Acute myeloid leukemia (AML) is the most common hematologic malignancy in adults with a 5-year survival rate of ~25% following diagnosis. While two-thirds of AML patients treated with standard high dose chemotherapy achieve remission, 50% of patients relapse after remission. The majority of relapses occur within two to three years of initial treatment, and every patient carries the risk of relapse due to the molecular heterogeneity of the disease. This has created an impetus to explore novel therapeutic approaches; in particular, immune-based therapies, since AML cells express both major histocompatibility complex (MHC) classes I and class II which makes them susceptible targets of innate and adaptive immune responses.
In our April 2017 model spotlight, we presented data on preclinical model development of the C1498-Luc-mCherry systemic acute myeloid leukemia model in C57BL/6 mice. The line is highly aggressive as a disseminated model, with a median tumor doubling time of 1.3 days based on bioluminescence imaging (BLI) and a median overall survival of ~23 days. In continued efforts to expand the model for immuno-oncology applications, we present here data on response to immune checkpoint blockade.
C1498-Luc-mCherry Tumor Cell Distribution
Following IV implantation of cells, we find that solid tumor masses will develop in a number of tissues including the ovaries, liver, and spine. To understand the distribution of C1498-Luc-mCherry tumor cells in the model, flow cytometry was performed on spleen, bone marrow, and tumors found on/around the ovaries. Samples were collected from five C57BL/6 mice 21 days post implant of C1498-Luc-mCherry. As the line is a myeloid malignancy it’s unsurprising that 97% of the cells analyzed were CD45+ in the tumors around the ovary. We determined, by examination of mCherry, that very few tumor cells were present in the spleen (~2%) and bone marrow (6%) while almost 78% of the CD45+ cells in the ovarian-based tumors were mCherry+ (Fig. 1A). Histopathological evaluation of H&E stained sections of ovarian-based tumors confirmed the presence of homogeneous populations of neoplastic cells with similar morphology. Tumor masses were composed of moderately pleomorphic tumor cells with round to oblong nuclei, and scant cytoplasm with a high number of mitotic figures (Fig. 1B).