Mini-intronic plasmid DNA vaccines in combination with LAG3 blockade
It is disclosed herein that (a) an anti-tumor DNA vaccine delivered using a MIP DNA vector is a less effective tumor treatment than the corresponding anti-tumor DNA vaccine delivered using a conventional pDNA vector, despite the MIP DNA vector eliciting a higher frequency of antigen-specific CD8+ T cells; and (b) tumor infiltrating CD8+ T cells in animals immunized with the MIP DNA vector express higher levels of the immune checkpoint protein LAG-3 than animals immunized with a conventional pDNA vector, while the expression levels of other immune checkpoint proteins was the same for both groups. Based on these findings, improved methods and compositions for administering DNA vaccines are disclosed. Specifically, DNA vaccines delivered with MIP DNA are administered along with a LAG-3 pathway blocking agent, resulting in a more effective vaccine-induced cellular immune response.
1. A method for reducing the number of cancer cells in a subject, the method comprising:
administering to the subject a mini-intronic plasmid (MIP) comprising an expression cassette comprising (a) a polynucleotide sequence encoding an antigen expressed by the cancer cells, wherein the antigen is selected from the group consisting of synovial sarcoma x breakpoint 2 (SSX2), androgen receptor ligand-binding domain (AR LBD), prostate-specific antigen (PSA), human epidermal growth factor receptor 2 (HER-2/neu), and prostatic acid phosphatase (PAP), and (b) an intron containing a bacterial origin of replication and a selectable marker, whereby antigen-specific CD8+ T cells are activated against the cancer cells; and
administering to the subject an antibody that binds to lymphocyte activation gene 3 (LAG-3), whereby the antibody reduces immunoinhibitory effects of increased LAG-3 expression in tumor infiltrating lymphocytes, relative to immunoinhibitory effects observed if no antibody is administered;
whereby the number of cancer cells is decreased in the subject.
2. The method of claim 1 , wherein the antibody to LAG-3 and MIP are co-administered simultaneously.
3. The method of claim 1 , wherein the intron is located in the expression cassette upstream of the polynucleotide sequence encoding for the antigen.
4. The method of claim 1 , wherein the method is performed without administering a programmed cell death protein 1 (PD-1) immune checkpoint protein blocking agent.
5. The method of claim 1 , wherein the antigen is SSX2.
6. The method of claim 1 , wherein the cancer is prostate cancer.