Going after glioblastoma

WEST LAFAYETTE, Ind.—While no cancer is what anyone would consider “easy” to treat, brain cancers are at the top of the list for difficulty, given limited treatment and surgical options. In fact, glioblastomas, the most common malignant brain tumor type, generally come with an estimated survival time of only 12 to 18 months from diagnosis. The issue is not just the location, but also the nature of glioblastoma—in addition to being extremely immunosuppressive, glioblastoma is resistant to treatment and very heterogeneous, with no single guaranteed mutation to target. The cancer takes advantage of multiple immunosuppressive mechanisms to evade the immune system.

However, a research team from Purdue University is looking to turn the immune system back onto these tumors by genetically modifying natural killer (NK) cells, a type of immune cell, to specifically target cancer cells.

“Multifunctionally engineering these cells is a potentially transformative way to enable the improved treatment of this disease,” Sandro Matosevic, an assistant professor in Purdue’s College of Pharmacy, commented in a press release. “Our solution is the first multifunctional, responsive immunotherapy for GBM (glioblastoma multiforme) based on engineered natural killer cells. By targeting multiple mechanisms at the same time, we severely limit the ability of GBM to avoid treatment.”

The Purdue team is working with the Purdue Research Foundation Office of Technology Commercialization to license its patent-pending technology, as well as seeking partners to further develop this approach.

The Matosevic lab published an article this summer in the Journal of Hematology & Oncology that discussed some of the team's efforts to leverage NK cells as a cancer treatment. Their work—which appeared in a paper titled “CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma,” authored by Matosevic and Kyle B. Lupo—focused on the CD155 antigen in particular.

“CD155, or poliovirus receptor (PVR), has recently emerged as a pro-tumorigenic antigen, overexpressed on GBM and contributing to increased GBM migration and aggressiveness,” the authors explained. “CD155 has also been established as an immunomodulatory receptor, able to both activate NK cells through interactions with CD226 (DNAM-1) and CD96 and inhibit them through interaction with TIGIT. However, NK cell TIGIT expression has been shown to be upregulated in cancer, establishing CD155 as a predominantly inhibitory receptor within the context of GBM and other solid tumors, and rendering it of interest as a potential target for antigen-specific NK cell-based immunotherapy.”

“CD155 modulates the immunoregulation of T and NK cells through interactions with TIGIT, DNAM-1, and CD96, with, in particular, interactions between TIGIT and CD155 thought to result in severe immunosuppression of NK and cytotoxic T cells in the tumor microenvironment (TME),” Lupo and Matosevic continued, noting that the antigen's overexpression plays a role in cell proliferation and cancer cell migration.

“By targeting this axis in NK cells, through engineered cell therapies and combinatorial antibody/cell therapy approaches, it is possible to suppress CD155-induced inhibition and enhance the natural cytolytic functions of NK cells.”

Lupo and Matosevic point out that while TIGIT/CD155-induced immunosuppression isn't the target, several other preclinical studies by other organizations are underway to assess the efficacy of engineered NK cells in glioblastoma. A trial being conducted at the Johann Wolfgang Goethe University Hospital is exploring “CAR-NK-92 cells engineered with a second-generation CAR targeting HER2,” they report, and other teams are looking at targets such as EGFRvIII, CXCR4, EGFR and Erb2.

“Not only is cell-based immunotherapy a highly unique and promising treatment approach, but natural killer cells have been shown to be able to kill GBM with high efficiency. They are also considered safer than other cell-based therapies such as T cells. In addition, it has been shown that clinically, patients benefit from a higher presence of NK cells in the tumor microenvironment,” Matosevic remarked.