Efficient preclinical treatment of cortical T cell acute lymphoblastic leukemia with T lymphocytes secreting anti-CD1a T cell engagers

Abstract

BackgroundThe dismal clinical outcome of relapsed/refractory (R/R) T cell acute lymphoblastic leukemia (T-ALL) highlights the need for innovative targeted therapies. Although chimeric antigen receptor (CAR)-engineered T cells have revolutionized the treatment of B cell malignancies, their clinical implementation in T-ALL is in its infancy. CD1a represents a safe target for cortical T-ALL (coT-ALL) patients, and fratricide-resistant CD1a-directed CAR T cells have been preclinically validated as an immunotherapeutic strategy for R/R coT-ALL. Nonetheless, T-ALL relapses are commonly very aggressive and hyperleukocytic, posing a challenge to recover sufficient non-leukemic effector T cells from leukapheresis in R/R T-ALL patients.MethodsWe carried out a comprehensive study using robustin vitroandin vivoassays comparing the efficacy of engineered T cells either expressing a second-generation CD1a-CAR or secreting CD1a x CD3 T cell-engaging Antibodies (CD1a-STAb).ResultsWe show that CD1a-T cell engagers bind to cell surface expressed CD1a and CD3 and induce specific T cell activation. Recruitment of bystander T cells endows CD1a-STAbs with an enhancedin vitrocytotoxicity than CD1a-CAR T cells at lower effector:target ratios. CD1a-STAb T cells are as effective as CD1a-CAR T cells in cutting-edgein vivoT-ALL patient-derived xenograft models.ConclusionsOur data suggest that CD1a-STAb T cells could be an alternative to CD1a-CAR T cells in coT-ALL patients with aggressive and hyperleukocytic relapses with limited numbers of non-leukemic effector T cells.

An Update on Clinical Trials and Potential Therapeutic Strategies in T-Cell Acute Lymphoblastic Leukemia

“…CD1a, a cell surface antigen, is specifically expressed in coT-ALL and retained in relapsed coT-ALL, but barely expressed in normal cells/tissues. CD1a-specific CAR-T therapy has been validated preclinically for relapsed/refractory coT-ALL [ 59 ]. A recent phase II clinical trial of anti-CD1a CAR-T in treating R/R T-ALL was initiated (NCT05745181).…”

“…Meanwhile, it is challenging to achieve sufficient effector T cells from relapsed/refractory patients owing to the aggressiveness and hyper leukocytic of the disease. A study suggests that engineered T cells secreting CD1a XCD3 T-cell-engaging antibodies (CD1a-STAb) may be applied for coT-ALL patients with limited numbers of effector T cells [ 59 ]. This study showed that CD1a-T-cell engagers induce specific T-cell activation through binding to CD1a and CD3 on the cell surface.…”

Chimeric Antigen Receptor (CAR) T-Cell Products for Pediatric Cancers: Why Alternative Development Paths Are Needed

“…First evidence of efficacy has recently been shown in phase I clinical trials of novel CAR T-cell products targeting CD30 in Hodgkin lymphoma 23 and CD7 in T-ALL, 24-26 with additional products for T-ALL under investigation. 27-29 Objective responses now also support the general promise of CAR T-cell targeting in pediatric solid cancers. 30-33 CAR T-cell therapy has been reported to be beneficial in diffuse intrinsic pontine gliomas, a cancer with a very poor prognosis, 32 and complete and even durable remissions have been obtained in neuroblastoma.…”

Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo

“…Sustained in vivo TCE secretion results in effective serum concentrations of the TCE (28). Furthermore, expansion and persistence of adoptively transferred STAb-T cells (29,30), as well as polyclonal recruitment of both genemodified STAb-T cells and unmodified bystander T cells to the tumor microenvironment (TME), can lead to substantially increased antitumor responses (29)(30)(31). The therapeutic potential of STAb-T cells has been demonstrated in B cell (29)(30)(31)(32) and T cell hematological malignancies (30).…”

“…Furthermore, expansion and persistence of adoptively transferred STAb-T cells (29,30), as well as polyclonal recruitment of both genemodified STAb-T cells and unmodified bystander T cells to the tumor microenvironment (TME), can lead to substantially increased antitumor responses (29)(30)(31). The therapeutic potential of STAb-T cells has been demonstrated in B cell (29)(30)(31)(32) and T cell hematological malignancies (30). Here, we report the generation of STAb-T cells secreting an anti-BCMA TCE and demonstrate their superior efficacy over BCMA-specific CAR-T cells under T cell-limiting conditions simulating those found in patients with multitreated MM.…”