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847 CF33-CD19t oncolytic virus (onCARlytics) in combination with off-the-shelf allogeneic CyCART-19 T cells targeting de novo CD19+ solid tumors
  1. Anthony Park1,
  2. Isabel Monroy1,
  3. Colin Cook1,
  4. Shuyang He2,
  5. Kathy Karasiewicz2,
  6. Monil Shah3,
  7. Nimali Withana3,
  8. Leslie Chong3,
  9. Robert Hariri2,
  10. Yuman Fong1 and
  11. Saul Priceman1
  1. 1City of Hope, Duarte, CA, United States
  2. 2Celularity, Warren, NJ, United States
  3. 3Imugene, Sydney, Australia


Background Autologous chimeric antigen receptor (CAR) T cell therapy has shown impressive clinical responses against CD19+ B-cell hematological malignancies and is being actively explored in the treatment of solid tumors. However, several barriers have precluded therapeutic responses in solid tumors, including limited tumor-restricted CAR targets and the immunosuppressive tumor microenvironment. We have recently reported the successful combination immunotherapy using a novel chimeric vaccinia-based oncolytic virus (OV), called onCARlytics (Imugene Limited), that is engineered to express a non-signaling, truncated CD19 (CD19t) antigen for tumor-selective delivery, enabling de novo targeting of tumor cells by autologous CD19-CAR T cells. One of the field’s unanswered questions is whether treatment-naïve allogeneic CAR T cells are superior to cancer patient-derived T cells for product manufacturing to improve overall responses against solid tumors.

Methods Here, we evaluated this combination strategy using two allogeneic CAR T cell products generated from peripheral blood mononuclear cells (PBMC) and placental T cells, respectively. PBMC-derived CAR-T cells were manufactured from normal, healthy donors. CYCART-19 (Celularity, Inc.) cells were derived from postpartum human placental T cells that are genetically modified to express the CD19 CAR followed by CRISPR-Cas9- mediated knockout of the endogenous TCR and expanded to produce multiple doses of allogeneic “off the shelf” treatment. For preclinical testing, we utilized in vitro co-culture assays. We evaluated tumor cell killing and T cell activation using flow cytometry and cytokine assays. Xenograft mouse models were used to evaluate anti-tumor activity of the combination in vivo.

Results CYCART-19 T cells induced potent cytolytic activity against solid tumor cells infected with onCARlytics. Interestingly, while we observed comparable anti-tumor activity between PBMC-derived CD19-CAR T cells and CYCART-19, significant differences in cytokine secretion were detected. This warrants the possibility that the placental-derived CAR T product may elicit reduced CRS potential in patients with maintained or improved efficacy. This combination approach demonstrated impressive in vivo anti-tumor response in human tumor xenograft models.

Conclusions In summary, our results have demonstrated that further development of this combination immunotherapy for the potential treatment of a wide array of solid tumors is warranted.

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