Immunotherapy for Glioblastoma: Current Progress and Challenges

Abstract

Glioblastoma is a highly lethal brain cancer with a median survival rate of less than 15 months when treated with the current standard of care, which consists of surgery, radiotherapy and chemotherapy. With the recent success of immunotherapy in other aggressive cancers such as advanced melanoma and advanced non-small cell lung cancer, glioblastoma has been brought to the forefront of immunotherapy research. Resistance to therapy has been a major challenge across a multitude of experimental candidates and no immunotherapies have been approved for glioblastoma to-date. Intra- and inter-tumoral heterogeneity, an inherently immunosuppressive environment and tumor plasticity remain barriers to be overcome. Moreover, the unique tissue-specific interactions between the central nervous system and the peripheral immune system present an additional challenge for immune-based therapies. Nevertheless, there is sufficient evidence that these challenges may be overcome, and immunotherapy continues to be actively pursued in glioblastoma. Herein, we review the primary ongoing immunotherapy candidates for glioblastoma with a focus on immune checkpoint inhibitors, myeloid-targeted therapies, vaccines and chimeric antigen receptor (CAR) immunotherapies. We further provide insight on mechanisms of resistance and how our understanding of these mechanisms may pave the way for more effective immunotherapeutics against glioblastoma.

Keywords: brain cancer; glioblastoma; immunotherapy; resistance to therapy; tumor microenvironment.

Figure 1

The current landscape of major glioblastoma immunotherapies and mechanisms of resistance. Immune checkpoint inhibitors (ICIs) target T cell exhaustion through blockade of immune checkpoints PD-1 and CTLA-4 to restore T cell function and antitumor activity. Myeloid-targeted therapies such as CSF-1R inhibitors reprogram immunosuppressive microglia (MG) or monocyte-derived macrophages (MDMs) (pro-tumorigenic) to become more anti-tumorigenic. Peptide vaccines, dendritic cell (DC)-vaccines and personalized vaccines educate T cells to target tumor neoantigen(s). Chimeric antigen receptor (CAR) immunotherapies involve genetically engineering a patient’s own T cells or non-patient NK-92 cells to express neoantigen-specific CARs, which are expanded in culture and adoptively transferred to the patient. Glioblastoma is highly resistant to therapy, and currently, none of the depicted immunotherapies have succeeded in improving treatment, although many clinical trials are currently ongoing. The grey boxes outline major mechanisms of resistance that are barriers to each immunotherapeutic approach, including intrinsic, adaptive and iatrogenic mechanisms. Image made with BioRender.com.