Clinical Results of a Phase 1 Trial Evaluating a HER2 Directed CAR-T Product Selective for the Tumor Microenvironment (TME) in Patients with GI & Other Solid Tumor Malignancies
Abstract #449 Key Points: HER2 is amplified in many solid tumors but also expressed in healthy tissue, increasing on-tumor, off-target toxicity (OTOTT) risk TMR CARs exploit tumor metabolism to improve selectivity and reduce OTOTT Single-center, investigator-initiated, dose-escalation trial enrolled 12 patients with HER2-positive Stage IV solid tumors (3 gastric, 1 esophageal, 4 colorectal, 4 breast). […]
mRNA encoding a CAR specific stimulating protein (CSSP) mediates tumor metabolism regulated (TMR) CAR signaling for CAR-T expansion beyond the tumor microenvironment.
Key Points: Unlike hematologic targets, TMR Chimeric Antigen Receptors (CARs) lack stimulatory signals for proliferation outside the tumor, limiting CAR-T exposure A surrogate CAR-Specific Stimulating Protein (CSSP) approach, encoded by synthetic mRNA and expressed in antigen-presenting cells, was developed to boost CAR-T proliferation in vitro and in vivo CSSPs selectively stimulated CAR-T cells through the […]
In vivo delivery of CD3-directed CD19-CAR lentivectors leads to the generation of CAR-T and NK-like (CAR-TaNK) cells capable of complete ablation of B cells in the blood, bone marrow, and tissue in NSG-SGM3 CD34+ humanized mice
Key Points: In vivo delivery of a CD3-directed lentivector that encodes a CD19 CAR leads to the generation of CAR+ cells with a T and NK (TaNK)-like phenotype The newly generated CAR-TaNK cells are capable of eliminating CD19 B cells in a dose dependent manner, relative to the amount of lentivector delivered. Mice injected with […]
In vivo generation of tumor-metabolism-regulated HER2-specific CAR+ cells eradicate established HER2+ gastric carcinomas with the novel subcutaneous route of administration of CD3-directed lentivector-loaded lymphocytes.
Key points: Subcutaneous injection of tumor microenvironment-regulated HER2 CAR lentivector-loaded lymphocytes results in the robust, in vivo proliferation of CAR+ cells that exhibit anti-tumor activity against HER2+ gastric carcinomas. Lymphocyte-specific fusion, internalization, and initiation of T cell activation are observed within four hours of exposure of lymphocytes to CD3-directed lentivector Rapid manufacturing process represents a […]
Generation of tertiary lymphoid structures and CD3pos CD8pos CD56pos NKG2Dpos CAR TaNK cells following subcutaneous injection of CD3-directed lentiviral vector-loaded PBMC
Abstract #560 Key Messages: Subcutaneous (SC) injection of peripheral blood mononuclear cells (PBMC) loaded for 4hrs with CD3-directed lentivector (LV) generate a novel CAR T and NK-like (TaNK) cell capable of enhanced proliferation and target elimination Following SC administration, CAR expression and expansion initiates at the site of injection from tertiary lymphoid structures comprised of […]
In vivo delivery of a novel CD3-targeted Lentiviral Vector generates CD19 CAR-T cells in two different humanized mouse models and results in complete B cell depletion
Abstract #3294 Key Messages: In vivo CD3-targeted Lentivectors (LV) delivery of CAR-T transgenes represents a promising CAR-T gene therapy approach (GCAR) CD3-directed CAR LV generate CD19 CAR-T cells in vivo, resulting in a complete depletion of hCD20+ B cells in circulation and in lymphoid organs This novel approach for the rapid and direct formation of […]
Subcutaneous injection of total nucleated cells rapidly isolated following four-hour peripheral whole blood exposure to CD3-directed CAR-T lentiviruses with a synthetic driver results in robust CAR-T proliferation and anti-tumor immunity
Abstract #1511 Key Messages Here we describe a novel approach for the rapid isolation of total nucleated cells (TNC) reverse eluted off a leukocyte reduction filter from whole blood exposed for four hours to CD3-directed CAR-T Lentiviruses (LV) CD3-directed CAR-T LVs induce TCR internalization (CD3 Dimming) in T cells including Naïve and Naïve-derived T cells […]
Rapid point-of-care subcutaneous CAR-T from blood draw to injection in 4 hours with modified LV encoding CARs and synthetic driver elements enables efficient CAR-T expansion and tumor regression
Abstract #117 Link to poster Key Messages: We demonstrate that subcutaneous (SC) delivery of human PBMCs modified by a 4- hour exposure to CD3-directed lentiviruses encoding a CD19 or a CD22 Chimeric Antigen Receptor (CAR) resulted in potent anti-tumor efficacy and robust in vivo expansion of CAR-T positive cells. CAR-T cells driven by a synthetic […]
Logic-gating HER2 CAR-T to the tumor microenvironment mitigates on-target, off-tumor toxicity without compromising cytotoxicity against HER2-over-expressing tumors
Link to virtual “poster” presentation Key Messages: The current work describes a high-throughput method for screening lymphoproliferative elements in vivo in a lentivirus format for next generation CAR-T A “logic-gated” HER2-targeted CAR-T was designed that preferentially recognizes HER2 in the tumor microenvironment (TME), thereby limiting on-target toxicity of low HER2 levels expressed in […]
Same Day Transduction and In Vivo Expansion of a Chimeric Antigen Receptor with a Synthetic Driver Construct for Adoptive Cellular Therapy
AACR 2019 Abstract #2327 Link to poster Key Messages: We demonstrate viral transfer feasibility in a point of care (POC) platform using an engineered lentiviral vector retargeted to CD3, which efficiently transduces freshly isolated resting human PBMCs in four hours POC modified cells successfully engraft and expand in vivo upon IV administration in mice The entire […]
