Exploiting Natural Killer Cell Engagers to Control Pediatric B-cell Precursor Acute Lymphoblastic Leukemia

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Natural killer (NK) cells are crucial for antitumor immunotherapy, especially in hematologic malignancies.
• NK cells demonstrate antileukemia activity within haploidentical hematopoietic stem cell transplantation (haplo-HSCT).
• Novel NK-cell engagers (NKCE) are designed for tumor-specific activation, minimizing off-target effects.

Purpose of the Study:

• To evaluate the in vitro efficacy of NKCEs targeting CD19 or CD20 via NKp46/NKp30 and CD16A.
• To assess NKCEs' ability to induce killing of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
• To investigate NKCEs' effectiveness with NK cells from healthy donors and post-haplo-HSCT patients.

Main Methods:

• Tested NKCEs triggering NKp46 or NKp30 with CD16A, targeting CD19 or CD20.
• Utilized BCP-ALL cell lines (NALM-16, MHH-CALL-4) and primary leukemia samples.
• Employed resting NK cells from healthy donors and pediatric patients post-haplo-HSCT.

Main Results:

• All tested NKCEs effectively killed the NK cell-resistant MHH-CALL-4 cell line, with enhanced degranulation and IFNγ production.
• NKCEs targeting CD19 showed potent activity against primary BCP-ALL, overcoming resistance and HLA-specific inhibition.
• NKp46- and NKp30-based NKCEs demonstrated comparable efficacy against BCP-ALL, including with NK cells from transplanted patients.

Conclusions:

• NKCEs targeting CD19 are effective against pediatric BCP-ALL, including refractory/relapsed cases.
• NKCEs can enhance NK cell activity and overcome inhibitory signals in the leukemia microenvironment.
• NKp46/CD16A/CD19-NKCEs show therapeutic potential in pre- and post-transplantation settings for BCP-ALL.