Immunotherapy Resistance in Glioblastoma

Abstract

Glioblastoma is the most common malignant primary brain tumor in adults. Despite treatment consisting of surgical resection followed by radiotherapy and adjuvant chemotherapy, survival remains poor at a rate of 26.5% at 2 years. Recent successes in using immunotherapies to treat a number of solid and hematologic cancers have led to a growing interest in harnessing the immune system to target glioblastoma. Several studies have examined the efficacy of various immunotherapies, including checkpoint inhibitors, vaccines, adoptive transfer of lymphocytes, and oncolytic virotherapy in both pre-clinical and clinical settings. However, these therapies have yielded mixed results at best when applied to glioblastoma. While the initial failures of immunotherapy were thought to reflect the immunoprivileged environment of the brain, more recent studies have revealed immune escape mechanisms created by the tumor itself and adaptive resistance acquired in response to therapy. Several of these resistance mechanisms hijack key signaling pathways within the immune system to create a protumoral microenvironment. In this review, we discuss immunotherapies that have been trialed in glioblastoma, mechanisms of tumor resistance, and strategies to sensitize these tumors to immunotherapies. Insights gained from the studies summarized here may help pave the way for novel therapies to overcome barriers that have thus far limited the success of immunotherapy in glioblastoma.

Driver Mutations Dictate the Immunologic Landscape and Response to Checkpoint Immunotherapy of Glioblastoma

“…The immunosuppressive milieu of GBM is considered to be a major impediment to the clinical efficacy of immune checkpoint blockade therapy ( 8, 9 ). We leveraged the divergent immune compositions of EGFR-WT and EGFRvIII GBMs to analyze the efficacy of checkpoint blockade therapy.…”

“…The current standard of care for patients with GBM is debulking surgical resection, fractionated irradiation concomitant with the DNA alkylating agent temozolomide (TMZ), followed by adjuvant TMZ. The recent success of checkpoint blockade immunotherapies in cancer has not translated in GBMs partly because GBMs have (i) a low incidence of intratumoral lymphocytes with immunologic features of elevated T-cell exhaustion, (ii) a high infiltration of MDSCs and immunosuppressive bone marrow–derived macrophages (BMDM), (iii) an impermeable blood brain barrier, (iv) a low abundance and/or ineffective antigen-presenting cells (APC), and (v) a low frequency of neoantigens and mutational burden ( 8, 9 ). GBMs develop asymptomatically until clinical manifestation of late disease stages is observed, which curtails detailed studies on the longitudinal evolution of GBM development using patient samples.…”

Progress and Challenges in the Diagnosis and Treatment of Brain Cancer Using Nanotechnology

“…25 Along with the tremendous phenotypic variability of tumor cells, glioblastoma multiforme (GBM) tumors have a potent immunosuppressive microenvironment that continues to be a significant obstacle to the success of immunotherapy. 26 Unfortunately, checkpoint inhibitors, which are reshaping cancer treatment for many other cancers, have not provided any benefit for either newly diagnosed or recurrent glioblastoma.…”

Tumor-Treating Fields in Glioblastomas: Past, Present, and Future

“…Recently, immunotherapy has become a hot spot and forefront of research with its success in treating many solid and blood cancers. Various immunotherapies have been investigated to treat GBMs, and several clinical trials have been conducted, including those for checkpoint inhibitors, vaccines, adoptive lymphocyte transfer, and oncolytic therapy, although with few encouraging findings [ 104 ]. Although no clinical trials have been published involving the use of immunotherapy in combination with TTFields, it cannot be denied that this new method may produce some breakthroughs, considering the effect of TTFields on the immune TME [ 8 , 13 , 77 ], which is promising.…”