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Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
Payload-delivering engineered γδ T cells display enhanced cytotoxicity, persistence, and efficacy in preclinical
Daniel Fowler1, Marta Barisa1, Alba Southern1
1UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research, 20 Guilford Street, WC1N 1DZ London, UK.
Abstract:
T cell-based cancer immunotherapy has typically relied on membrane-bound cytotoxicity enhancers such as chimeric antigen receptors expressed in autologous αβ T cells. These approaches are limited by tonic signaling of synthetic constructs and costs associated with manufacturing. γδ T cells are an emerging alternative for cellular therapy, having innate antitumor activity, potent antibody-dependent cellular cytotoxicity, and minimal alloreactivity. We present an immunotherapeutic platform technology built around the innate properties of the Vγ9Vδ2 T cell, harnessing specific characteristics of this cell type and offering an allocompatible cellular therapy that recruits bystander immunity. We engineered γδ T cells to secrete synthetic tumor-targeting opsonins in the form of an scFv-Fc fusion protein and a mitogenic IL-15Rα-IL-15 fusion protein (stIL15). Using GD2 as a model antigen, we show that GD2-specific opsonin-secreting Vγ9Vδ2 T cells (stIL15-OPS-γδ T cells) have enhanced cytotoxicity and promote bystander activity of other lymphoid and myeloid cells. Secretion of stIL-15 abrogated the need for exogenous cytokine supplementation and further mediated activation of bystander natural killer cells. Compared with unmodified γδ T cells, stIL15-OPS-γδ T cells exhibited superior in vivo control of subcutaneous tumors and persistence in the blood. Moreover, stIL15-OPS-γδ T cells were efficacious against patient-derived osteosarcomas in animal models and in vitro, where efficacy could be boosted with the addition of zoledronic acid. Together, the data identify stIL15-OPS-γδ T cells as a candidate allogeneic cell therapy platform combining direct cytolysis with bystander activation to promote tumor control.
Insights
Engineered gamma delta T cells secrete tumor-targeting opsonins and IL-15, enhancing cancer immunotherapy. These cells show improved tumor control and bystander immune activation, offering a promising allogeneic cell therapy platform.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- T cell-based cancer immunotherapy often uses autologous αβ T cells with chimeric antigen receptors, facing limitations like tonic signaling and high manufacturing costs.
- Gamma delta (γδ) T cells present an alternative cellular therapy due to their innate antitumor activity, antibody-dependent cellular cytotoxicity, and low alloreactivity.
Purpose of the Study:
- To develop an allogeneic cellular therapy platform using Vγ9Vδ2 T cells engineered to secrete tumor-targeting opsonins and a mitogenic IL-15Rα-IL-15 fusion protein (stIL15).
- To evaluate the efficacy of these engineered γδ T cells (stIL15-OPS-γδ T cells) in enhancing direct tumor cell killing and recruiting bystander immune cells for improved tumor control.
Main Methods:
- Engineering Vγ9Vδ2 T cells to secrete GD2-specific scFv-Fc opsonins and stIL15.
- Assessing the cytotoxicity and bystander immune cell activation of engineered γδ T cells in vitro.
- Evaluating the in vivo efficacy and persistence of engineered γδ T cells in mouse models with subcutaneous tumors and patient-derived osteosarcomas.
Main Results:
- Engineered stIL15-OPS-γδ T cells demonstrated enhanced cytotoxicity and promoted bystander activity in lymphoid and myeloid cells.
- Secretion of stIL-15 by engineered cells obviated the need for exogenous cytokines and activated bystander natural killer cells.
- stIL15-OPS-γδ T cells showed superior in vivo tumor control and persistence compared to unmodified γδ T cells, with efficacy against patient-derived osteosarcomas, further enhanced by zoledronic acid.
Conclusions:
- Engineered Vγ9Vδ2 T cells secreting tumor-targeting opsonins and stIL15 represent a potent allogeneic cell therapy platform.
- This approach combines direct tumor cell lysis with robust bystander immune activation, offering a promising strategy for enhanced cancer immunotherapy.
- The developed platform has potential for treating various cancers, including osteosarcoma, with potential for synergistic effects with agents like zoledronic acid.
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