Journal
JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 9, Issue 11, Pages -Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2021-003679
Keywords
immunotherapy; central nervous system neoplasms; T lymphocytes
Categories
Funding
- Duke University [P50-CA190991, P01-CA225622, U01-NS090284, R01-NS099463, R01-CA175517, R01-CA235612]
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Glioblastoma is the most common primary brain tumor in adults with a uniformly lethal prognosis. While immunotherapies have not shown significant clinical benefit in treatment, bispecific T-cell engagers are promising antibody fragment therapies. However, the challenges posed by the tumor microenvironment, immune privilege, and blood-brain barrier suggest that a single agent approach may be insufficient for lasting antitumor efficacy.
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.
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