G2 - Immune Targeting and Approaches with Genetically-Modified Cells and Cell Therapies (Including CAR-T, CAR-NK, TCR editing)
2: In Vivo Generation of Both CAR T Cells and CAR NK Cells Using a CD7 Targeted Lentiviral Vector
Type: General Session
Presentation Details
Session Title: Presidential Symposium
CAR-T cell therapy has shown remarkable clinical efficacy against various cancers, including hematologic malignancies. CAR-NK cells have shown promising results in cancer therapy, especially B-cell lymphoma, with a lower risk of GVHD, serious cytokine release syndrome (CRS) and immune effector-cell associated neurotoxic syndrome (ICANS) compared to allogenic CAR-T cells
1. INT2104 utilizes a lentiviral vector platform that incorporates CD7-targeting to specifically transduce T cells and NK cells upon intravenous (i.v.) administration. Here we describe the ability of a single i.v. administration of INT2104 to transduce both T and NK cells
in vivo generating functional CAR20+ cells resulting in the depletion of CD20+ B cells.
In vitro assessments of INT2104 confirmed transduction of both CD7+ NK cells and T cells, including CD4+ and CD8+ subsets. A humanized CD34-engrafted NSG-Tg (Hu-IL15) mouse model, which constitutively expresses human interleukin-15 to enhance NK-cell development in these mice, was utilized to demonstrate effective NK cell transduction following INT2104 administration. Mice receiving a single bolus INT2104 dose of 1 x 10
7 transducing units by tail vein injection were compared to control mice receiving no vector. Weekly analysis of blood confirmed CD20+ B cell depletion compared to untreated control mice. At select timepoints throughout the study, the distribution and persistence of transduced CAR+ NK cells and T cells was assessed examining select tissues from euthanized animals. Beginning on Day 7 post INT2104 administration, CAR T and NK cells were detected in bone marrow, spleen, and liver. After demonstrating targeted gene delivery to T and NK cells using humanized mouse models, CAR20 vector was administered i.v. to cynomolgus macaques. Depletion of peripheral blood B cells in vector-treated NHPs was evident as early as Day 4 post administration. The complete absence of circulating B cells was maintained in one animal and analysis of secondary lymphoid organs in this animal confirmed systemic B cell depletion at necropsy 1-year post treatment. Separately, to demonstrate that both CAR+ T cells and NK cells were generated in NHPs following i.v. administration of a CAR20 vector, two NHPs were treated with CAR20 vector and sacrificed 4 days post treatment. Immunohistochemical analyses of spleen and liver were conducted with an anti-CAR antibody and markers for T cells (CD3), NK cells (NKG2A), as well as hepatocytes (HNF4α). CAR+ cells were detected in spleen with CAR+ signal colocalizing to both CD3+ T cells (Figure 1a) and NKG2A+ NK cells (Figure 1b). No CAR+ hepatocytes were detected among the 8685 hepatocytes present in the representative liver sections analyzed to date. These data highlight the selectivity in targeting and transducing CD7+ T cells and NK cells, with no off-target transduction observed in hepatocytes. A FIH study for INT2104 is scheduled to begin in 4Q2024.
1Liu, E., et al. “Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors.” The New England Journal of Medicine. 382(6) (2020): 545-553.
Karla F. Mullen, Daniel Grubaugh
, Kayla R. Welsh
, Jeffery Foss
, Julia L. A. Nguyen
, Nishi Gheewala
, Leticia Kuri-Cervantes
, James I. Andorko
, Bruce C. Schnepp
, Timothy D. Culp
, Philip R. Johnson
Interius BioTherapeutics, Philadelphia, PA"