Abstract 4909: The oncolytic peptide LTX-315 enhances tumor-specific immune responses and tumor regression in murine 4T1 breast cancer when combined with doxorubicin

Abstract

Abstract The oncolytic effect of LTX-315 involves perturbation of the plasma membrane and distortion of the mitochondrial membrane with subsequent release of DAMPs (Damage-Associated Molecular Pattern molecules) such as ATP, cytochrome C and HMGB1 (1,2). Also multidomain proteins from the BCL-2 family seem to be partially involved in LTX-315 mediated killing (3). In addition, LTX-315 induces the hallmarks of immunogenic cell death (4). Preclinical studies have demonstrated that LTX-315 is able to induce complete tumour regression after intra-tumoral treatment (5,6). In this study the effect of combining intratumoral administration of LTX-315 and systemic treatment with Doxorubicin was investigated in the murine 4T1 breast cancer model. The combination treatment was investigated both in s.c. tumors and in tumors established in the mammary fat pad. The 4T1 cell were labeled with mcherry reporter gene in order to assess tumor growth by whole body imaging. LTX-315 (1 mg in 50 ìl) was injected intratumorally for three consecutive days. Doxorubicin (8mg/kg) was injected into the tail vein as a single dose together with the first injection of LTX-315. Tumor growth was assessed by caliper measurements and whole body luminescence. The combination of local administration of LTX-315 and systemic Doxorubicin, demonstrated significant synergy in both s.c. tumors and in tumors growing in the mammary fat pad. Furthermore, the combination induced a systemic tumour specific immune response since tumors did not develop in cured animals when re-challenged with tumor cells. The tolerable safety profile and novel mode of action of LTX-315 indicate a rationale for combining LTX-315 with other immunotherapies, targeted agents, and chemotherapy.