A CD22-specific T-cell receptor enables effective adoptive T-cell therapy for B-cell malignancies

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• CD19 chimeric antigen receptor (CAR) T-cell therapy is standard for B-cell malignancies but relapses occur due to CD19-low/negative clones.
• Bispecific CD19/CD22 CAR-T cells show limited efficacy due to antigen downregulation and poor persistence.
• CD22 is ubiquitously expressed in B-cell lymphomas and leukemias, making it a viable immunotherapeutic target.

Purpose of the Study:

• To evaluate the efficacy of T-cell receptor (TCR) engineered T-cells targeting CD22.
• To compare CD22 TCR-T cells with CD19 CAR-T cells and CD22 CAR-T cells in preclinical models.
• To assess the potential of CD22 TCR-T cells in treating relapsed B-cell malignancies post-CD19 therapy.

Main Methods:

• Identification of a high-affinity CD22-specific TCR targeting a CD22 epitope presented by HLA-A*02:01 using a humanized mouse model.
• In-vitro assessment of CD22 TCR-T cell specificity and efficacy against CD22-positive cell lines and patient-derived tumor samples.
• In-vivo validation of CD22 TCR-T cell activity in a Nalm6 B-cell leukemia model, comparing it with CD22 CAR-T cells.

Main Results:

• CD22 TCR-T cells demonstrated high specificity and efficacy in vitro.
• CD22 TCR-T cells outperformed CD22 CAR-T cells in recognizing CD22low tumor cells, including those resistant to CD19 T-cell therapy.
• CD22 TCR-T cells effectively targeted tumor cells expressing intracellular CD22, unlike CD22 CAR-T cells.
• In-vivo studies confirmed superior activity of CD22 TCR-T cells against CD22low B-cell leukemia.

Conclusions:

• CD22 TCR-based therapy is a potent treatment option for CD22low B-cell malignancies.
• This approach shows promise for patients relapsing after CD19 CAR-T therapy.
• CD22 TCR-T cells offer an effective strategy against antigen escape mechanisms in B-cell cancers.