Session: 702. CAR-T Cell Therapies: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Autoimmune disorders, Lymphoid Leukemias, Acute Myeloid Malignancies, Translational Research, Lymphomas, Plasma Cell Disorders, Diseases, Immune Disorders, Lymphoid Malignancies
To reduce CCT-related toxicities, enable broad outpatient access, and promote durable elimination of AID-associated pathogenic cells, we have developed a multiplexed-engineered, next-generation (NxG) CAR T cell therapy derived from a clonal induced pluripotent stem cell line (CAR iT cell). These NxG CAR iT cells incorporate a suite of novel synthetic edits which are designed to specifically target and eliminate multiple subsets of aberrant immune cells through enhanced homing and bio-distribution to secondary and tertiary tissues, and to mitigate the need for intense CCT administration.
Anti-CD19 NxG CAR iT cells consist of a clonal population of genetically edited cells that are deficient in endogenous TCRα chain expression, exhibit a CD8αβ T cell phenotype comparable to that of a potent cytotoxic T cell poised for activation, and lack expression of canonical exhaustion markers following CAR-mediated activation. Moreover, anti-CD19 NxG CAR iT cells demonstrate robust and specific elimination of CD19+ B cells in multiple in vitro cytotoxicity assays, including those containing patient peripheral blood mononuclear cells (PBMCs) as well as those designed to test NxG CAR iT-cell cytotoxic durability over multiple rounds of target cell challenge. In xenograft murine models, where disseminated disease resides in primary, secondary and tertiary tissues, anti-CD19 NxG CAR iT cells displayed tissue-wide functional persistence, including durable elimination of CD19+ B cells in the bone marrow.
The addition of a second CAR, targeting B cell maturation antigen (BCMA), to anti-CD19 NxG CAR iT cells showed robust elimination of both CD19 and BCMA expressing B and plasma cells, respectively (target cell depletion >95% p<0.001 vs single CAR containing controls). Similarly, the addition of an anti-CD38 CAR also exhibited enhanced engagement and elimination of aberrant B cells, plasma cells and activated T cells. Both dual-CAR targeting strategies, CD19xBCMA and CD19xCD38, serve as innovative approaches to eliminate many aberrant immune cell types, which can collectively drive disease pathology, and to promote complete remission in AID. These dual-CAR strategies are also applicable in BCM settings, such as lymphoma and multiple myeloma where multiple aberrant immune cells are implicated in disease progression.
To overcome the need for administration of intense CCT, NxG CAR iT cells also contain a novel allo-immune defense receptor (ADR), which has been shown to promote CAR T cell expansion, function, and persistence in an allogeneic setting. ADR-armed NxG CAR iT cells displayed enhanced persistence and cytotoxicity in an in vitro allogeneic re-stimulation assay, relative to control T cells without ADR, eliminating target cells through multiple rounds of re-challenge in the presence of alloreactive PBMCs. Similarly, ADR-armed NxG CAR iT cells maintained tumor growth inhibition and persistence in vivo in the presence of unmatched T cells. Importantly, NxG CAR iT cells can be reproducibly manufactured at scale to support off-the-shelf availability and cost-effective utilization.
Collectively, NxG CAR iT cells represent a promising off-the-shelf approach to cell therapy for the treatment of AID and BCM, with the unique potential to elicit durable elimination of an array of aberrant immune cells, to avoid toxicities associated with intense CCT, and to maximize patient access and reach.
Disclosures: Goulding: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jelcic: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Morales-Mantilla: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Reiser: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. O'Connor: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mbofung: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Williams: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lu: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Yang: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gutierrez: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Meza: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Pan: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tuncel: Fate Therapeutics: Current Employment. Hancock: Fate Therapeutics: Current Employment. Sherman: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Witty: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Peralta: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hosking: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Wong: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lee: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Goodridge: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company. Valamehr: Fate Therapeutics: Current Employment, Current equity holder in publicly-traded company.
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