| Autor: |
Lu YJ; Endocyte, Inc., West Lafayette, IN, United States., Chu H; Endocyte, Inc., West Lafayette, IN, United States., Wheeler LW; Endocyte, Inc., West Lafayette, IN, United States., Nelson M; Endocyte, Inc., West Lafayette, IN, United States., Westrick E; Endocyte, Inc., West Lafayette, IN, United States., Matthaei JF; Ben Towne Center for Childhood Cancer Research (BTCCCR), Seattle Children's Research Institute, Seattle, WA, United States., Cardle II; Ben Towne Center for Childhood Cancer Research (BTCCCR), Seattle Children's Research Institute, Seattle, WA, United States., Johnson A; Ben Towne Center for Childhood Cancer Research (BTCCCR), Seattle Children's Research Institute, Seattle, WA, United States., Gustafson J; Ben Towne Center for Childhood Cancer Research (BTCCCR), Seattle Children's Research Institute, Seattle, WA, United States., Parker N; Endocyte, Inc., West Lafayette, IN, United States., Vetzel M; Endocyte, Inc., West Lafayette, IN, United States., Xu LC; Endocyte, Inc., West Lafayette, IN, United States., Wang EZ; Endocyte, Inc., West Lafayette, IN, United States., Jensen MC; Ben Towne Center for Childhood Cancer Research (BTCCCR), Seattle Children's Research Institute, Seattle, WA, United States., Klein PJ; Endocyte, Inc., West Lafayette, IN, United States., Low PS; Endocyte, Inc., West Lafayette, IN, United States.; Department of Chemistry, Purdue University, West Lafayette, IN, United States., Leamon CP; Endocyte, Inc., West Lafayette, IN, United States. |
| Abstrakt: |
Chimeric antigen receptor (CAR)-T cell therapy has transformed pediatric oncology by producing high remission rates and potent effects in CD19+ B-cell malignancies. This scenario is ideal as CD19 expression is homogeneous and human blood provides a favorable environment for CAR-T cells to thrive and destroy cancer cells (along with normal B cells). Yet, CAR-T cell therapies for solid tumors remain challenged by fewer tumor targets and poor CAR-T cell performances in a hostile tumor microenvironment. For acute myeloid leukemia and childhood solid tumors such as osteosarcoma, the primary treatment is systemic chemotherapy that often falls short of expectation especially for relapsed and refractory conditions. We aim to develop a CAR-T adaptor molecule (CAM)-based therapy that uses a bispecific small-molecule ligand EC17, fluorescein isothiocyanate (FITC) conjugated with folic acid, to redirect FITC-specific CAR-T cells against folate receptor (FR)-positive tumors. As previously confirmed in rodents as well as in human clinical studies, EC17 penetrates solid tumors within minutes and is retained due to high affinity for the FR, whereas unbound EC17 rapidly clears from the blood and from receptor-negative tissues. When combined with a rationally designed CAR construct, EC17 CAM was shown to trigger CAR-modified T cell activation and cytolytic activity with a low FR threshold against tumor targets. However, maximal cytolytic potential correlated with (i) functional FR levels (in a semi-log fashion), (ii) the amount of effector cells present, and (iii) tumors' natural sensitivity to T cell mediated killing. In tumor-bearing mice, administration of EC17 CAM was the key to drive CAR-T cell activation, proliferation, and persistence against FR+ pediatric hematologic and solid tumors. In our modeling systems, cytokine release syndrome (CRS) was induced under specific conditions, but the risk of severe CRS could be easily mitigated or prevented by applying intermittent dosing and/or dose-titration strategies for the EC17 CAM. Our approach offers the flexibility of antigen control, prevents T cell exhaustion, and provides additional safety mechanisms including rapid reversal of severe CRS with intravenous sodium fluorescein. In this paper, we summarize the translational aspects of our technology in support of clinical development. |
