Burst of radiation and vesicles-based immunotherapy suppress brain
cancer growth

Date:
January 31, 2022
Source:
Massachusetts General Hospital
Summary:
The priming of glioblastoma with a burst of radiation increased
dramatically the uptake of extracellular vesicles-based
immunotherapy by the tumor and the surrounding microenvironment,
halting tumor growth, inducing anti-tumor immunity, and prolonging
survival in animal models.

In glioblastomas primed with radiation, extracellular vesicles
allowed the immunotherapy to cross the blood-brain barrier,
recruiting immune cells to the tumor site and reversing the
expression of PD-L1, the protein responsible for immunosuppression
of the larger tumor environment.



FULL STORY ========================================================================== Short bursts of radiation therapy dramatically enhanced the efficiency of targeting glioblastomas with natural nanoparticle-based immunotherapy,
thus suppressing growth of the deadly tumor, inducing anti-tumor
immunity and prolonging survival in animal models, a research team
at Massachusetts General Hospital (MGH) has discovered. The combined
strategy, described in ACS Nano, uses extracellular vesicles (EVs) to
deliver the immunotherapeutic to the brain, bridging the blood-brain
barrier and reversing immune suppression of both the tumor and the
surrounding microenvironment.


==========================================================================
"We showed that priming glioblastoma with a single burst of radiation
results in the recruitment of immune cells to the tumor site and increases
by nearly fivefold the uptake by the tumor and the microenvironment of therapeutic EVs," says senior author Bakhos Tannous, PhD, director of
the Experimental Therapeutics Unit in the Department of Neurology at
MGH. "These EVs are loaded with immunotherapeutic small interfering RNA (siRNA), and when combined with radiation they significantly increase the activity of CD8+ cytotoxic T cells, halting tumor growth and increasing
animal survival." Glioblastoma is the most common, deadliest and most treatment-resistant of cancers of the central nervous system, with a
median survival of fewer than 15 months after standard-of-care surgery, chemotherapy and radiation therapy.

While immune checkpoint blockade, a revolutionary new class of drugs that enables the body's immune system to recognize and attack cancer cells,
has produced responses in some cancers, glioblastoma has shown limited to
no benefit. Scientists believe one reason may be the blood-brain barrier, composed of tightly packed cells in the brain's capillaries that prevent medications from gaining entry to the brain. Another reason could be the profoundly immune suppressive environment characteristic of glioblastoma,
and the narrow therapeutic window of dose escalation due to the potential
for serious safety issues.

MGH researchers overcame these hurdles by using extracellular vesicles,
which are secreted by cells in the body and are known to facilitate intercellular communications governing diverse processes, such as immune response. EVs have come into the scientific limelight recently through
studies showing their efficacy in delivering therapeutics, as well as
their ability to cross biologic barriers. "We developed a unique targeted therapy for EV delivery across the blood- brain/tumor barrier by modifying
the EV surface with a brain-tumor- targeting peptide and loading it with immunotherapeutic siRNA," explains lead author Tian Tian, PhD, with the
MGH Experimental Therapeutics Unit and the Department of Neurobiology
at Nanjing Medical University in China. "This approach reverses within glioblastomas and tumor-associated myeloid cells the expression of
PD-L1 (programmed cell death-ligand 1), the protein responsible for immunosuppression of the larger tumor environment." While extracellular vesicles are a highly effective vector for drug delivery, Tannous stresses
that radiation is the key to making the novel treatment strategy uncovered
by the MGH team work. "A short burst of radiation -- akin to stereotactic radiosurgery -- is critical to recruiting immune cells to the tumor site
and to optimizing the effects of PD-L1 inhibition," he notes. "We've shown
that the combination of radiation with EV-based checkpoint inhibition
can be a safe and effective way to target a cancer that has proven
extremely resistant to treatment over the years." Tannous is associate neuroscientist at MGH and associate professor of Neurology at Harvard
Medical School (HMS). Lead author Tian Tian is an investigator with MGH
and the Department of Neurobiology, Nanjing Medical University, China. Co- authors include Jun Gao, PhD, professor and dean of the Department
of Neurobiology, Nanjing Medical University; E. Antonio Chiocca, MD,
PhD, neurosurgeon-in-chief and chairman, Department of Neurosurgery,
Brigham and Women's Hospital; and Ralph Weissleder, MD, PhD, director,
Center for Systems Biology, MGH, and professor of Systems Biology, HMS.

The study was funded by the National Institute of Neurological Disorders
and Stroke (NINDS).

special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by Massachusetts_General_Hospital. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Tian Tian, Ruyu Liang, Gulsah Erel-Akbaba, Lorenzo Saad, Pierre
J. Obeid,
Jun Gao, E. Antonio Chiocca, Ralph Weissleder, Bakhos
A. Tannous. Immune Checkpoint Inhibition in GBM Primed with
Radiation by Engineered Extracellular Vesicles. ACS Nano, 2022;
DOI: 10.1021/acsnano.1c05505 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220131132804.htm

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