CTA: What drugs are able to cross the blood-brain barrier in glioblastoma?


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Dr Mochizuki: The current thinking is that there are varying degrees of blood-brain barrier disruption in glioblastoma — it can be quite heterogeneous depending on the type of [glioblastoma] and even different geographic regions of the same tumor. As such, the degree of drug penetration can be quite variable within different parts of the tumor. We can surmise, based on the infiltration of IV contrast and vasogenic edema that are evident on MRI, the degree of blood-brain barrier disruption, and as such, utilize some drugs that are known to normally have poor penetration (eg, antibodies). There is a good review of this by Sarkaria et al in the January 2018 issue of Neuro-Oncology, showcasing the fact that there is significant variation in the tissue distribution of different drugs in glioma.5 However, we do feel that activated T cells are able to have surveillance across the normal blood-brain barrier.
Dr Sonabend: The vast majority of drugs have poor penetration across blood-brain barrier. A noticeable exception to this is temozolomide, which was specifically designed to penetrate into the brain, and thus, has become the standard chemotherapy for these tumors. Recently, technologies relying on ultrasound for blood-brain barrier disruption are showing promise in enhancing the delivery of chemotherapy to the brain. An interesting trial in this context was recently published.6

CTA: What is the best sequencing strategy to employ to best capture genetic information from glioblastoma tumors?

Dr Mochizuki: We typically think  that bulk RNA sequencing gives us a good overall idea of what proteins are actively being transcribed in the tumor, as opposed to DNA sequencing, which really only lets you examine mutations in the genome. But when considering the tumor and the surrounding tumor microenvironment, RNA sequencing provides a much broader understanding [of what is] happening in this space. RNA sequencing enabled us to do an unbiased screen for which gene sets demonstrated the most variability between our 2 treatment groups, revealing highly significant differences in cell-cycle signatures. It is unclear what additional value single-cell RNA sequencing would provide, but this simply wasn’t feasible [in our study], as [it] was a multi-institution study.

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Dr Sonabend: Combining genomic and transcriptomic analysis allows unbiased interrogation of the tumor genotype, including mutations, gene fusions, and copy number alterations, as well as tumor phenotype, including gene expression by tumor cells and other components of the microenvironment that clearly contribute to the response to immunotherapy.

Disclosures: Some of the studies and authors disclosed funding from pharmaceutical companies. For a full list of disclosures, please refer to the original studies.

References

  1. Cloughesy TF, Mochizuki AY, Orpilla JR, et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma [published online February 11, 2019]. Nat Med. doi: 10.1038/s41591-018-0337-7
  2. Zhao J, Chen AX, Gartrell RD, et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma [published online February 11, 2019]. Nat Med. doi: 10.1038/s41591-019-0349-y
  3. Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma [published online February 11, 2019]. Nat Med. doi: 10.1038/s41591-018-0339-5
  4. Arrieta VA, Cacho-Díaz B, Zhao J, Rabadan R, Chen L, Sonabend AM. The possibility of cancer immune editing in gliomas. A critical review. Oncoimmunology. 2018;7(7):e1445458.
  5. Sarkaria JN, Hu LS, Parney IF, et al. Is the blood–brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro Oncol. 2018;20(2):184-191. doi: 10.1093/neuonc/nox175
  6. Carpentier A, Canney M, Vignot A, et al. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med. 2016;8(343):343re2.