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262 Multiple targeting of solid tumors with iPSC-derived gamma delta CAR T cells in combination with therapeutic antibodies
  1. Hillary Millar Quinn,
  2. Justin Bianchini,
  3. Liam Campion,
  4. Katherine Santostefano,
  5. Toshinobu Nishimura,
  6. Sydney Bucher,
  7. Buddha Gurung,
  8. Shelby Keating,
  9. Rebecca Genovese,
  10. Steven DeLuca,
  11. Bruno Bonanno,
  12. David Walker,
  13. Marilda Beqiri,
  14. Chris Dower,
  15. Kaitlin Idank,
  16. Tomas Aramburu,
  17. Michael Naso,
  18. Luis Borges and
  19. Mark Wallet
  1. Century Therapeutics, Philadelphia, PA, USA


Background CAR-T cell therapies have proven safe and efficacious for hematologic malignancies, but there remains a significant unmet need for effective cell therapy options for solid tumors. CAR-engineered induced pluripotent stem cell (iPSC)-derived effector cells allow for the treatment of cancer as an off-the-shelf allogeneic cell therapy. Gamma delta (γδ) T cells exhibit the cytolytic features of conventional alpha beta (αβ) CD8+ T cells with additional capabilities for innate recognition of tumors. For example, expression of CD16 on γδ T cells can mediate antibody-dependent cellular cytotoxicity (ADCC) against tumors. Here we describe development of an iPSC-derived CAR γδ T cell platform which can target solid tumors through both CAR-mediated recognition and ADCC when combined with a therapeutic antibody.

Methods Primary γδ T cells were enriched and expanded in culture to enable reprogramming to iPSCs by delivery of pluripotency genes. These T cell derived iPSCs (TiPSCs) were used to produce γδ T cells using a proprietary differentiation process. The TiPSC line was engineered with a CAR targeting EGFR and a membrane bound form of IL-15 to enhance T cell persistence. Tumor spheroids were generated from EGFR+Her-2+ SKOV-3 ovarian tumor cells. Cytolysis of spheroids was evaluated using CAR-T cells alone or in combination with anti-HER2 antibody (trastuzumab).

Results Batches of CAR-T cells were generated using a proprietary differentiation process yielding >90% pure CAR+ γδ T cells. The TiPSCs contained the rearranged γδ TCR gene and upon differentiation to T cells, uniformly expressed a Vγ9Vδ2 TCR and expressed high levels of CD16. CAR γδ T cells were effective in killing SKOV-3 spheroids. When cultured with SKOV-3 spheroids in an ADCC assay, CAR γδ T cells exhibited enhanced cytotoxicity in the presence of trastuzumab but not isotype control antibody. Activity of the γδ T cells was not reliant on additional exogenous cytokine due to the engineered form of membrane-associated IL-15.

Conclusions We have demonstrated that iPSC-derived γδ T cells mediate anti-tumor activity in human solid tumor models through multiple pathways. The combination of two modes of tumor recognition (CAR and CD16/antibody) enabled more potent killing of solid tumor spheroids. The ability to manufacture large batches of iPSC derived CAR γδ T cells will enable a true off-the-shelf allogenic cell therapy for solid tumors.

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