Recombinant MVA or MVAΔE3L expressing human FLT3L and use thereof as immuno-therapeutic agents against solid tumors
The present invention relates generally to the fields of oncology, virology and immunotherapy. More particularly, it concerns the use of a recombinant modified vaccinia Ankara (MVA) virus comprising an MVA harboring a human Fms-like tyrosine kinase 3 ligand (hFlt3L) (MVA-hFtl3L). The foregoing vaccinia Ankara (MVA) virus can be delivered to tumor cells of a subject afflicted with a malignant solid tumor, to treat the tumor. In a related aspect, the present disclosure concerns a recombinant modified vaccinia Ankara virus with deletion of vaccinia virulence factor E3 (MV At.E3L) modified to express human Fms-like 5 tyrosine kinase 3 ligand (hFlt3L) isolated, suitable for use as an immunotherapeutic agent against a malignant solid tumor.
1. A method of eliciting an immune response in a subject in need thereof comprising delivering to biological cells of the subject a composition comprising a therapeutically effective amount of a recombinant modified vaccinia Ankara (MVA) virus, wherein the recombinant MVA comprises a deletion of vaccinia virulence factor E3 and expresses human Fms-related tyrosine kinase 3 ligand (MVAΔE3L-hFlt3L), thereby inducing at least one or more of the following:
proliferating and activating CD8+ cytotoxic T cells;
proliferating and activating CD4 + effector T cells;
increasing the ratio of cytotoxic CD8 + T cells/regulatory T cells;
increasing the ratio of conventional T cells/regulatory T cells;
increasing the ratio of effector CD4 + cells/regulatory T cells;
increasing CD45 + cells; and
reducing at least one of CD24 + , CD103 + , or CD11b + dendritic cells.
2. The method of claim 1 , wherein the composition further comprises MVA harboring hFlt3L (MVA-hFlt3L).
3. The method of claim 1 , wherein the MVAΔE3L-hFlt3L delivered to the cells is effective to recruit and activate CD4 + effector T cells accompanied by a reduction of regulatory CD4 + cells.
4. The method of claim 1 , wherein the MVAΔE3L-hFlt3L is delivered parenterally, intratumorally, intravenously, or intraperitoneally.
5. The method of claim 1 , wherein the MVAΔE3L-hFlt3L is delivered at a dosage per administration of about 10 6 to about 10 10 plaque-forming units (pfu).
6. The method of claim 1 , wherein the delivery is repeated with a frequency within the range from once per month to once per week or more, and continues for several weeks, months, or years, or indefinitely until a maximum tolerated dose is reached.
7. The method of claim 1 , wherein the subject is a human.
8. The method of claim 1 , further comprising conjointly administering to the subject a second amount of an immune checkpoint blocking agent or an immune checkpoint agonist.
9. The method of claim 8 , wherein the administration of the immune checkpoint blocking agent or immune checkpoint agonist is by parenteral route; or wherein the delivery of the recombinant MVA virus is by intratumoral injection and the administration of the immune checkpoint blocking agent or immune checkpoint agonist is by intravenous route; or wherein both the delivery of the recombinant MVA virus and the administration of the immune checkpoint blocking agent or immune checkpoint agonist are by intravenous route; or wherein both the delivery of the recombinant MVA virus and the administration of the immune checkpoint blocking agent or immune checkpoint agonist are by intratumoral injection.
10. The method of claim 8 , wherein the immune checkpoint blocking agent is selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, inhibitory antibodies against LAG-3 (lymphocyte activation gene 3), TIM3 (T cell Immunoglobulin and Mucin-3), B7-H3, and TIGIT (T-cell immunoreceptor with Ig and ITIM domains); CD80, CD86, PDL2, B7-H4, II and DLBCL inhibitors, BTLA, and any combination thereof; and the immune checkpoint agonist is selected from the group consisting of anti-ICOS antibody, anti-OX40 antibody, agonist antibody against 4-IBB (CD 137) and against GITR.