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Published on: June 13, 2014
Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies
Candice R Gurbatri1, Ioana Lia1, Rosa Vincent1
1Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
Abstract:
Checkpoint inhibitors have revolutionized cancer therapy but only work in a subset of patients and can lead to a multitude of toxicities, suggesting the need for more targeted delivery systems. Because of their preferential colonization of tumors, microbes are a natural platform for the local delivery of cancer therapeutics. Here, we engineer a probiotic bacteria system for the controlled production and intratumoral release of nanobodies targeting programmed cell death-ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) using a stabilized lysing release mechanism. We used computational modeling coupled with experimental validation of lysis circuit dynamics to determine the optimal genetic circuit parameters for maximal therapeutic efficacy. A single injection of this engineered system demonstrated an enhanced therapeutic response compared to analogous clinically relevant antibodies, resulting in tumor regression in syngeneic mouse models. Supporting the potentiation of a systemic immune response, we observed a relative increase in activated T cells, an abscopal effect, and corresponding increases in systemic T cell memory populations in mice treated with probiotically delivered checkpoint inhibitors. Last, we leveraged the modularity of our platform to achieve enhanced therapeutic efficacy in a poorly immunogenic syngeneic mouse model through effective combinations with a probiotically produced cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF). Together, these results demonstrate that our engineered probiotic system bridges synthetic biology and immunology to improve upon checkpoint blockade delivery.
Insights
Engineered probiotic bacteria deliver targeted cancer therapies, improving tumor regression and immune response. This novel platform enhances checkpoint blockade efficacy for improved cancer treatment outcomes.
Area of Science:
- Synthetic biology
- Cancer immunology
- Microbiome therapeutics
Background:
- Checkpoint inhibitors (e.g., anti-PD-L1, anti-CTLA-4) show promise in cancer therapy but have limitations.
- Limited patient response and toxicities necessitate improved delivery methods for cancer therapeutics.
- Microbes offer a natural platform for targeted, local delivery of therapeutic agents within tumors.
Purpose of the Study:
- To engineer a probiotic bacterial system for controlled intratumoral delivery of nanobodies targeting PD-L1 and CTLA-4.
- To optimize the genetic circuit for maximal therapeutic efficacy using computational modeling and experimental validation.
- To evaluate the therapeutic efficacy and immune response potentiation of the engineered probiotic system in syngeneic mouse models.
Main Methods:
- Engineering a probiotic bacteria system with a stabilized lysing release mechanism.
- Utilizing computational modeling and experimental validation to determine optimal genetic circuit parameters.
- Administering a single injection of the engineered system in syngeneic mouse models and assessing tumor regression and immune cell populations.
Main Results:
- The engineered probiotic system demonstrated enhanced therapeutic response and tumor regression compared to clinically relevant antibodies.
- Probiotic delivery of checkpoint inhibitors potentiated a systemic immune response, including increased activated T cells and an abscopal effect.
- The platform showed modularity, enabling enhanced efficacy when combined with a probiotically produced cytokine (GM-CSF) in a poorly immunogenic model.
Conclusions:
- Engineered probiotic bacteria represent a viable platform for targeted delivery of cancer therapeutics, improving checkpoint blockade efficacy.
- This synthetic biology approach bridges immunology and microbial delivery for enhanced cancer treatment.
- The developed system offers a promising strategy to overcome limitations of current checkpoint inhibitor therapies.
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