A modular CAR T-cell platform could allow clinicians to modify the behavior and targeting of engineered immune cells after they have been administered.
The “meditope-enabled” CAR, or meCAR, developed at City of Hope contains a molecular docking site that binds externally administered protein adaptors. In preclinical experiments, researchers used these adaptors to track CAR T cells, promote their expansion, and redirect them toward additional cancer targets without further genetic engineering.
Conventional CAR T cells are designed to recognize a predetermined tumor antigen. This fixed specificity can limit their effectiveness against heterogeneous tumors, in which cancer cells express different antigens or lose the targeted antigen during treatment.
The new platform replaces the conventional single-chain variable fragment used for antigen recognition with an engineered antibody fragment containing a binding pocket for meditope peptide, a 12-amino acid cyclic peptide. Therapeutic proteins or imaging agents fused to this peptide can then dock with the CAR T cells.
The meCAR T cells demonstrated antigen binding and tumor-cell killing comparable to conventional CAR T cells in laboratory experiments, according to the study in Cancer Immunology Research.
The researchers subsequently attached the meditope peptide to an interleukin-15 superagonist. The resulting adaptor selectively activated and expanded meCAR T cells in vitro. In mouse tumor models, combining the adaptor with meCAR T cells increased T-cell expansion, reduced tumor burden, and extended survival compared with the cells alone.
A second set of adaptors was designed to broaden antigen recognition. HER2-targeting meCAR T cells were paired with meditope-linked antibodies against CD20 or PD-L1, enabling them to attack cancer cells expressing those alternative targets. In a mouse model containing a mixture of HER2-positive and CD20-positive tumor cells, the combination reduced tumor growth and prolonged survival.
“The power of this platform is its flexibility,” said co-senior author Christine Brown in a City of Hope press release. “Instead of hardwiring every function into a CAR T cell, we can use protein-adaptor plug-ins to add new capabilities as needed.”
Because CAR T-cell activity depends partly on the presence and dose of the adaptor, the platform may also provide a way to regulate treatment activity. However, the researchers found that excessive adaptor concentrations could reduce productive interactions, indicating that dosing and pharmacokinetics will require careful optimization.
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