Session: 703. Cellular Immunotherapies: Basic and Translational: Exploring Novel Platforms for Next-Gen CAR-Based Therapies
Hematology Disease Topics & Pathways:
Biological therapies, Research, Translational Research, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Therapies, Immunotherapy
Mice (NSG MHCI/II knockout): Mice were engrafted with CD19+ Nalm6 tumors and resting human PBMCs, followed by intraperitoneal administration of varying doses of VivoVec™ carrying an aCD19 CAR payload. Absolute CAR T-cell numbers in peripheral blood were quantified by flow cytometry, and Nalm6 tumor burden was assessed by bioluminescence imaging.
Non-Human Primates (Macaca nemestrina): VivoVec™ surface engineered with NHP-specific surrogate MDF and carrying a human/NHP cross-reactive aCD20 CAR payload. VivoVec™ was administered via intranodal injection to 3 animals at doses of 0.77e8/kg TU in 1 animal and 2.50 e8/kg TU in 2 animals. aCD20 CAR T expansion and B-cell depletion were continuously evaluated by flow cytometry approximately weekly over ~4 months. Body weight, body temperature, neurological exams, serum chemistry panels, and complete blood counts were assessed weekly for the duration of the study.
VivoVec™ cultured with resting PBMCs selectively bind T cells and some NK cells in an MDF surface engineering-dependent manner, resulting in T cell activation, transduction, and CAR expression. The resultant CAR T cells demonstrate polyfunctional activity through antigen-specific tumor cell killing of Nalm6 tumor cells, cytokine secretion, and proliferation in response to serial antigen exposure. VivoVec™ administration led to dose-dependent generation of CAR T cells in Nalm6-tumor bearing humanized NSG MHCI/II knockout mice. In vivo generated CAR T cells expanded and mediated potent and durable anti-Nalm6 tumor activity.
Non-Human Primates: In the two animals receiving 2.50e8 TU/kg of particles, aCD20 CAR T cells were detected in peripheral blood by flow cytometry with an early peak expansion by day 10 (representing 25.9% or 61.3% of total T cells, respectively). In the first animal, B-cell aplasia was observed from day 7 to day 42, when a small recovering B-cell population was detectable. This was closely followed by a secondary CAR T-cell expansion peaking at day 51: the CAR T cell population represented 43.2% of T cells present in the blood and resulted in recurrent B-cell aplasia sustained through day 70. Persistent B cell aplasia in the second animal receiving the 2.50e8 TU/kg dose began at day 7 and continues to be monitored.
VivoVec™ was well-tolerated with no evidence of toxicity associated within, or shortly after the period of administration. Mild CRS was observed in association with both early and late CAR T cell expansions.
Conclusions: VivoVec™ with MDF surface engineering enables potent and specific generation of functional CAR T cells in vivo in multiple preclinical models, including immune competent NHPs. Importantly, the generation and expansion of CAR T cells occurs in the absence of lymphodepleting chemotherapy, or supportive exogenous cytokines, thus the MDF engineering could impart properties consistent with a natural T cell effector response followed by formation of functional memory T cells. VivoVec™ represents a novel therapeutic platform in oncology that has the potential to overcome many of the challenges associated with the current ex vivo CAR T cell approaches. Additional data from ongoing NHP studies will be provided at the time of presentation.
Disclosures: No relevant conflicts of interest to declare.
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