Tumor cell lysate-loaded immunostimulatory spherical nucleic acids as therapeutics for triple-negative breast cancer

Abstract

Highly heterogenous cancers, such as triple-negative breast cancer (TNBC), remain challenging immunotherapeutic targets. Herein, we describe the synthesis and evaluation of immunotherapeutic liposomal spherical nucleic acids (SNAs) for TNBC therapy. The SNAs comprise immunostimulatory oligonucleotides (CpG-1826) as adjuvants and encapsulate lysates derived from TNBC cell lines as antigens. The resulting nanostructures (Lys-SNAs) enhance the codelivery of adjuvant and antigen to immune cells when compared to simple mixtures of lysates with linear oligonucleotides both in vitro and in vivo, and reduce tumor growth relative to simple mixtures of lysate and CpG-1826 (Lys-Mix) in both Py230 and Py8119 orthotopic syngeneic mouse models of TNBC. Furthermore, oxidizing TNBC cells prior to lysis and incorporation into SNAs (OxLys-SNAs) significantly increases the activation of dendritic cells relative to their nonoxidized counterparts. When administered peritumorally in vivo in the EMT6 mouse mammary carcinoma model, OxLys-SNAs significantly increase the population of cytotoxic CD8+ T cells and simultaneously decrease the population of myeloid derived suppressor cells (MDSCs) within the tumor microenvironment, when compared with Lys-SNAs and simple mixtures of oxidized lysates with CpG-1826. Importantly, animals administered OxLys-SNAs exhibit significant antitumor activity and prolonged survival relative to all other treatment groups, and resist tumor rechallenge. Together, these results show that the way lysates are processed and packaged has a profound impact on their immunogenicity and therapeutic efficacy. Moreover, this work points toward the potential of oxidized tumor cell lysate-loaded SNAs as a potent class of immunotherapeutics for cancers lacking common therapeutic targets.

The role of dendritic cells in tumor microenvironments and their uses as therapeutic targets

“…In addition, whole-tumor lysates can be delivered within liposomal spherical nucleic acids (SNAs) composed of adjuvants. For example, a complex consisting of murine triple-negative breast-cancer cell lysates encapsulated with SNAs consisting of CpG on the surface induced tumor rejection and in vitro activation of BM-DCs ( 84 ).…”

Impact of Liposomal Spherical Nucleic Acid Structure on Immunotherapeutic Function

“… 10 , 28 For cancers without identified TAAs, L-SNAs have been used to encapsulate tumor cell lysates as potent antigen sources. 9 In mouse models of triple-negative breast cancer (TNBC), it has been found that the process by which lysates are generated prior to L-SNA incorporation changes the available antigen pool, which impacts the immunotherapeutic potency of the construct.…”

Covalent Organic Frameworks for Biomedical Applications

“…Nanoparticles have been used to develop new vaccine delivery mechanisms and mimic the immune system attack on cancer cells. [ 209–212 ] These nanoparticles can be designed to deliver the payload to specific tissues and regions in the body to treat targeted areas. For example, layer‐by‐layer assembly of lipids can encapsulate antigen and can also be functionalized with different physiochemical and biological properties.…”