Personalized therapeutic vaccines to treat brain cancer

Not all cancers are created equal. Some cancers, when caught early, boast a cure rate above 90%¹. Others are especially difficult. Among the most challenging is a brain cancer called glioblastoma. Despite billions of dollars in research over many years, prognosis remains poor, and the standard treatment has not changed in decades². However, new treatments that harness the patient’s own immune system to target the cancer cells offer promise.

What is glioblastoma? Why is it so hard to treat?

Glioblastoma is a very aggressive cancer that arises from glia, which are the cells that support neurons within the brain³. Treatment for glioblastoma is typically delivered in three parts. First, if possible, surgery is performed to remove the visible tumor and alleviate symptoms. Second, radiation is delivered to the region to kill cancer cells that may have been left behind. Third, chemotherapy is given in an effort to kill cells that broke away from the bulk tumor but are too small to be seen with imaging.

Unfortunately, this is almost never enough to prevent the rapid appearance of additional tumors. This occurs for two main reasons. The first is that glioblastoma does not grow as a contained mass, but rather more like an octopus with invisible tentacles that extend outward into many areas of the brain. This means that even if a surgeon is able to remove the visible tumor, many cancer cells usually remain⁴. The second is the blood brain barrier. This is a membrane that protects the brain by keeping various chemicals, pathogens, or other substances out⁵. In the absence of cancer, this is a good thing, but the downside is that many chemotherapies cannot get into the brain to kill the tumor.

How do personalized cancer vaccines work?

A conventional, preventive vaccine is an inert piece of material, usually from a virus or bacteria, that is introduced to the body to generate an immune response. That response trains the immune system, so that when the pathogen is encountered, the body can react quickly and prevent an infection.

Designing a therapeutic cancer vaccine is more difficult than for a bacteria or virus. This is because cancer is not a foreign pathogen with a single genetic makeup, where a single vaccine can be used for millions of people. Even with glioblastoma, one person’s tumor is quite different from that of another ⁶. This means each individual needs a vaccine that uniquely targets the cancer’s mutations and does not target other cells in the body. To do this, scientists use one of two approaches.

• In one method, the entire set of DNA from an individual’s tumor is sequenced and compared to the person’s normal cells. The differences are identified, and a vaccine is made that targets those changes, which activates the immune system to go after only the cancer cells⁷.
• In the second method, a piece of tumor tissue is exposed to a patient’s own immune cells, which have been extracted and put in a dish. These cells are “trained” and then put back into the patient, ready to start the attack on the tumor⁸.

Cancer vaccines are promising for glioblastoma.

Because the therapeutic vaccines use the body’s own immune system against the cancer, they can activate cells that cross the blood brain barrier, overcoming an obstacle that chemotherapy often cannot. Furthermore, once in the brain, the activated immune cells are not constrained to seeking only the visible tumor. They have the potential to go after the tentacles, overcoming a limitation of surgery and radiation.

Over the past several years, cancer vaccines have shown real-world progress for glioblastoma. They generate a robust immune response against the tumors^9,10. Furthermore, there have been many hints of effectiveness. Long-term survivors who received cancer vaccines for glioblastoma have come forward to tell their stories. Becky (here) received a cancer vaccine in Germany and is well beyond the standard life expectancy. Brad (here) received a vaccine where his immune cells were trained in a dish to hunt cancer. He is more than 10 years cancer-free, a remarkable outcome for glioblastoma.

Lastly, final data from an important trial¹¹ was recently presented (here) and demonstrated that use of a personalized cancer vaccine extends glioblastoma survival. This was the first time that this has been shown in a large trial for glioblastoma in nearly 20 years. Overall, there is more work to be done in the effort to cure glioblastoma, but for some patients, personalized cancer vaccines may be a way to do it.

References

1. Wang, S. et al. A Review on Curability of Cancers: More Efforts for Novel Therapeutic Options Are Needed. Cancers (Basel) 11, doi:10.3390/cancers11111782 (2019).
2. Fernandes, C. et al. in Glioblastoma   (ed S. De Vleeschouwer)  (2017).
3. Yao, M. et al. Cellular origin of glioblastoma and its implication in precision therapy. Cell Mol Immunol 15, 737-739, doi:10.1038/cmi.2017.159 (2018).
4. Hanif, F., Muzaffar, K., Perveen, K., Malhi, S. M. & Simjee Sh, U. Glioblastoma Multiforme: A Review of its Epidemiology and Pathogenesis through Clinical Presentation and Treatment. Asian Pac J Cancer Prev 18, 3-9, doi:10.22034/APJCP.2017.18.1.3 (2017).
5. Kadry, H., Noorani, B. & Cucullo, L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS 17, 69, doi:10.1186/s12987-020-00230-3 (2020).
6. Nicholson, J. G. & Fine, H. A. Diffuse Glioma Heterogeneity and Its Therapeutic Implications. Cancer Discov 11, 575-590, doi:10.1158/2159-8290.CD-20-1474 (2021).
7. Lang, F., Schrors, B., Lower, M., Tureci, O. & Sahin, U. Identification of neoantigens for individualized therapeutic cancer vaccines. Nat Rev Drug Discov 21, 261-282, doi:10.1038/s41573-021-00387-y (2022).
8. Eagles, M. E. et al. Dendritic cell vaccines for high-grade gliomas. Ther Clin Risk Manag 14, 1299-1313, doi:10.2147/TCRM.S135865 (2018).
9. Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234-239, doi:10.1038/s41586-018-0792-9 (2019).
10. Shibao, S. et al. A pilot study of peptide vaccines for VEGF receptor 1 and 2 in patients with recurrent/progressive high grade glioma. Oncotarget 9, 21569-21579, doi:10.18632/oncotarget.25131 (2018).
11. Liau, L. M. et al. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med16, 142, doi:10.1186/s12967-018-1507-6 (2018).