Simple Summary T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and still orphan hematologic malignancy. No effective immunotherapeutic strategies are presently available for this poor prognosis disease. We here report the development and the preclinical evaluation of a novel bispecific T-cell engager (BTCE) that simultaneously targets CD1a and CD3 epsilon (CD1a x CD3 epsilon), therefore recruiting T cells against T-ALL cells. We demonstrate that this CD1a x CD3 epsilon BTCE induces activation, proliferation, and cytokine release by T cells in co-cultures with CD1a expressing T-ALL cells, resulting in a concentration-dependent killing of leukemic cells in vitro. Moreover, CD1a x CD3 epsilon BTCE inhibits the in vivo growth of human T-ALL xenografts and improves survival of immunocompromised mice reconstituted with human PBMC from healthy donors. We believe that this BTCE is suitable for clinical development for the treatment of CD1a-expressing T-ALL patients. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy burdened by poor prognosis. While huge progress of immunotherapy has recently improved the outcome of B-cell malignancies, the lack of tumor-restricted T-cell antigens still hampers its progress in T-ALL. Therefore, innovative immunotherapeutic agents are eagerly awaited. To this end, we generated a novel asymmetric (2 + 1) bispecific T-cell engager (BTCE) targeting CD1a and CD3 epsilon (CD1a x CD3 epsilon) starting from the development of a novel mAb named UMG2. UMG2 mAb reacts against CD1a, a glycoprotein highly expressed by cortical T-ALL cells. Importantly, no UMG2 binding was found on normal T-cells. CD1a x CD3 epsilon induced high T-cell mediated cytotoxicity against CD1a+ T-ALL cells in vitro, as demonstrated by the concentration-dependent increase of T-cell proliferation, degranulation, induction of cell surface activation markers, and secretion of pro-inflammatory cytokines. Most importantly, in a PBMC-reconstituted NGS mouse model bearing human T-ALL, CD1a x CD3 epsilon significantly inhibited the growth of human T-ALL xenografts, translating into a significant survival advantage of treated animals. In conclusion, CD1a x CD3 epsilon is a novel BTCE highly active against CD1a-expressing cortical-derived T-ALL cells suitable for clinical development as an effective therapeutic option for this rare and aggressive disease.

A Novel Bispecific T-Cell Engager (CD1a x CD3ε) BTCE Is Effective against Cortical-Derived T Cell Acute Lymphoblastic Leukemia (T-ALL) Cells

Talarico, Gabriella;Gentile, Massimo;
2022-01-01

Abstract

Simple Summary T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and still orphan hematologic malignancy. No effective immunotherapeutic strategies are presently available for this poor prognosis disease. We here report the development and the preclinical evaluation of a novel bispecific T-cell engager (BTCE) that simultaneously targets CD1a and CD3 epsilon (CD1a x CD3 epsilon), therefore recruiting T cells against T-ALL cells. We demonstrate that this CD1a x CD3 epsilon BTCE induces activation, proliferation, and cytokine release by T cells in co-cultures with CD1a expressing T-ALL cells, resulting in a concentration-dependent killing of leukemic cells in vitro. Moreover, CD1a x CD3 epsilon BTCE inhibits the in vivo growth of human T-ALL xenografts and improves survival of immunocompromised mice reconstituted with human PBMC from healthy donors. We believe that this BTCE is suitable for clinical development for the treatment of CD1a-expressing T-ALL patients. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy burdened by poor prognosis. While huge progress of immunotherapy has recently improved the outcome of B-cell malignancies, the lack of tumor-restricted T-cell antigens still hampers its progress in T-ALL. Therefore, innovative immunotherapeutic agents are eagerly awaited. To this end, we generated a novel asymmetric (2 + 1) bispecific T-cell engager (BTCE) targeting CD1a and CD3 epsilon (CD1a x CD3 epsilon) starting from the development of a novel mAb named UMG2. UMG2 mAb reacts against CD1a, a glycoprotein highly expressed by cortical T-ALL cells. Importantly, no UMG2 binding was found on normal T-cells. CD1a x CD3 epsilon induced high T-cell mediated cytotoxicity against CD1a+ T-ALL cells in vitro, as demonstrated by the concentration-dependent increase of T-cell proliferation, degranulation, induction of cell surface activation markers, and secretion of pro-inflammatory cytokines. Most importantly, in a PBMC-reconstituted NGS mouse model bearing human T-ALL, CD1a x CD3 epsilon significantly inhibited the growth of human T-ALL xenografts, translating into a significant survival advantage of treated animals. In conclusion, CD1a x CD3 epsilon is a novel BTCE highly active against CD1a-expressing cortical-derived T-ALL cells suitable for clinical development as an effective therapeutic option for this rare and aggressive disease.
ALL
BTCE
BiTE
CD1a
T-ALL
acute lymphoblastic leukemia
bispecific T cell engager
hematological malignancies
immunotherapy
translational medical research
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11770/342539
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