Engineered CD47 protects T cells for enhanced antitumour immunity

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Adoptively transferred T cells and CD47-SIRPα axis blockers are promising cancer immunotherapeutics.
• Combining these approaches aims to enhance anti-tumour efficacy but faces challenges with T cell clearance.

Purpose of the Study:

• To investigate the challenge of rapid macrophage-mediated clearance of engineered T cells when combined with anti-CD47 antibodies.
• To develop a strategy to overcome this clearance and enhance the efficacy of combined T cell and macrophage-based cancer therapies.

Main Methods:

• Administered anti-CD47 antibodies with adoptively transferred T cells (CAR T or TCR T).
• Engineered T cells to express a CD47 variant (47E) resistant to anti-CD47 antibody-mediated clearance.
• Assessed T cell persistence, macrophage recruitment, and anti-tumour efficacy in vivo.

Main Results:

• Anti-CD47 antibodies caused rapid clearance of standard CAR T cells, acting as a safety switch.
• T cells expressing the CD47 variant (47E) resisted macrophage clearance after anti-CD47 antibody treatment.
• The combined therapy with 47E-expressing T cells enhanced macrophage recruitment and demonstrated synergistic anti-tumour efficacy.

Conclusions:

• Macrophages are key regulators of T cell persistence in combined immunotherapies.
• Engineered CD47 variants can overcome anti-CD47 antibody-mediated T cell depletion.
• This approach offers a strategy to simultaneously harness T cell and macrophage anti-tumour activity for enhanced solid tumour treatment.