B-cell lymphomas include Hodgkin's, and non-Hodgkin's lymphoma (NHL) (eg. mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma). More than 70,000 people will be diagnosed with these B-cell malignancies in the U.S. this year and more than 19,000 will die from NHL alone. B-cell lymphomas can affect numerous organs including the lymph nodes, spleen, liver, and bone marrow. Many patients who receive treatment for B-cell lymphomas become refractory to all available therapies and often die from disease. Thus, there is a significant need to identify newer therapeutics with greater activity and fewer side effects. The novel biologic agent Leukothera(R) (leukotoxin;LtxA) specifically targets active leukocyte function antigen-1 (LFA-1) expressed on white blood cells (WBCs). Malignant WBCs constantly express high levels active LFA-1, allowing LtxA to target specifically diseased cells while minimally affecting healthy cells and tissue. LtxA employs several mechanisms of cell death to intoxicate susceptible WBCs. We have found that cell lines and primary cells from patients with newly diagnosed, relapsed, and refractory leukemia and lymphoma are highly sensitive to LtxA. In preclinical studies, LtxA shows significant efficacy using humanized mouse models for leukemia. In addition, single- dose LtxA administered intravenously into rhesus monkeys was active, highly specific for WBCs, and well-tolerated. No effect was seen on red blood cells, platelets, hemoglobin, or markers of organ toxicity. However, no studies have yet examined LtxA for the treatment of B- cell lymphoma. Thus, based on our encouraging preclinical studies for leukemia, we propose to test LtxA using in vitro and in vivo B-cell lymphoma model systems. The data that we generate from the work described in this application is necessary to provide proof-of-principle and mechanistic knowledge for subsequent clinical testing in lymphoma patients.
B-cell lymphomas kill thousands of people each year. We are developing a biotherapeutic agent (leukotoxin) that has targeted specificity for malignant white blood cells. Our studies will test the hypothesis that leukotoxin can be used for the treatment of B-cell lymphomas employing in vitro and in vivo models.
|DiFranco, Kristina M; Johnson-Farley, Nadine; Bertino, Joseph R et al. (2015) LFA-1-targeting Leukotoxin (LtxA; Leukothera®) causes lymphoma tumor regression in a humanized mouse model and requires caspase-8 and Fas to kill malignant lymphocytes. Leuk Res 39:649-56|
|Kaur, Manpreet; Kachlany, Scott C (2014) Aggregatibacter actinomycetemcomitans leukotoxin (LtxA; Leukothera) induces cofilin dephosphorylation and actin depolymerization during killing of malignant monocytes. Microbiology 160:2443-52|