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Published on: December 26, 2016
Tumor cell lysate-loaded immunostimulatory spherical nucleic acids as therapeutics for triple-negative breast cancer
Cassandra E Callmann1,2, Lisa E Cole1,2, Caroline D Kusmierz1,2
1Department of Chemistry, Northwestern University, Evanston, IL 60208.
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.
Insights
Researchers developed novel liposomal spherical nucleic acids (SNAs) loaded with oxidized triple-negative breast cancer (TNBC) cell lysates and CpG adjuvants. These OxLys-SNAs demonstrated significant antitumor activity and enhanced immune responses in TNBC mouse models, offering a promising new immunotherapy.
Area of Science:
- Immunology
- Nanotechnology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) is a highly heterogeneous cancer with limited immunotherapeutic options.
- Developing effective immunotherapies requires strategies to enhance antigen and adjuvant delivery to immune cells.
- Spherical nucleic acids (SNAs) offer a promising platform for targeted drug and nucleic acid delivery.
Purpose of the Study:
- To synthesize and evaluate immunotherapeutic liposomal spherical nucleic acids (SNAs) for triple-negative breast cancer (TNBC) therapy.
- To investigate the impact of oxidized tumor cell lysates and SNA encapsulation on immunogenicity and therapeutic efficacy.
- To assess the potential of these novel immunotherapeutics in preclinical TNBC models.
Main Methods:
- Synthesis of liposomal SNAs encapsulating TNBC cell lysates (antigens) and CpG oligonucleotides (adjuvants).
- Evaluation of Lys-SNAs and oxidized Lys-SNAs (OxLys-SNAs) in vitro and in vivo using TNBC mouse models (Py230, Py8119, EMT6).
- Analysis of immune cell activation (dendritic cells, CD8+ T cells) and tumor microenvironment modulation (MDSCs).
Main Results:
- Lys-SNAs enhanced codelivery of antigens and adjuvants, reducing tumor growth compared to simple mixtures.
- Oxidation of TNBC cell lysates prior to SNA encapsulation (OxLys-SNAs) significantly increased dendritic cell activation.
- OxLys-SNAs promoted cytotoxic CD8+ T cell infiltration, reduced suppressive MDSCs, and demonstrated significant antitumor activity and survival benefits, leading to tumor resistance upon rechallenge.
Conclusions:
- The processing and packaging of tumor cell lysates significantly impact their immunogenicity and therapeutic potential.
- Oxidized tumor cell lysate-loaded SNAs represent a potent new class of immunotherapeutics for challenging cancers like TNBC.
- This approach holds promise for developing effective treatments for cancers with limited targeted therapeutic options.
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