Summary
Adoptive T cell therapies are a new class of living drugs, achieving durable results in a subset of patients with aggressive malignancies. These transformative outcomes are not shared with the majority of patients with solid tumors that remain resistant to current T cell therapies. As engineered T cell therapy is usually directed against a single antigen, it is especially vulnerable to antigen loss as a tumor resistance mechanism. Moreover, cancer immunotherapy often leads to severe immune-related adverse events (irAE) by destructive self-reactivity that must be evaluated together with the therapeutic benefit. While T cell therapies with tumor-infiltrating lymphocytes might circumvent these shortcomings, tumor tissue availability is limited and T cells are poorly responsive to ex-vivo perturbation. These therapeutic challenges highlight the gaps in our knowledge of how to engineer curative anti-tumor immunity.
We recently developed foundational platforms for CRISPR engineering, TCR repertoire manipulation, and single-cell omics of primary human T cells. We plan to leverage these opportune achievements to address the critical gaps in adoptive T cell therapies. We will focus on three important aspects of engineered anti-tumor immunity: efficacy, safety, and specificity. We will tune TCR sensitivity by perturbing key genes to determine how TCR signaling balances burst-like effector function and long-term persistence. We will also reveal the sequestered self-reactive T cell compartment to control for irAE following immunotherapy. Finally, we will directly uncouple anti-tumor TCR repertoires from their dysfunctional state to mount a polyclonal anti-tumor immune response. This strategy is radically different from current T cell therapies as it is agnostic to specific tumor antigens and leverages pre-existing polyclonal antitumor immunity. These studies will chart novel blueprints for robust, safe, and specific engineered cell therapies targeting solid tumors.
We recently developed foundational platforms for CRISPR engineering, TCR repertoire manipulation, and single-cell omics of primary human T cells. We plan to leverage these opportune achievements to address the critical gaps in adoptive T cell therapies. We will focus on three important aspects of engineered anti-tumor immunity: efficacy, safety, and specificity. We will tune TCR sensitivity by perturbing key genes to determine how TCR signaling balances burst-like effector function and long-term persistence. We will also reveal the sequestered self-reactive T cell compartment to control for irAE following immunotherapy. Finally, we will directly uncouple anti-tumor TCR repertoires from their dysfunctional state to mount a polyclonal anti-tumor immune response. This strategy is radically different from current T cell therapies as it is agnostic to specific tumor antigens and leverages pre-existing polyclonal antitumor immunity. These studies will chart novel blueprints for robust, safe, and specific engineered cell therapies targeting solid tumors.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/101042941 |
| Start date: | 01-10-2022 |
| End date: | 30-09-2027 |
| Total budget - Public funding: | 1 812 500,00 Euro - 1 812 500,00 Euro |
Cordis data
Original description
Adoptive T cell therapies are a new class of living drugs, achieving durable results in a subset of patients with aggressive malignancies. These transformative outcomes are not shared with the majority of patients with solid tumors that remain resistant to current T cell therapies. As engineered T cell therapy is usually directed against a single antigen, it is especially vulnerable to antigen loss as a tumor resistance mechanism. Moreover, cancer immunotherapy often leads to severe immune-related adverse events (irAE) by destructive self-reactivity that must be evaluated together with the therapeutic benefit. While T cell therapies with tumor-infiltrating lymphocytes might circumvent these shortcomings, tumor tissue availability is limited and T cells are poorly responsive to ex-vivo perturbation. These therapeutic challenges highlight the gaps in our knowledge of how to engineer curative anti-tumor immunity.We recently developed foundational platforms for CRISPR engineering, TCR repertoire manipulation, and single-cell omics of primary human T cells. We plan to leverage these opportune achievements to address the critical gaps in adoptive T cell therapies. We will focus on three important aspects of engineered anti-tumor immunity: efficacy, safety, and specificity. We will tune TCR sensitivity by perturbing key genes to determine how TCR signaling balances burst-like effector function and long-term persistence. We will also reveal the sequestered self-reactive T cell compartment to control for irAE following immunotherapy. Finally, we will directly uncouple anti-tumor TCR repertoires from their dysfunctional state to mount a polyclonal anti-tumor immune response. This strategy is radically different from current T cell therapies as it is agnostic to specific tumor antigens and leverages pre-existing polyclonal antitumor immunity. These studies will chart novel blueprints for robust, safe, and specific engineered cell therapies targeting solid tumors.
Status
SIGNEDCall topic
ERC-2021-STGUpdate Date
09-02-2023
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