New research published in Nature Medicine suggests that PD-1 inhibitors in the neoadjuvant setting in patients with recurrent, resectable glioblastoma may provide a survival benefit.1 Drugs in this class could prime the immune system to launch a better response against tumor cells, including against any residual cells that still remain following resection. Researcher Aaron Mochizuki, DO, a pediatric hematology/oncology fellow at the University of California, Los Angeles, told Cancer Therapy Advisor that the apparent benefit of checkpoint blockade is likely “driven by the systemic modulation of the immune compartment, wherein tumor-specific T cell clones after checkpoint release can become activated and expand in response to the large antigenic burden present with the tumor still in place.”
In a separate study published in Nature Medicine, another research team performed a longitudinal characterization of glioblastomas, comparing samples in patients before and after immunotherapy.2 These researchers also concluded that PD-1 inhibitors could be effective for patients with glioblastomas (but, specifically for those bearing alterations in the MAPK pathway). Despite this conclusion, they also found that in response to immunotherapy, “glioblastoma tumors suffer immunoediting of tumor clones that are antigenic, and by this means, tumors might evade immune recognition,” said corresponding author Adam Sonabend, MD, assistant professor of neurosurgery at Northwestern University Feinberg School of Medicine in Chicago, Illinois. He added that glioblastomas with PTEN mutations, specifically, were associated with lack of response to PD-1 blockade, and that tumors with this mutation have immunosuppressive features that influence the tumor microenvironment. And, contrary to some other cancers, explained Dr Sonabend, “the number of mutations did not influence response” to PD-1 inhibitors.
A third article published in Nature Medicine in conjunction with these studies added to this evidence; it showed that the use of neoadjuvant nivolumab in patients with relapsed glioblastoma followed by surgery was safe and feasible.3
Cancer Therapy Advisor asked Drs Mochizuki and Sonabend to discuss the tumoral immune evasion mechanisms that should be of highest concern to drug developers, the enduring issues with the delivery of drugs to the brain, and the methods of sequencing that provide the most useful information about glioblastoma and the immune mechanisms that are likely at play in the tumor microenvironment.
Cancer Therapy Advisor (CTA): Is antigen escape the biggest concern surrounding the development of immunotherapies?
Dr Mochizuki: Antigen escape is certainly a concern in therapies such as [chimeric antigen receptor T (CAR-T)] cells, which focus on a very specific target and often lead to the loss of antigen expression, as we’ve seen with anti-CD20 CAR-T cells. Anti-PD-1 therapy does stimulate the expansion of a number of T cell clones with different antigenic specificity, but [in our study] we also demonstrated the upregulation of other immunoinhibitory markers on peripheral blood T cells, such as CTLA4. Due to this, it certainly makes sense to perform trials utilizing combination immunotherapy, where we can subvert multiple tumoral immune evasion mechanisms.
Dr Sonabend: Immunoediting is an important problem limiting efficacy of immunotherapies for cancer. This often involves antigen escape, and loss of ability to present these antigens by tumors. Other mechanisms involve the acquisition of immunosuppressive features by these tumors.
In case you were interested in looking at this more, we reviewed the evidence suggesting immunoediting in glioblastomas in [a paper by] Arrieta [and colleagues].4