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1230 VivoVec lentiviral vector particles surface-engineered with T cell activating and co-stimulatory ligands enhance in vivo CAR T cell generation and antitumor activity
  1. Chris Nicolai,
  2. Jim Qin,
  3. Way Wu,
  4. Mollie McDonnell,
  5. Erica Shirazi,
  6. Greyson Hamilton,
  7. Max Chen,
  8. Don Parrilla,
  9. Susana Hernandez,
  10. Kathryn Michels,
  11. Shon Green,
  12. Andrew Scharenberg,
  13. Laurie Beitz,
  14. Ryan Larson,
  15. Byoung Ryu and
  16. Wai-Hang Leung
  1. Umoja Biopharma, Seattle, WA, USA


Background Autologous chimeric antigen receptor (CAR) T cell therapies have revolutionized the treatment of B cell malignancies, leading to long-term remission in 30-40% of certain patient populations. Despite the promising clinical efficacy of CAR T cells in hematologic malignancies, major limitations hinder their widespread application, including challenges for patient access, complex manufacturing, and high cost.

Methods To overcome these challenges, we have developed VivoVec, a surface-engineered lentiviral vector-based platform harboring a CAR transgene that is being developed for off-the-shelf use for the generation of CAR T cells in vivo. To achieve specific and efficient in vivo T cell transduction, VivoVec particles are pseudotyped with the Cocal fusion glycoprotein and an anti-CD3 single chain variable fragment (scFv), and we have previously shown that these first-generation particles generate CAR T cells in vivo that mediate antitumor activity.

Results We have advanced the VivoVec platform through incorporating costimulatory molecules into the particle surface, in addition to the anti-CD3 scFv and Cocal fusion glycoprotein. These second-generation VivoVec particles exhibit enhanced T cell binding and activation, resulting in increased transduction and greater numbers of CAR+ T cells in vitro. In addition, CAR T cells generated with second-generation VivoVec particles exhibited a less-differentiated, central memory-like phenotype and enhanced CAR-antigen-specific polyfunctionality, including cytokine production, proliferation, and tumor cell killing. Finally, in a humanized NSG mouse model of B cell malignancy we observed that second-generation VivoVec particles generated greater numbers of CAR T cells in the blood, resulting in enhanced antitumor activity at lower doses compared to first-generation particles. Our results indicate that incorporation of costimulatory molecules onto the surface of VivoVec particles increases both the overall number and functionality of the resulting CAR T cells, greatly augmenting VivoVec mediated CAR T cell generation and antitumor activity in vivo.

Conclusions Overall, these data demonstrate that second-generation VivoVec particles efficiently generate large numbers of highly functional CAR T cells able to mediate durable tumor control in a preclinical model of B cell malignancy. VivoVec particles have the potential to overcome many of the limitations associated with the current class of CAR T cell therapies.

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