Mouse Model Of non-Hodgkin Lymphoma Research Articles

Sequential Administration of Selinexor then CD19 CAR-T Cells Exhibits Enhanced Efficacy in a Mouse Model of Human Non-Hodgkin's Lymphoma

Novel therapeutic approaches are urgently needed for many patients with Non-Hodgkin's Lymphoma (NHL). Approximately 30% of patients die within 5 years of diagnosis and many more relapse. Chimeric Antigen Receptor T cells (CAR-T) directed toward NHL antigens (e.g. CD19) are a promising new class of therapeutics for some patients with relapsed/refractory NHL, though a high percentage of patients (~50%) still fail to enter remission or relapse within one year of CD19 CAR-T therapy. Another approved therapeutic for treatment of a subtype of NHL patients is the nuclear export inhibitor, selinexor. Selinexor binds to exportin 1 and exhibits anti-tumor activity by impairing nuclear export of proteins including oncogenes and tumor suppressor proteins. As both CD19 CAR-T cells and selinexor exhibit activity against lymphoma cells, but suboptimal long term efficacy in patients, we assessed the combination of both treatments in a mouse model of NHL. The combinatorial efficacy was assessed using a circulating model of human NHL whereby RAJI-luciferase cells were intravenously injected into immunocompromised mice. Initial studies initiated treatment 7 days post tumor cell injection. Mice (n=5 NSG mice per cohort) were treated with selinexor alone (10mg/kg gavage 2x week) for study duration, CD19 CAR-T cells alone (single injection of 2.5x106 million cells) or a concurrent combination. Mice were imaged weekly for bioluminescence to monitor tumor progression. While CD19 CAR-T cells alone led to inhibition of tumor growth, there was no further enhancement in efficacy with the addition of concurrent treatment with selinexor (Figure 1A). Interestingly, when selinexor instead was administered only prior to CAR-T cell injection (10mg/kg gavage Day 1 and Day 3 post tumor cell injection followed by CAR-T injection Day 7 post tumor cell injection), there was a significant reduction in tumor burden in the combination group (Figure 1B). These results suggest that the tumor cells become sensitized to CD19 CAR-T mediated cell killing from selinexor administration. As both agents are FDA approved for certain NHL patients, this therapeutic strategy has high clinical relevance. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ATR-FTIR spectral discrimination between normal and tumorous mouse models of lymphoma and melanoma from serum samples

This study presents, attenuated total reflection Fourier transforms infrared spectroscopy of dried serum samples in an effort to assess biochemical changes induced by non-Hodgkin’s lymphoma and subcutaneous melanoma. An EL4 mouse model of non-Hodgkin lymphoma and a B16 mouse model of subcutaneous melanoma are used to extract a snapshot of tumor-associated alteration in the serum. The study of both cancer-bearing mouse models in wild types and their corresponding control types, emphasizes the diagnostic potential of this approach as a screening technique for non-Hodgkin lymphoma and melanoma skin cancer. Infrared absorbance values of the different spectral bands, hierarchical clustering and integral values of the component bands by curve fitting, show statistically significant differences (student’s t-test, two-tailed unequal variance p-value < 0.05) between spectra representing healthy and tumorous mouse. This technique may thus be useful for having individualized route maps for rapid evaluation of lymphoma and melanoma status and associated therapeutic modalities.

Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target

We have generated mouse models of non-Hodgkin lymphoma (NHL) that rely on the cooperation between MYC overexpression and B-cell antigen receptor (BCR) signaling for the initiation and maintenance of B-cell lymphomas. Using these mouse models of NHL, we have focused on the identification of BCR-derived signal effectors that are important for the maintenance of NHL tumors. In the present study, we concentrate on Spleen tyrosine kinase (Syk), a nonreceptor tyrosine kinase required to transduce BCR-dependent signals. Using a genetic approach, we showed that Syk expression is required for the survival of murine NHL-like tumors in vitro and that tumor cells deficient in Syk fail to expand in vivo. In addition, a pharmacologic inhibitor of Syk was able to induce apoptosis of transformed B cells in vitro and led to tumor regression in vivo. Finally, we show that genetic or pharmacologic inhibition of Syk activity in human NHL cell lines are generally consistent with results found in the mouse models, suggesting that targeting Syk may be a viable therapeutic strategy.