Adoptive cellular therapy
The invention provides improved compositions and methods for the treatment of solid cancers.
1. A recombinant oncolytic herpes simplex virus (HSV) comprising: (i) a polynucleotide encoding a target antigen; (ii) one or more tumor suppressor miR target sequences inserted into one or more essential viral genes required for viral replication, and (iii) a polynucleotide encoding a non-HSV polypeptide inserted into the gD gene or the gC gene.
2. The recombinant oncolytic herpes simplex virus of claim 1 , wherein the target antigen is selected from the group consisting of: tumor associated antigens (TAA), tumor specific antigens (TSA), NKG2D ligands, γδ T cell receptor (TCR) ligands, and αβ TCR ligands, or wherein the target antigen is selected from the group consisting of: alpha folate receptor (FRα), αvβ6 integrin, B cell maturation antigen (BCMA), B7-H3 (CD276), B7-H6, carbonic anhydrase IX (CAIX), CD16, CD19, CD20, CD22, CD30, CD33, CD37, CD38, CD44, CD44v6, CD44v7/8, CD70, CD79a, CD79b, CD123, CD133, CD138, CD171, carcinoembryonic antigen (CEA), C-type lectin-like molecule-1 (CLL-1), CD2 subset 1 (CS-1), chondroitin sulfate proteoglycan 4 (CSPG4), cutaneous T cell lymphoma-associated antigen 1 (CTAGE1), epidermal growth factor receptor (EGFR), epidermal growth factor receptor variant III (EGFRvIII), epithelial glycoprotein 2 (EGP2), epithelial glycoprotein 40 (EGP40), epithelial cell adhesion molecule (EPCAM), ephrin type-A receptor 2 (EPHA2), fibroblast activation protein (FAP), Fc Receptor Like 5 (FCRL5), fetal acetylcholinesterase receptor (AchR), ganglioside G2 (GD2), ganglioside G3 (GD3), Glypican-3 (GPC3), EGFR family including ErbB2 (HER2), IL-11R□, IL-13R□2, Kappa, cancer/testis antigen 2 (LAGE-1A), Lambda, Lewis-Y (LeY), L1 cell adhesion molecule (L1-CAM), melanoma antigen gene (MAGE)-A1, MAGE-A3, MAGE-A4, MAGE-A6, MAGEA10, melanoma antigen recognized by T cells 1 (MelanA or MART1), Mesothelin (MSLN), MUC1, MUC16, MHC class I chain related proteins A (MICA), MHC class I chain related proteins B (MICB), neural cell adhesion molecule (NCAM), cancer/testis antigen 1 (NY-ESO-1), polysialic acid; placenta-specific 1 (PLAC1), preferentially expressed antigen in melanoma (PRAME), prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), synovial sarcoma, X breakpoint 2 (SSX2), Survivin, tumor associated glycoprotein 72 (TAG72), tumor endothelial marker 1 (TEM1/CD248), tumor endothelial marker 7-related (TEM7R), trophoblast glycoprotein (TPBG), UL16-binding protein (ULBP) 1, ULBP2, ULBP3, ULBP4, ULBP5, ULBP6, vascular endothelial growth factor receptor 2 (VEGFR2), and Wilms tumor 1 (WT-1).
3. The recombinant oncolytic herpes simplex virus of claim 1 , wherein the target antigen is BCMA or CD19.
4. The recombinant oncolytic herpes simplex virus of claim 1 , further comprising one or more polynucleotides encoding one or more therapeutic polypeptides selected from the group consisting of: a bispecific T cell engager (BiTE), a checkpoint inhibitor, a cytokine, a protease, and an extracellular matrix remodeling enzyme.
5. The recombinant oncolytic herpes simplex virus of claim 1 , further comprising a modification of one or more non-essential viral genes.
6. The recombinant oncolytic HSV of claim 1 , wherein the one or more viral genes are selected from the group consisting of: the joint region, one or both copies of ICP-34.5, UL39 (ICP6), and US12 (ICP47, α47).
7. The recombinant oncolytic HSV of claim 1 , wherein the non-HSV polypeptide is a ligand selected from the group consisting of: an antibody or antigen binding fragment thereof, a hormone, or a growth factor, or a ligand that specifically or selectively binds a protein on the surface of the target cell.
8. The recombinant oncolytic HSV of claim 1 , wherein the non-HSV polypeptide binds:
a) a growth factor receptor expressed on a target cell;
b) an epidermal growth factor receptor (EGFR) or splice variant thereof, expressed on a target cell;
c) a checkpoint protein expressed on a target cell; and/or
d) a checkpoint protein selected from the group consisting of: PD-L1, PD-L2, and PD-1.
9. The recombinant oncolytic virus of claim 4 , wherein the extracellular remodeling enzyme is MMP-9.
10. A method of treating a subject in need thereof comprising:
a) administering to the subject an oncolytic herpes simplex virus according to claim 1 ;
b) isolating immune effector cells from the subject;
c) transducing the immune effector cells with vector encoding an engineered antigen receptor; and
d) administering the transduced immune effector cells to the subject;
wherein the transduced immune effectors cells bind the target antigen expressed on the target cell and induce cytolysis of the target cell.
11. A method of treating a subject that has cancer comprising:
a) intra-tumorially administering to a solid cancer in the subject, an effective amount of a pseudotyped oncolytic HSV-1 comprising: a polynucleotide encoding a target antigen selected from the group consisting of CD19 and BCMA; a polynucleotide encoding human MMP-9 inserted into a non-essential viral gene and/or deleted joint region; and one or more tumor suppressor miR target sequences recognized and/or bound by a miR selected from the group consisting of hsa-miR-1-3p, hsa-miR-124-3p, hsa-miR-143-3p, hsa-miR-145-5p, hsa-miR-451a, and hsa-miR-559 inserted into one or more essential viral genes required for viral replication selected from the group consisting of ICP4 and ICP27;
b) isolating immune effector cells from the subject about 1 week to about 4 weeks after administering the oncolytic HSV-1;
c) transducing the immune effector cells with retroviral or lentiviral vector encoding an anti-CD19 CAR or anti-BCMA CAR; and
d) administering the transduced immune effector cells to the subject; and optionally repeating steps a) through d).