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E - Disease Models and Clinical Applications -> Cancer – Targeted Gene and Cell Therapy

90: Potent In Vivo Transduction by iGPS Particles Generates CAR T Cells with Durable Anti-Tumor Activity

Type: Oral Abstract Session

Presentation Details
Session Title:

CAR Engineering and Production Advances for Targeting Hematologic and Solid Tumor Malignancies

Location: Room 502 AB
Start Time: 5/17/2023 16:15
End Time: 5/17/2023 16:30

Adoptive autologous cell therapies have proven to be effective treatments for hematological malignancies. Access to such treatments is severely constrained by the length and complexity of ex vivo manufacturing. Allogeneic approaches are aimed at overcoming scalability and time to treatment but remain limited by inferior clinical responses. A chimeric antigen receptor (CAR) T cell therapy that improves patient access and reduces manufacturing complexity without sacrificing clinical benefit of autologous cell therapies is needed. CAR gene delivery to T cells in vivo is a potential solution that also eliminates the need for conditioning chemotherapy required for cell engraftment. Here we describe an in vivo gene placement system (iGPSTM), an advanced lentiviral vector (LVV) particle harboring envelope modifications to improve in vivo gene transfer efficiency and tropism molecules to facilitate T cell-specific gene delivery. When an anti-BCMA CAR transgene was expressed by iGPS particles, low intravenous (i.v.) dose levels caused potent and durable multiple myeloma regression in preclinical models.
In vitro culture of normal human peripheral blood mononuclear cells (PBMC) with iGPS particles without T cell-activating antibodies demonstrated concentration-dependent T cell transduction. Even at a low multiplicity of infection of 1, an average of 14% T cell transduction (VCN=1.2) was achieved. Transduction efficiency in vivo was assessed in humanized mouse models after a single i.v. dose of 2e7 TU iGPS particles. An average of 1.9% transduced blood T cells was observed with iGPS particles. Matched doses of “standard” VSVg-pseudotyped LVV particles with and without T cell tropism molecules resulted in 0.27% and 0% transduced T cells, respectively. These data indicate iGPS envelope modifications drive efficient in vivo transduction and preferential outgrowth of T cells.
We evaluated anti-tumor activity of anti-BCMA CAR T cells generated in vivo by i.v. treatment with iGPS particles. Complete regression of established multiple myeloma tumors was possible at the lowest dose level tested (1e7 TU). A single dose of 2.5e7 TU iGPS particles resulted in complete tumor control comparable to mice adoptively transferred with anti-BCMA CAR T cells generated ex vivo using established methods. To evaluate functional persistence of iGPS particle-generated CAR T cells, animals were rechallenged with multiple myeloma tumor cells ~2 weeks after primary tumor clearance. All animals treated with iGPS particles were completely protected against secondary tumor challenge, whereas animals treated with ex vivo-generated CAR T cells showed tumor progression.
Off-target transduction was evaluated after infusion of iGPS particles at a therapeutic dose level of 2.5e7 TU in humanized mice. One week following i.v. iGPS administration, a comprehensive set of tissues including heart, brain, ovaries, intestinal tract lung and liver were analyzed for transduction. Across animals, the average T cell transduction was 3.9% and 14% in the blood and spleen, respectively. Strikingly, transduction of other tissues was limited to phagocytes like Kupffer cells, which are expected to nonspecifically take up iGPS particles. No transduction was detected in vital organs or in progenitor cells.
iGPS particles can deliver CAR molecules to T cells in vivo with high efficiency and tissue specificity at therapeutic dose levels. Anti-BCMA CAR T cells generated with iGPS particles exhibit anti-tumor potency and functional persistence. These data demonstrate the potential for iGPS particles to be a highly effective, safer, off-the-shelf therapy for patients with multiple myeloma.

Shannon Grande Contrastano, Emily T. Beura, Denise Wong, Gabrielle Ndakwah, Howard J. Latimer, Jenifer Obrigewitch, Jose Sanabria, Alexander J. Najibi, Daniel Wambua, Jeff Wood, Jessica Murray, Maggie Lau, Josue Figueroa, Alyson Warr, Connor S. Dobson, Molly R. Perkins, Kevin Friedman

Kelonia Therapeutics, Boston, MA
  S.G. Contrastano: 1; Commercial Interest i.e. Company X; Kelonia Therapeutics. 1; What was received? i.e. Honorarium; Salary. 1; For what role? i.e. Speaker; Employee.

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