Review: The Role of Antibody-Based Therapies in Neuro-Oncology
Key findings
- This review describes the mechanisms of action of antibody-based therapies being used in neuro-oncology and the results of clinical trials
- Immune checkpoint inhibitors and immunomodulatory antibodies are showing promise, particularly in glioblastoma, but important obstacles include the blood–brain barrier and a hostile tumor microenvironment
- Advanced technologies being employed in neuro-oncology include antibody–drug conjugates, bispecific T-cell engagers and CAR T-cell therapy
Antibody-based therapies are a promising frontier in cancer treatment, although the central nervous system presents unique challenges: the immunosuppressive tumor microenvironment and limited access because of the blood–brain barrier (BBB).
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In Antibodies (Basel), physicians at Massachusetts General Hospital recently reviewed trials of longstanding and more recent antibody-based therapies in neuro-oncology.
The authors are Rishab Ramapriyan, medical student, Elizabeth R. Gerstner, MD, neuro-oncologist and associate professor in the Department of Neurology, William T. Curry, MD, chief medical officer of Mass General and director of Neurosurgical Oncology at Mass General, Bryan D. Choi, MD, PhD, associate director of the Center for Brain Tumor Immunology and Immunotherapy and a neurosurgeon in the Stephen E. and Catherine Pappas Center for Neuro-Oncology, and colleagues.
Immune Checkpoint Inhibitors
Immune checkpoint proteins such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) ordinarily prevent immune responses from being so strong that they destroy healthy cells. Tumor cells can hijack the interactions of these proteins with their ligands and create a suppressed immune environment favorable to tumor growth.
Monoclonal antibodies targeting PD-1 or its ligand PD-L1 (e.g., pembrolizumab and nivolumab) or CTLA-4 (e.g., ipilimumab) release the "brakes" on the immune system and allow it to destroy tumor cells.
In neuro-oncology, these immune checkpoint inhibitors (ICIs) are promising for a subset of patients with glioblastoma, and anti–PD-1 therapies are also being investigated for meningiomas. Newer ICIs target other immune checkpoints: T-cell immunoreceptor with Ig and ITIM domains (TIGIT) or lymphocyte-activation gene 3 (LAG3).
Tumor Microenvironment Modulation
Myeloid-derived suppressor cells (MDSC) and immunosuppressive tumor-associated macrophages (TAM) can substantially blunt natural immunity and engineered antibody-based therapies. One approach to overcome these cells is through the use of an antibody drug called bavituximab:
- Phosphatidylserine (PS) is an immunosuppressive target widely expressed on the surface of cancer cells, including brain tumors
- Bavituximab is an antibody that specifically recognizes and binds to PS
- At Massachusetts General Hospital, the authors led a clinical trial showing that bavituximab can be used to successfully modulate MDSC and TAM cells in patients with glioblastoma
Antibody–Drug Conjugates (ADCs)
ADCs—the fusion of a monoclonal antibody and another potent cytotoxic agent—fall into two categories:
- Immunotoxins link antibodies with a naturally derived bacterial toxin, such as Pseudomonas exotoxin A
- Radiolabeled antibodies (also called radioimmunoconjugates) link antibodies with a radionuclide, such as iodine-124
So far ADCs have not proven effective against glioblastoma, but various targets, payloads, and combination strategies are being explored.
Bispecific T-cell Engagers or T-cell Engaging Antibody Molecules (BiTEs or TEAMs)
TEAM antibodies are constructed of two single-chain variable fragments. One identifies a specific surface antigen on a target cell and another binds to a T cell–specific molecule, usually CD3.
It's theorized that these antibody molecules can reach the brain by piggybacking on circulating T cells. In a preclinical study published in PNAS, a BiTE that targets epidermal growth factor receptor vIII facilitated the destruction of EGFRvIII-expressing glioma.
Adoptive Cell Therapy
In chimeric antigen receptor (CAR) T-cell therapy, a patient's own immune cells can be modified to secrete antibodies, cytokines, chemokines or enzymes, acting as "living micropharmacies."
A key benefit of this strategy in neuro-oncology is to exploit the T cell's ability to cross the BBB, travel to tumor sites and deliver a payload. Moreover, localized delivery of antibodies in the tumor microenvironment could reduce toxicity compared with systemic infusion.
At Mass General, the authors are leading a clinical trial, studying the use of CAR T-cells that are engineered to secrete TEAMs within the tumor microenvironment for patients with glioblastoma.
Fundamental Questions Remain
How the immune dynamics of the brain may influence antibody delivery strategies is still unclear. For example:
- Do ICIs need to penetrate the BBB or can they peripherally activate T cells that then traffic to the brain?
- Are ICIs more effective when combined with radiation, chemotherapy, virotherapy or strategies that target the tumor microenvironment?
- What is the optimal sequencing of antibody-based therapies?
Despite limitations and uncertainties, antibody-based therapies have significant potential in neuro-oncology, and Mass General is proud to be engaged in research and innovation.
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