Session: 703. Cellular Immunotherapies: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Biological therapies, Therapies, Immunotherapy, Natural Killer (NK) Cell Therapies
To address many of these challenges, we thought to combine our alloimmune defense receptor (ADR) that targets 41BB+ activated immune cells while providing a CD3z signaling boost upon engagement, with our CAR NK cell construct that has been fine-tuned for NK cell biology and targets B-lymphocyte antigen CD19. These two synthetic modalities were incorporated into a master induced pluripotent stem cell (iPSC) line to serve as a renewable starting material for the derivation of iPSC-derived NK cells uniformly expressing ADR and anti-CD19 CAR (ADR+ CAR19 iNK cells).
The ability of ADR+ CAR19 iNK cells to resist host-mediated rejection was tested by co-culturing ADR+ CAR19 iNK cells with allogeneic PBMCs in a mixed lymphocyte reaction (MLR) assay. Notably, co-cultured ADR+ CAR19 iNK cells not only persisted, but also expanded over the duration of the assay, while co-cultured ADR- CAR19 iNK cells were eliminated (Figure 1A, p<.001). To further increase the stringency of our assessment, we substituted naïve PBMCs with T cells primed and enriched for alloreactivity (primed-T cells) against the iNK cell. As observed with naïve PBMCs, ADR- CAR19 iNK cells co-cultured with primed-T cells were depleted and expression of 41BB was detected among a large subset of primed-T cells. In contrast, ADR+ CAR19 iNK cells persisted, and the primed-T cells in the co-culture were reduced in number and had no detectable 41BB expression. Together, these allogeneic models demonstrate that ADR+ CAR19 iNK cells have the unique ability to target 41BB+ alloreactive T cells and to persist in an intact immune system, suggesting the potential to function without conditioning chemotherapy.
To confirm that ADR+ CAR19 iNK cells retain potent anti-tumor efficacy, we performed a rigorous tri-culture MLR study that combined daily-dosed CD19+ Nalm6 tumor cells and a single dose of primed- T cells with either ADR+ CAR19 or ADR- CAR19 iNK cells (Figure 1B). In co-cultures with repeat restimulation of Nalm6 tumor cells, we found that tumor growth was well controlled with CAR19 iNK cells +/- ADR over the course of the assay. However, when primed-T cells were added, the tri-culture assay with ADR- CAR19 iNK cells lost tumor control and 41BB+ primed-T cells were expanded. In contrast, ADR+ CAR19 iNK cells in the tri-culture assay suppressed 41BB+ primed-T cell expansion, persisted through the end of the assay, and demonstrated enhanced tumor growth inhibition which was similar to the control culture without primed-T cells (Figure 1B). Allogeneic xenograft tumor models assessing the ability of ADR+ CAR19 iNK cells to control lymphoma and leukemia in vivo in the presence of alloreactive T cells are ongoing and will be presented.
Our data suggest that ADR+ CAR19 iNK cells have the unique ability to withstand immune cell-mediated attack with uncompromised effector function. In preclinical alloreactivity models, ADR+ CAR19 iNK cells expand, functionally persist, and maintain anti-tumor activity in the presence of activated T cells. Collectively, ADR+ CAR19 iNK cells represent a promising approach to reduce the intensity of, or eliminate the need for, lymphodepletion. The favorable therapeutic index of cell-based cancer immunotherapies without conditioning potentially facilitates their broad clinical use through multiple lines of therapy, including in patients with newly-diagnosed disease.
Disclosures: Williams: Fate Therapeutics: Current Employment. Hayama: Fate Therapeutics: Current Employment. Pan: Fate Therapeutics: Current Employment. Groff: Fate Therapeutics: Current Employment. Mbofung: Fate Therapeutics Inc: Current Employment. Chang: Fate Therapeutics: Current Employment. Chen: Fate Therapeutics: Current Employment. Fong: Fate Therapeutics: Current Employment. Brookhouser: Fate Therapeutics: Current Employment. Mandefro: Fate Therapeutics: Current Employment. Abujarour: Fate Therapeutics: Current Employment. Lee: Fate Therapeutics: Current Employment. Mamonkin: Allogene Therapeutics: Patents & Royalties; Fate Therapeutics: Patents & Royalties. Clarke: Fate Therapeutics: Current Employment. Bjordahl: Fate Therapeutics: Current Employment. Goodridge: Fate Therapeutics: Current Employment. Valamehr: Fate Therapeutics: Current Employment.
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