Yang et al. engineered iPSC-derived T cells that uniformly coexpressed a CAR targeting a surface antigen, a TCR targeting an intracellular/neoantigen or a tumor-associated antigen or metabolite, and a high-affinity non-cleavable CD16a (FcγRIII) variant that signaled through CD3ζ. These cells were shown to be most similar to αβ lineage-committed CD8+ T cells, supported ADCC when combined with therapeutic Abs, and mediated antigen-specific targeting of multiple types of liquid and solid tumors in vitro and in xenograft tumor models in mice. The activation of all three modalities cooperated to mediate maximal antitumor efficacy and mitigate antigen escape.
Contributed by Paula Hochman
ABSTRACT: Although chimeric antigen receptor (CAR) T cells have demonstrated therapeutic activity in hematopoietic malignancies, tumor heterogeneity has impeded the efficacy of CAR T cells and their extension into successful solid tumor treatment. To address these challenges, induced pluripotent stem cell (iPSC)-derived T (iT) cells are engineered to uniformly express CAR and T cell receptor (TCR), enabling targeting of both surface and intracellular antigens, respectively, along with a high-affinity, non-cleavable variant of CD16a (hnCD16) to support antibody-dependent cellular cytotoxicity (ADCC) when combined with therapeutic antibodies. Co-expression of each antitumor strategy on engineered iT cells enables independent and antigen-specific targeting across a diverse set of liquid and solid tumors. In heterogeneous tumor models, coactivation of these modalities is required for measurable antitumor efficacy, with activation of all three modalities displaying maximal efficacy. These data highlight the therapeutic potential of an off-the-shelf engineered iPSC-derived trimodal T cell expressing CAR, TCR, and hnCD16 to combat difficult-to-treat heterogeneous tumors.
Author Info: (1) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (2) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (3) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (4) Fate Therap
Author Info: (1) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (2) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (3) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (4) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (5) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (6) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (7) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (8) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (9) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (10) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (11) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (12) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (13) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (14) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (15) Fate Therapeutics, Inc., San Diego, CA 92131, USA. (16) Fate Therapeutics, Inc., San Diego, CA 92131, USA. Electronic address: eigen.peralta@fatetherapeutics.com. (17) Fate Therapeutics, Inc., San Diego, CA 92131, USA. Electronic address: bob.valamehr@fatetherapeutics.com.
