot restrain tumor progression. One such inhibitory receptor and ligand pair are the programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1). They prevent the killing of cancer cells by cytotoxic T-lymphocytes. We have developed a humanized patient-derived orthotopic xenograft (hPDOX) model for CRC that was used to investigate the potential efficacy of combining of immune checkpoint inhibitors (ICIs) with standard therapy Fluorouracil (5FU).
Humanized mice were established by intraperitoneal injection of donor peripheral blood mononuclear cells (PBMCs) into recombinase activating gene 2 (Rag2) and common cytokine receptor gamma chain gene (IL2Rγ) double knockout Rag2 mice. Luciferase-tagged patient tumor cells were injected intra-rectally (IR) into the Rag2 mice. Groups of mice received anti-PD-1 and anti-PDL1 antibodies (Nivolumab, 200 g/mouse and Atezolizumab, 200 g/mouse), and 5 FU (50 mg/kg) once a week for 4 weeks, alone or in combination. Tumor growth was measured weekly by bioluminescent imaging (BLI). At necropsy, tumor weights were measured. Human CD45+ hematopoietic cells and CD4+ or CD8+ T cells were detected in peritoneal lavage, blood and spleen by flow cytometry.
Combination of 5FU with anti-PD-1 and anti-PDL1 antibodies showed a decreased BLI compared to controls as well as to anti-PD-1/PDL1 antibodies treatment alone (p<0.05). Tumor weights were also significantly lower for those mice treated with combination of 5FU and anti PD-1/PDL1 antibodies compared to control as well as to both PD-1/PDL1 and 5FU alone with a p<0.05.
This study provides preclinical evidence of treatment efficacy with ICI and 5FU combination therapy by significantly inhibiting tumor growth and it also establishes use of humanized Rag2 mice as a hPDOX model for CRC.
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