Abstract 5091: Activity of Bcl-2 antisense therapeutic in aggressive non-Hodgkin's lymphoma

Abstract

Abstract Aggressive non-Hodgkin's lymphoma (NHL) progresses rapidly. It makes up about 60% of all NHL cases in the United States. The chemotherapy regimen R-CHOP could cure up to 70% of patients with aggressive NHL. Nonetheless, up to 30% of patients with aggressive NHL relapse from R-CHOP within 2 years of initial treatment. Novel therapeutics are urgently needed for patients with relapsed, aggressive NHL. Bcl-2 is a potential therapeutic target for aggressive NHL because high expression of Bcl-2 has been reported in NHL and correlated with adverse prognosis for NHL patients. To inhibit the expression of Bcl-2 protein, BP1002 was developed. BP1002 is comprised of an uncharged P-ethoxy antisense oligodeoxynucleotide targeted against Bcl-2 mRNA. The P-ethoxy antisense backbone does not have an adverse effect on bleeding and complement activation, which are some of the toxicities that have been reported for other antisense analogs. The Bcl-2 antisense is incorporated in neutral liposomes so that it can be delivered systemically via intravenous infusion. The inhibitory activity of BP1002 was determined in human lymphoma cell lines, which included germinal center B-cell (GCB) diffuse large B cell lymphoma (DLBCL), activated B-cell (ABC) DLBCL, mantle cell lymphoma (MCL) and Burkitt’s lymphoma (BL). The lymphoma cell lines were incubated with BP1002 for four days. The sulforhodamine B cytotoxicity assay showed that BP1002, at 200 micrograms/mL, induced ≥50% inhibition in 5 of 8 GCB DLBCL lines, 3 of 3 ABC DLBCL lines, 1 of 1 MCL line, and 1 of 1 BL line. We also determined the activity of BP1002 in animal models. Severe combined immunodeficiency (SCID) mice were implanted with CJ cells, which are transformed follicular lymphoma cells that express high levels of Bcl-2 protein. In experiment I, 4 groups of mice were used: Group 1 - untreated mice; Group 2 - mice treated with 10 mg of BP1002 per kg of mouse body weight; Group 3 - mice treated with 20 mg of BP1002 per kg of mouse body weight; Group 4 - mice treated with control empty liposomes equivalent to 20 mg/kg of BP1002. One week after tumor implantation, mice were injected with BP1002 or empty liposomes intravenously twice per week. When mice were euthanized in week 5, all untreated mice and mice treated with control empty liposomes reached moribund state. However, no mouse in the BP1002 treatment groups reached moribund state. In experiment II, 3 groups of mice were used: Group 1 - untreated mice; Group 2 - mice treated with 20 mg/kg of liposome-incorporated control oligodeoxynucleotide; Group 3 - mice treated with 20 mg/kg of BP1002. All untreated mice and control mice were moribund in week 5, but only 40% of BP1002-treated mice were moribund. These in vivo experiments indicate that BP1002 could extend the survival of mice bearing aggressive NHL. Together, our data indicate that BP1002 is a novel therapeutic for aggressive NHL. Citation Format: Ana Tari Ashizawa, Yolanda Gutierrez-Puente, Richard Ford, Gabriel Lopez-Berestein. Activity of Bcl-2 antisense therapeutic in aggressive non-Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5091. doi:10.1158/1538-7445.AM2017-5091