Genetic Modification of CAR NK Cells for Improved Therapeutic Efficacy Against Cancer — ASN Events
  1. Schedule
  2. Poster Session Two
  3. Genetic Modification of CAR NK Cells for Improved Therapeutic Efficacy Against Cancer

Genetic Modification of CAR NK Cells for Improved Therapeutic Efficacy Against Cancer (#198)

Matea Menjak 1 2 , Karlotta Bartels 2 3 , Melanie Grimm 2 3 , Bianca Marx 2 3 , Philip Bucher 2 3 , Meike Thiemann 2 3 , Judith Feucht 2 3 , Josef Leibold 1 2
  1. Department of Medical Oncology and Pneumology, University Hospital Tübingen, University of Tübingen, Tübingen, Germany
  2. Cluster of Excellence 2180 "Image-guided and Functionally Instructed Tumor Therapies" (iFIT), University of Tübingen, Tübingen, Germany
  3. Department of Pediatric Hematology and Oncology, University Children's Hospital Tübingen, University of Tübingen, Tübingen, Germany

Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising immunotherapy that elicits remarkable clinical results in the context of hematologic malignancies. However, CAR T cell therapy can cause serious side effects and requires a challenging manufacturing process for autologous products. Natural killer (NK) cells offer an alternative approach as effector cells for CAR therapy. Early clinical data suggests that CAR NK cells have minimal toxicities when applied under allogeneic conditions, while still inducing promising responses against hematologic tumors. However, CAR NK cells face several challenges as they lack durable persistence in vivo and show limited efficacy against solid tumors.

Therefore, we are employing CRISPR/Cas9-based editing strategies to reprogram CAR NK cells and enhance their antitumor activity. We have performed knockouts of selected transcription factors associated with mature NK cell function. By altering the transcriptional profile, we have improved proliferation, activation and cytotoxicity of CAR NK cells against hematologic and solid tumors in vitro. Furthermore, we have enhanced their proliferative potential in vivo. These beneficial effects are augmented by synergistic knockout of two transcription factors. Ongoing analysis aims to elucidate the mechanism associated with the transcriptional changes and the enhanced antitumor potency. In addition, we have established a base editing platform to fine-tune signaling activities in CAR NK cells.

In summary, CAR NK cell therapy represents a promising off-the-shelf treatment option for vulnerable cancer patients. Engineering CAR NK cells to enhance persistence and effector function is a prerequisite to further improve the outcome of these patients. By changing the transcriptional profile through genetic modifications, we have improved the therapeutic efficacy of CAR NK cells both against hematologic and solid malignancies. Our results provide novel insights into the biology of NK cells and offer promising engineering strategies to further optimize CAR NK cell products.