Natarajan Muthusamy

T-cell bispecific antibodies (T-BsAbs) such as blinatumomab hold great promise for cancer immunotherapy. A better understanding of the in vivo immune response induced by T-BsAbs is crucial to improving their efficacy and safety profile. However, such efforts are hindered by the limitations of current preclinical models. To address this, we developed a syngeneic murine model with humanized CD3 and target antigen (CD20). This model enables the development of disseminated leukemia with a high tumor burden, which mirrors clinical findings in human patients with relapsed/refractory acute lymphoblastic leukemia. Treatment of this model with T-BsAbs results in cytokine release syndrome, with cytokine profiles and levels reflecting observations made in human patients. This model also faithfully recapitulates the dynamics of T-cell activation seen in human patients, including the temporary disappearance of T cells from the bloodstream. During this phase, T cells are sequestered in secondary lymphoid organs and undergo activation. Clinical correlative studies that rely primarily on peripheral blood samples are likely to overlook this critical activation stage, leading to a substantial underestimation of the extent of T-cell activation. Furthermore, we demonstrate that surface expression of the T-BsAb target antigen by leukemia cells triggers a swift immune response, promoting their own rejection. Humanizing the target antigen in the recipient mice is crucial to facilitate tolerance induction and successful establishment of high tumor burden. Our findings underscore the importance of meticulously optimized syngeneic murine models for investigating T-BsAb–induced immune responses and for translational research aimed at improving efficacy and safety.

Cytotoxic T lymphocyte antigen 4 (CTLA4) is a major immune checkpoint and target for cancer immunotherapy. Although originally discovered and primarily studied on T cells, its role on other cell types has also been recognized in recent years. Here we describe an unexpected interaction between ibrutinib (a targeted inhibitor of Bruton tyrosine kinase [BTK]) and CTLA4 expression on malignant chronic lymphocytic leukemia (CLL) cells. Although BTK itself does play a role in CTLA4 expression in CLL, we demonstrate that ibrutinib’s main suppressive effect on CTLA4 protein expression and trafficking occurs through non-BTK targets influenced by this drug. This suppression is not seen in T cells, indicating a different mechanism of CTLA4 regulation in CLL vs T cells. Appreciating this distinct mechanism and the beneficial non-BTK effects of ibrutinib may contribute to understanding the immune benefits of ibrutinib treatment and lead to therapeutic approaches to improve immune function in patients with CLL by suppressing CTLA4 expression.