Breast cancer vaccines delivered by dendritic cell-targeted lentivectors induce potent antitumor immune responses and protect mice from mammary tumor growth

Abstract

Breast cancer immunotherapy is a potent treatment option, with antibody therapies such as trastuzumab increasing 2-year survival rates by 50%. However, active immunotherapy through vaccination has generally been clinically ineffective. One potential means of improving vaccine therapy is by delivering breast cancer antigens to dendritic cells (DCs) for enhanced antigen presentation. To accomplish this in vivo, we pseudotyped lentiviral vector (LV) vaccines with a modified Sindbis Virus glycoprotein so that they could deliver genes encoding the breast cancer antigen alpha-lactalbumin (Lalba) or erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) directly to resident DCs. We hypothesized that utilizing these DC-targeting lentiviral vectors as a breast cancer vaccine could lead to an improved immune response against self-antigens found in breast cancer tumors. Indeed, single injections of the vaccine vectors were able to amplify antigen-specific CD8 T cells 4–6 fold over naïve mice, similar to the best published vaccine regimens. Immunization of these mice completely inhibited tumor growth in a foreign antigen environment (LV-ERBB2 in wildtype mice), and it reduced the rate of tumor growth in a self-antigen environment (LV-Lalba in wildtype or LV-ERBB2 in MMTV-huHER2 transgenic). These results show that a single injection with targeted lentiviral vectors can be an effective immunotherapy for breast cancer. Furthermore, they could be combined with other immunotherapeutic regimens to improve outcomes for patients with breast cancer.

Trial watch: dendritic cell vaccination for cancer immunotherapy

“…302 Bryson et al (from University of Southern California, Los Angeles, CA, USA) used a Sindbis virus-based method to deliver breast cancer-associated antigens to tumor-resident DCs, resulting in a potent vaccination effect in situ that amplified CD8 + CTL-dependent immunity against murine breast cancer. 303 Liu et al (from University of North Carolina at Chapel Hill, Chapel Hill, NC, USA) formulated a nanoparticle-based method to deliver mucin 1 (MUC1)coding mRNA to lymph node-resident DCs in a mannose receptor-dependent fashion, culminating with expansion of MUC1-reactive T cells and regression of MUC1-expressing 4T1 mammary carcinomas, especially in the context of cytotoxic T-lymphocyte associated protein 4 (CTLA4) blockage. 304 Oberli et al (from Harvard Medical School, Boston, Massachusetts, USA) created a cancer vaccine consisting of DCs, macrophages and neutrophils transfected with an mRNA coding for melanoma antigens and delivered with lipid nanoparticles, which effectively eradicated B16 melanomas in a CD8 + CTL-dependent manner.…”

HER2-Positive Breast Cancer Immunotherapy: A Focus on Vaccine Development

“…Transfection of DCs with specific mRNA, to drive adaptive immunity response, has confirmed to be an effective approach to induce expansion of CD4 + and CD8 + T cells. Bryson et al (2017) prepared a multifunctional vaccine made from a modified lentivirus, loaded with two breast cancer antigens including alpha lactalbumin, and HER2, which could directly target the resident DCs. Single injections of the DCtargeted lentiviral vectors resulted in tumor self-antigen-specific cellular immunity, decreasing tumor development and rendering an effective immunotherapy for HER2-positive breast cancer (Bryson et al 2017).…”

“…Bryson et al (2017) prepared a multifunctional vaccine made from a modified lentivirus, loaded with two breast cancer antigens including alpha lactalbumin, and HER2, which could directly target the resident DCs. Single injections of the DCtargeted lentiviral vectors resulted in tumor self-antigen-specific cellular immunity, decreasing tumor development and rendering an effective immunotherapy for HER2-positive breast cancer (Bryson et al 2017). Another preclinical study evaluated the efficacy of DCs transfected with an adenovirus expressing the HER2/neu gene (AdNeuTK) and IL-12.…”

The Role of the Tumor Microenvironment in Developing Successful Therapeutic and Secondary Prophylactic Breast Cancer Vaccines

“…First, in the direct DC vaccine strategy, autologous myeloid-lineage cells can be pulsed ex vivo to increase specific antigen presenting capabilities and then reinfused into the patient. Secondly, adjuvants that stimulate DCs in vivo can be used to stimulate maturity, such GM-CSF (granulocyte-macrophage colony-stimulating factor), CD40 agonists, TLR agonists, or lentiviral administration of antigens [ 72 ] with or without the use of DC vaccines. Thus, both ex vivo and in vivo strategies are sometimes used in tandem.…”