LV305, a dendritic cell-targeting integration-deficient ZVex TM -based lentiviral vector encoding NY-ESO-1, induces potent anti-tumor immune response

Abstract

We have engineered an integration-deficient lentiviral vector, LV305, to deliver the tumor antigen NY-ESO-1 to human dendritic cells in vivo through pseudotyping with a modified Sindbis virus envelop protein. Mice immunized once with LV305 developed strong, dose-dependent, multifunctional, and cytotoxic NY-ESO-1-specific cluster of differentiation 8 (CD8) T cells within 14 days post-immunization and could be boosted with LV305 at least twice to recall peak-level CD8 T-cell responses. Immunization with LV305 protected mice against tumor growth in an NY-ESO-1-expressing CT26 lung metastasis model, with the protective effect abrogated upon depletion of CD8 T cells. Adoptive transfer of CD8 T cells, alone or together with CD4 T cells or natural killer cells, from LV305-immunized donor mice to tumor-bearing recipient mice conferred significant protection against metastatic tumor growth. Biodistribution of injected LV305 in mice was limited to the site of injection and the draining lymph node, and injected LV305 exhibited minimal excretion. Mice injected with LV305 developed little to no adverse effects, as evaluated by toxicology studies adherent to good laboratory practices. Taken together, these data support the development of LV305 as a clinical candidate for treatment against tumors expressing NY-ESO-1.

Dendritic cell–targeted lentiviral vector immunization uses pseudotransduction and DNA-mediated STING and cGAS activation

“…The direct injection of SVGmu-pseudotyped LV into mice specifically transduces conventional DCs (cDCs) in vivo and not other immune cells (1, 26, 27). To assess whether DCs were pseudotransduced in vivo, we subcutaneously injected SVGmu-pseudotyped VLP carrying GFP into the hindleg of wild-type mice and, after 1 day, harvested lymphoid tissue to analyze cells for GFP expression.…”

First-in-Class, First-in-Human Study Evaluating LV305, a Dendritic-Cell Tropic Lentiviral Vector, in Sarcoma and Other Solid Tumors Expressing NY-ESO-1

“…LV305 induces the expression of full-length NY-ESO-1 protein (5)(6)(7), which is a highly immunogenic cancer testis antigen expressed in up to 40% of non-small cell lung, ovarian, and melanoma cancers, and in greater than 70% of certain sarcoma subtypes [e.g., synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL); refs. [8][9][10][11].…”

“…NY-ESO-1-directed vaccination has obtained some promising clinical results in early phase I/II studies, and adoptive cell therapy has resulted in partial responses (PR) in 60% of NY-ESO-1-expressing sarcomas in small phase I trials (12). In preclinical studies, a single immunization with LV305 transduced DCs in vivo, generated multifunctional CD8 T-cell responses, and controlled the growth of NY-ESO-1-expressing murine tumors (7).…”

HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells

“…Integration deficiency of ZVex was achieved through genetic inactivation of the integrase (D64V mutation) and extended deletion of the 3′ region of the vector genome 45, 46. In mice, ZVex induced robust polyfunctional effector and memory CD8 + T cell responses with prophylactic and therapeutic effects in infectious disease and tumor challenge models after single injection 45, 65. ZVex is currently being evaluated in phase 1 and 2 cancer therapy studies in humans.…”

“…ID-LV was produced as described previously using the ZVex (also known as VP02) platform 45, 46, 65. Briefly, ZVex ID-LV was produced via transient transfection of 293T cells with five plasmids: (1) the transfer vector that encodes the ZVex genome and tHIVconsv1 or tHIVconsv2, (2) a modified rev-independent gagpol transcript, (3) accessory protein Rev from HIV-1, (4) accessory protein Vpx from SIVmac, and (5) the SinVar1 (E1001) envelop glycoprotein modified variant derived from Sindbis virus.…”