CAR T Cells Targeting Membrane-Bound Hsp70 on Tumor Cells Mimic Hsp70-Primed NK Cells

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Late-stage cancers, including colorectal cancers (CRCs), require novel strategies to enhance anti-tumor immunity.
• Current immunotherapies like cytokine stimulation and chimeric antigen receptor (CAR) T cells show promise but face challenges with tumor-specific antigens, the tumor microenvironment, and off-tumor toxicities.
• Membrane-bound heat shock protein 70 (mHsp70) is specifically expressed on aggressive tumor cells, offering a potential therapeutic target.

Purpose of the Study:

• To develop and evaluate a novel cell-based immunotherapy targeting mHsp70.
• To assess the efficacy of anti-mHsp70 CAR T cells and cytokine-stimulated natural killer (NK) cells against mHsp70-expressing colorectal cancers.

Main Methods:

• Engineered anti-Hsp70 CAR into primary T cells.
• Co-cultured anti-Hsp70 CAR T cells and TKD/IL-2 stimulated NK cells with human colorectal cancer cells expressing high mHsp70.
• Measured the release of granzyme B (GrB) and interferon-gamma (IFN-γ) as indicators of anti-tumor activity.

Main Results:

• Both anti-Hsp70 CAR T cells and TKD/IL-2 stimulated NK cells were attracted to and activated by mHsp70-positive colorectal cancer cells.
• Activated cells triggered the release of cytotoxic granzyme B and pro-inflammatory interferon-gamma.
• Stimulated NK cells and anti-Hsp70 CAR T cells demonstrated comparable anti-tumor effects with distinct kinetics.

Conclusions:

• Anti-Hsp70 CAR T cells and stimulated NK cells represent a promising dual approach for targeting mHsp70-expressing cancers.
• This strategy holds potential for addressing unmet clinical needs in various cancer types due to the broad expression of mHsp70.
• Further development of these cell-based immunotherapies could lead to effective treatments for therapy-resistant cancers.