Novel Nano Immunoconjugates Induces Local Immune Responses in Glioblastoma Treatment

MRI of the brain. snapshot

A new study helps to create a better understanding how immunotherapies works and how one day, treatments that help the body’s immune system fight cancer, can be used in the treatment of brain cancer.

A study, published Nature Communications, demonstrates that a new type of nano-immunotherapy traversed the blood-brain barrier in laboratory mice, inducing a local immune response in brain tissue surrounding the tumors. [1]

The tumor cells stopped multiplying, and survival rates increased.

This is good news for patients with glioblastoma, the most common and also most deadly form of brain cancer.

A new study led by Julia Ljubimova, MD, PhD, could help scientists develop immunotherapies for brain tumors. Courtesy: Cedars-Sinai
A new study led by Julia Ljubimova, MD, PhD, could help scientists develop immunotherapies for brain tumors. Courtesy: Cedars-Sinai

“Immunotherapies could ultimately hold the key to longer survival,” noted Julia Ljubimova, MD, Ph.D, senior author of the study and professor of Neurosurgery and Biomedical Sciences at Cedars-Sinai.

“This study showed a promising and exciting outcome,” she added said.

“Currently clinically proven methods of brain cancer immunotherapy do not ensure that therapeutic drugs cross the blood-brain barrier. Although our findings were not made in humans, they bring us closer to developing a treatment that might effectively attack brain tumors with systematic drug administration,” Ljubimova explaind.

Using the body’s own defenses
Harnessing the power of the body’s own immune system to attack tumors is a concept that has intrigued investigators for decades. Scientists have been studying ways to persuade the immune system to attack tumors in the same way that it attacks, for example, a virus.

While indeed very promising, this concept presents some key challenges. This is especially the case when it comes to brain tumors.

One reason is that the environment of the brain can be hard to penetrate with drugs or other therapies because the ‘extra defenses’ protecting the brain and extracellular fluid in the central nervous system.

This highly selective semipermeable border called the blood-brain barrier separates the circulating blood in the body from the brain to naturally block toxins and other harmful substances in the bloodstream from getting into the brain. But it can also keep out potentially lifesaving treatments away from the brain.

“In addition, brain tumors seem to have the effect of suppressing their local immune systems. Tumors accumulate immunological guards such as T regulatory cells (Tregs) and special macrophages, which block the body’s anti-cancer immune cells, protecting the tumor from attack,” Ljubimova noted.

In order to allow tumor-killing immune cells to activate, investigators needed to find a way to arrest or deactivate the tumor-protecting Tregs and macrophages.

While some immunotherapies have successfully triggered an immune response in the whole body, which can slow the growth of tumors and extend the life of patients, this treatment is one of the first of its kind to demonstrate the activation of both whole body and local immune systems around the tumor in laboratory mice.

Novel approach
The immunotherapy tested in this study works by delivering checkpoint inhibitors, a type of antibody drug that can arrest and block Tregs and macrophages. As a result, the tumor can’t use them to block the incoming tumor-killing immune cells.

Ljubimova and her team used targeted nanoscale immunoconjugates or NICs on a natural biopolymer scaffold, poly(β-L-malic acid), with covalently attached a-CTLA-4 or a-PD-1 for systemic delivery across the blood-brain barrier.

Those checkpoint inhibitors, an immunotherapy designed to block proteins that stop the immune system from attacking the cancer cells, are attached with a biodegradable polymer to a protein or peptide that enables the drug to traverse the blood-brain barrier.

“The checkpoint inhibitors can then block the Tregs and macrophages, allowing the local immune cells to get activated and do their job-fight the tumor,” Ljubimova explained.

With the tumor-shielding cells blocked, immune cells like cytotoxic lymphocytes and microglial cells can then attack and destroy the cancer cells.

“Drug delivery is the major obstacle for the treatment of central nervous system diseases, including brain conditions,” Ljubimova said.

“The horizon for treatment of brain cancer is getting clearer. We hope that by delivering multifunctional new-generation drugs through the blood-brain barrier, we can explore new therapies for many neurological conditions,” she concluded.

However, Ljubimova warned that further tests are needed before this therapy can be tested in humans.

Reference
[1] Galstyan A, Markman JL, Shatalova ES, Chiechi A, Korman AJ, Patil R, Klymyshyn D, et al. Blood-brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy. Nat Commun. 2019 Aug 28;10(1):3850. doi: 10.1038/s41467-019-11719-3.[Pubmed][Article]