Research Published February 2019 Proposes PD-1 Inhibitors Increase Survival in Patients with Resectable Recurrent Glioblastoma.

New discoveries by American and European scientists suggest that glioblastoma responds to immunotherapy.

PD-1 inhibitors can stimulate the immune system to attack tumor cells more aggressively.

It is a valuable remedy against cells that remain in the brain after resection..

PD-1 inhibitors in the treatment of glioblastoma.

Researcher Aaron Mochizuki, an expert in pediatric hematology / oncology at the University of California, Los Angeles, claims clear benefits of immune checkpoint blockers.

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In a study by Zhao and Chen, published in the pages of Nature Medicine, another research team presented the characterization of glioblastomas by comparing tissue samples from patients before and after immunotherapy..

This analysis also confirmed that PD-1 inhibitors may be effective in patients with glioblastomas (especially in patients with impaired MAPK pathway). But there is a detailed darkening of this discovery.

“In response to immunotherapy, glioblastoma has seen immuno-editing of tumor clones and thus tumors can evade recognition by the immune system,” said Adam Zonabend, assistant professor of neurosurgery at Northwestern University's Feinberg School of Medicine..

Zonabend adds that glioblastomas with PTEN mutations are characterized by an absence of a pronounced response to PD-1 inhibitors.. Glioblastomas with this mutation have immunosuppressive properties that extend to the tumor microenvironment.. Unlike some other cancers, the number of mutations did not determine the response of glioblastoma to PD-1 inhibitors..

Third Study by Schalper and Rodriguez-Ruis Complements Evidence for Immunotherapy for Glioblastoma. The authors found that neoadjuvant therapy with nivolumab (anti-PD-1) in patients with resectable recurrent glioblastoma followed by surgery was safe and feasible..

Interview with experts in glioblastoma immunotherapy.

Let's learn about the mechanisms of tumor evasion first-hand - from Dr. Mochizuki and Zonabend. They agreed to talk about the peculiarities of the delivery of immunotherapeutic drugs, DNA sequencing of tumor cells before treatment, and other important aspects of immunotherapy..

- Do you think antigen evasion is the main problem for the development of immunotherapy?

- Mochizuki: Antigen evasion is definitely a problem for treatments like CAR-T cell therapy, which focus on a very specific target. They often result in loss of antigen expression, as we observed with anti-CD20 CAR-T cells..

PD-1 inhibitors stimulate the multiplication of T-lymphocyte clones with different antigenic specificities. In our study, we also demonstrated the activation of other immunoinhibitory markers on peripheral blood T cells, such as CTLA4.

In this regard, it makes sense to conduct trials using combined immunotherapy, where doctors can act on multiple tumor mechanisms of evasion of the immune system..

- Zonabend: Immuno-editing is a key issue limiting the effectiveness of immunotherapy in cancer. This phenomenon is often associated with removal of antigen and loss of the ability to present these antigens to tumors. Other pathways include the acquisition of immunosuppressive functions by tumors.

- What drugs are able to overcome the blood-brain barrier in glioblastoma?

- Mochizuki: Glioblastoma is currently thought to have varying degrees of disruption of the blood-brain barrier. They can be very heterogeneous depending on the type of glioblastoma and even different variants of localization of the same tumor..

Thus, the degree of drug penetration can be highly variable in different parts of the tumor.. We can assume, based on intravenous contrast infiltration and the site of vasogenic edema on MRI, some degree of destruction of the blood-brain barrier..

This allows the use of certain drug molecules for the treatment of glioblastoma, which are known to poorly penetrate the normal intact BBB (including large antibodies).

The January 2018 issue of Neurooncology published an excellent overview of this issue (Sarkaria et al.). The authors demonstrated that in glioblastoma, the distribution of drugs in different parts of the tissue is different.. However, we believe that activated T cells can perform their functions even if the blood-brain barrier is intact..

- Zonabend: The vast majority of molecules poorly penetrate the blood-brain barrier. The notable exception is temozolomide, which is specially formulated to penetrate the brain and has become the standard chemotherapy for these tumors..

Recently, great hopes have been pinned on technologies based on the use of pulsed ultrasound to destroy the blood-brain barrier.. They improve the delivery of chemotherapy drugs to the brain. An interesting study on this topic was published by Carpentier and Canney (2016).

- Which sequencing method is best for collecting genetic information from glioblastoma?

- Mochizuki: Bulk RNA sequencing usually gives a good general idea of \u200b\u200bwhich proteins are transcribed in the tumor. In contrast, DNA sequencing allows us to study only mutations in the glioblastoma genome.. But when looking at the tumor in the context of the microenvironment, RNA sequencing provides a broader understanding of what is happening in this space..

RNA sequencing allowed us to conduct an impartial screening, determining the variability of the genetic set for treatment, revealing very significant differences in the signatures of the cell cycle.

It is not clear what additional value single-cell RNA sequencing could provide, but this is simply not feasible in our study, since the project was multicenter..

- Zonabend: Combining genomic and transcriptome analysis enables the impartial study of tumor genotype, including mutations, gene fusions, copy number changes, and tumor phenotype.We can assess gene expression by tumor cells and other microenvironmental components that reliably contribute to the response to glioblastoma immunotherapy.

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