Short Lytic Anticancer Peptides as a Novel Therapy against Cancer

Abstract

Cancer is the leading cause of deaths worldwide, with a significant increase in the number of annual incidents. Concurrently, cancer-related therapy has been met with a number of challenges, such as toxic side effects and an increase in multi-drug resistant cancer cells, thereby spawning a need for new and improved therapies. Cationic antimicrobial peptides (CAPs) are naturally occurring molecules found in most species, often as an integral part of the first line of defense against pathogens. Several CAPs have shown promising potential as novel anticancer agents with an ability to selectively kill cancer cells.

Structure-activity relationship studies on bovine lactoferricin allowed us to de novo design short chemically modified lytic anticancer peptides (ACPs) with an improved therapeutic potential compared to bovine lactoferricin. The intratumoral (i.t.) administration of LTX-302 induced a complete regression of- and a long-term and transferrable tumor-specific immune protection against syngeneic A20 B cell lymphomas. A more active nonapeptide, LTX-315, was able to induce complete regression and a long-term tumor immune protection against highly aggressive and low immunogenic syngeneic B16 melanomas. By inducing rapid necrosis and local inflammation due to the release of Danger-Associated Molecular Pattern molecules, i.t. administration of the ACPs stimulated the infiltration of immune cells into the tumor parenchyma, thus creating a synergistic relationship between the direct disruptive effects and the indirect immunomodulatory effects of the peptides.

This thesis also demonstrates that ACPs with a high cell membrane disruptive potential such as LTX-315 can be used in an immune augmenting adjuvant setting due to its potential to stimulate immune responses. Intradermal administration of LTX-315 induced reversible tissue damage, leading to local inflammation and the infiltration of immune cells at the injection site. When used together with a tumor cell lysate, the combination was able to mount a long-term tumor immune protection against syngeneic B16 melanomas.

Taken together, the data presented in this thesis demonstrates that i.t. treatment with short lytic LTX-ACPs can have potential as new immunotherapeutic agents by enlisting local tumor control, followed by protective immune responses. Moreover, LTX-315 has an immune augmenting adjuvant potential when used in combination with a whole cell cancer vaccine.