For whom the T cells troll? Bispecific T-cell engagers in glioblastoma

Abstract

Glioblastoma is the the most common primary brain tumor in adults. Onset of disease is followed by a uniformly lethal prognosis and dismal overall survival. While immunotherapies have revolutionized treatment in other difficult-to-treat cancers, these have failed to demonstrate significant clinical benefit in patients with glioblastoma. Obstacles to success include the heterogeneous tumor microenvironment (TME), the immune-privileged intracranial space, the blood–brain barrier (BBB) and local and systemic immunosuppressions. Monoclonal antibody-based therapies have failed at least in part due to their inability to access the intracranial compartment. Bispecific T-cell engagers are promising antibody fragment-based therapies which can bring T cells close to their target and capture them with a high binding affinity. They can redirect the entire repertoire of T cells against tumor, independent of T-cell receptor specificity. However, the multiple challenges posed by the TME, immune privilege and the BBB suggest that a single agent approach may be insufficient to yield durable, long-lasting antitumor efficacy. In this review, we discuss the mechanism of action of T-cell engagers, their preclinical and clinical developments to date. We also draw comparisons with other classes of multispecific antibodies and potential combinations using these antibody fragment therapies.

Dual Antigen T Cell Engagers Targeting CA9 as an Effective Immunotherapeutic Modality for Targeting CA9 in Solid Tumors

“…Our data demonstrates long term efficacy of the DATE in tumors with CA9 expressed homogeneously throughout the tumor at a high level, yet short term efficacy in models where the proportion of CA9 positivity is lower. These findings demonstrate that the DATE is very effective at eliminating antigen positive cells and that recurrence is perhaps a reflection of both regrowth driven by antigen negative cells (68) and the short half-life of the DATE (72). This suggests that the CA9-DATE treatment strategy can benefit from combinatorial tumor targeting strategies such as CAR T therapies or oncolytic viruses, including those that are engineered to secrete bifunctional T cell engagers (73)(74)(75), targeting additional GBM tumor associated antigens along with CA9.…”

“…The development of novel immunotherapeutic strategies to engage the immune system to treat GBMs have provided renewed hope for improving patient outcomes ( 67 , 68 ). GBMs are typically classified as an immunologically cold tumor ( 69 ) and contain T cells at low abundance ( 70 , 71 ).…”

“…GBMs are typically classified as an immunologically cold tumor ( 69 ) and contain T cells at low abundance ( 70 , 71 ). Overcoming this with strategies that can direct the T cells to critical tumor associated antigens has led to the development of bifunctional T cell engagers which are currently being evaluated clinically in GBM ( 68 ). Here we propose that CA9 is an important tumor associated antigen that may be exploited using this strategy.…”

Oncolytic vaccinia virus expressing a bispecific T-cell engager enhances immune responses in EpCAM positive solid tumors

“…Despite the superior antitumor performance of VV-EpCAM BiTE in the treatment of solid tumors, it did not completely cure the tumor-bearing mice. We hypothesized that activation of T cells by CD3 alone in a suppressive tumor environment would not be sufficient to eradicate tumor burdens and that the persistence of T cells is the key to ensure long-term tumor control ( 51 ). Additional genetic modification of VV-EpCAM BiTE with transgenes that encode costimulatory molecules or cytokinesis is a potential strategy to improve its antitumor efficacy.…”

Current Immunotherapeutic Approaches for Malignant Gliomas

“…Both significant antigenic heterogeneity and few mutations that could be targeted immunotherapeutically in glioblastoma are problems in tumor vaccine immunotherapy for glioblastoma [ 14 113 ]. Therefore, it has been reported the possible efficacy of bispecific or tri-specific antibody immunotherapy for glioblastoma [ 114 115 ]. In addition, against these limitations, personalized neoantigen-based DC vaccines have raised new expectations for glioblastoma immunotherapy.…”