Host Interactions with Engineered T-cell Micropharmacies.

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Adoptively transferred T cells show promise for cancer treatment but struggle with solid tumors due to tumor heterogeneity and immune evasion.
• Existing engineered T cells, like chimeric antigen receptor (CAR) T cells, face limitations in complex host environments.
• Previous Synthetic Enzyme-Armed KillER (SEAKER) cells showed efficacy in lymphoma models but required testing in immunocompetent hosts for solid tumors.

Purpose of the Study:

• To develop and evaluate T-cell receptor (TCR)-engineered SEAKER cells for targeting solid-tumor melanomas in syngeneic mouse models.
• To assess the efficacy and host interactions of SEAKER cells in immunocompetent hosts.
• To demonstrate the broad applicability of the SEAKER platform for various adoptive cell therapies.

Main Methods:

• Engineering T cells with T-cell receptor (TCR) specificity for melanoma.
• Incorporating prodrug-activating enzymatic functions into SEAKER cells.
• Testing SEAKER cell efficacy and tumor localization in syngeneic, immunocompetent mouse models.

Main Results:

• TCR-engineered SEAKER cells specifically localized to solid tumor sites.
• SEAKER cells successfully activated bioactive prodrugs within the tumor microenvironment, overcoming host immune responses.
• The engineered SEAKER cells demonstrated significant efficacy in immunocompetent hosts, validating their therapeutic potential.

Conclusions:

• The SEAKER cell platform is effective against solid tumors, even in the presence of host immune responses.
• TCR-engineered SEAKER cells represent a versatile and potent tool for adoptive cell therapy.
• This technology holds significant promise for advancing cancer treatment strategies, particularly for solid tumors.