A nanobody-based tri-specific NK cell engager targeting CD5 triggers antitumor immunity

Area of Science:

• Immunotherapy
• Oncology
• Cellular Biology

Background:

• Recurrent or refractory T cell malignancies have a poor prognosis, necessitating novel immunotherapies.
• CD5 is a key marker on malignant T cells but also present on normal T cells, posing a challenge for targeted therapies.
• Natural killer (NK) cells, lacking CD5 expression, present a potential alternative for safer T cell malignancy treatment.

Purpose of the Study:

• To develop and evaluate a CD5-targeted NK cell engager (NKCE) for treating T cell malignancies.
• To assess the enhanced efficacy and safety profile of a modified tri-NKCE incorporating IL-15Rα/IL-15.
• To compare the therapeutic potential of tri-NKCE with existing chimeric antigen receptor (CAR)-T cell therapies.

Main Methods:

• Generation of a CD5-targeted NKCE using a CD16a nanobody and an anti-CD5 antibody.
• In vitro assessment of NKCE antitumor potency against CD5+ malignant cells.
• In vitro and in vivo evaluation of modified tri-NKCE efficacy, including cytokine/chemokine production and NK cell proliferation.
• Comparative analysis of tri-NKCE and CAR-T cell toxicity towards normal T cells.

Main Results:

• The generated NKCE demonstrated in vitro antitumor activity.
• The modified tri-NKCE exhibited enhanced antitumor efficacy against CD5+ malignant tumor cells, increasing cytokine and chemokine production.
• In vivo studies showed tri-NKCE enhanced NK cell proliferation and exhibited potent cytotoxicity.
• Tri-NKCE demonstrated no toxicity to normal T cells, unlike CAR-T cells.

Conclusions:

• CD5-targeted NKCE represents a viable immunotherapy strategy for T cell malignancies.
• The tri-NKCE, enhanced with IL-15Rα/IL-15, shows superior antitumor efficacy and a favorable safety profile.
• Tri-NKCE offers a potentially safer and more cost-effective immunotherapy option compared to CAR-T cell therapy for T cell malignancies.