mRNA-Based Therapy for Breast Cancer
Breast cancer is the most commonly diagnosed cancer among women. The risk factors of breast cancer include endocrine, reproductive and potential modifiable risk factors (such as drinking, physical inactivity and obesity). To date, there are several therapeutic strategies for breast cancer, including surgery, radiotherapy, chemotherapy, endocrinotherapy and so on. With the development of molecular biology and immunology, immunotherapy has become a promising new treatment for treating breast cancer. Here, we focus on mRNA-based therapy, an attractive field in breast cancer immunotherapy.
Breast cancer is immunogenic
Breast cancer is immunogenic, and several tumor-associated antigens (TAAs) are overexpressed in this cancer. These TAAs, including HER-2 and Mucin 1 (MUC1), have been successfully targeted for new drug development (such as a bispecific antibody and cancer vaccine). Besides, some of these TAAs have been translated into tumor-specific immune responses and are shown to be clinically beneficial. A growing amount of evidence suggests that the immune cells in the tumor microenvironment have a significant impact on (promote or inhibit) the growth of the tumor, which can be utilized as a prognostic indicator for breast cancer. In breast cancer tissue, immune cells comprise T-cells (70%–80%), antigen-presenting cells (APCs), natural killer cells and so on. T-cells can be activated by the recognition to tumor antigens submitted by APCs, and the level of activation signals are associated with various receptor-ligand interactions.
mRNA-based therapy for breast cancer
Intratumoral TriMix injections in early breast cancer patients
The TriMix platform is composed of three major mRNAs encoding proteins (caTLR4, CD40L and CD70), which can synergistically deliver optimal activation of dendritic cells and further mobilize the immune system to attack cancer cells by inducing a T-cell response. Since the mRNA-based TriMix platform has been demonstrated clear clinical benefits in advanced melanoma patients. Researchers have started to investigate the safety and Immune-modulatory effect of the TriMix product as neo-adjuvant treatment (treatment before planned surgery) for early breast cancer patients. The study will conduct intratumoral administration of mRNA to patients with non-metastatic breast cancer irrespective of subtype of breast cancer. The estimated primary completion date is expected to be September 30, 2022.
Intratumoral injections of c-Met-CAR T cells in the treatment of metastatic breast cancer
The cell-surface molecule c-Met, a cell-surface protein tyrosine kinase, is expressed in ∼50% of breast tumors, which prompting the construction of a CAR T cell specific for c-Met to halt tumor growth. Previous research conducted intratumoral administration of mRNA-transfected c-Met-CAR T cells to patients with metastatic breast cancer and evaluated the safety as well as the feasibility of the treatment. The results showed that intratumoral injections of mRNA c-Met-CAR T cells are well-tolerated as well as elicit an inflammatory response within tumors.
mRNA-based immunotherapy in triple-negative breast cancer (TNBC)
According to the recent studies, breast cancer can be classified into four subtypes: Luminal A (ER+/PR+/HER2−, grade 1 or grade 2), Luminal B (ER+/PR+/HER2+, or ER+/PR+/HER2− grade 3), HER2 overexpression (ER−/PR−/HER2+), and triple negative breast cancer (TNBC, ER−/PR−/HER2−). Among them, TNBC, defined by the negative expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), constitutes 10%–20% of all breast cancers. TNBC is connected to aggressive progression, a high rate of metastasis, and a poor prognosis. This subtype of breast cancer has unique biological characteristics and strong heterogeneity, and recently there is no standard treatment for it (chemotherapy is suggested). Hopefully, cancer vaccines based on tumor-associated antigens represent is emerging as an effective therapeutic strategy for metastatic triple-negative breast cancer.
A previous study had demonstrated that nanoparticle (NP)-based mRNA vaccine encoding tumor antigen MUC1 can be delivered to dendritic cells (DCs) in lymph nodes and successfully activate as well as expand tumor-specific T cells in TNBC. MUC1 is a heavily glycosylated type 1 transmembrane mucin and can be observed in various cancers, including breast cancer. In recent years, MUC1 has been used in immunotherapeutic approaches for the development of different types of vaccines (including DNA- and DC-based vaccines). Besides, combination immunotherapy of an anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) monoclonal antibody and the mRNA vaccine could significantly enhance anti-tumor immune response. This highlights potential combination immunotherapy of the NP-based mRNA vaccine and the CTLA-4 inhibitor for TNBC.
Combination immunotherapy of MUC1 mRNA nano-vaccine and CTLA-4 blockade effectively inhibits growth of triple negative breast cancer. (Liu, L., et al, 2018)
Creative Biogene is a forward-looking research institute as well as a leading custom service provider in mRNA-based drug research and development (R&D). Our team is experienced in the customized synthesis of mRNA, mRNA optimization, and mRNA delivery system development. We are devoted to offering high-quality service and achieving the best outcome for our customers from all over the world. If you are interested in this area, please feel free to contact us. We look forward to providing services for your next project.
References
- Liu, L., et al. (2018). "Combination immunotherapy of MUC1 mRNA nano-vaccine and CTLA-4 blockade effectively inhibits growth of triple negative breast cancer." Molecular Therapy, 26(1), 45-55.
- Tchou, J., et al. (2017). "Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer." Cancer immunology research, 5(12), 1152-1161.
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