An "off-the-shelf" CD2 universal CAR-T therapy for T-cell malignancies

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• T-cell malignancies have poor prognoses due to limited targeted treatments.
• Chimeric antigen receptor T-cell (CAR-T) therapy offers a potential avenue but faces challenges in pan T-cell applications.

Purpose of the Study:

• To develop an allogeneic, universal CAR-T cell therapy (UCART2) targeting CD2 for broad efficacy in T-cell malignancies.
• To investigate the role of CD2 expression in CAR-T cell function and efficacy.
• To evaluate the therapeutic potential of UCART2 combined with recombinant human interleukin-7 fused to an Fc fragment (rhIL-7-hyFc).

Main Methods:

• Development of UCART2 with CD2 targeting, CD2 antigen deletion, and T-cell receptor removal to prevent fratricide and graft-versus-host disease (GvHD).
• Assessment of UCART2 efficacy in T-cell acute lymphoblastic leukemia (T-ALL) and cutaneous T-cell lymphoma (CTCL) models.
• Generation of CD19 CAR-T cells with and without CD2 deletion for comparative analysis using single-cell secretome analysis and xenograft models.
• In vivo evaluation of UCART2 and rhIL-7-hyFc combination therapy in tumor re-challenge and patient-derived T-ALL models.

Main Results:

• UCART2 demonstrated significant efficacy against T-ALL and CTCL, prolonging survival in tumor-bearing mice.
• CD2 deletion in CAR-T cells reduced effector cytokine production and anti-tumor efficacy.
• The diminished efficacy due to CD2 deletion was restored by co-administration with rhIL-7-hyFc.
• rhIL-7-hyFc treatment enhanced UCART2 persistence and improved survival in preclinical models.

Conclusions:

• Allogeneic, fratricide-resistant UCART2 is a viable strategy for treating T-cell malignancies.
• Combining UCART2 with rhIL-7-hyFc represents a promising therapeutic approach to overcome limitations and improve outcomes in T-cell malignancies.