Immunotherapy has shown promising success in a variety of solid tumor types, but efficacy in glioblastoma is yet to be demonstrated. Barriers to the success of immunotherapy in glioblastoma include a heterogeneous tumor cell population, a highly immunosuppressive microenvironment, and the blood-brain barrier, to name a few. Several immunotherapeutic approaches are actively being investigated and developed to overcome these limitations 1)
Immunotherapy approaches include the use of checkpoint inhibitors, chimeric antigen receptor (CAR) T-Cell therapy, vaccine-based approaches, viral vector therapies, and cytokine-based treatment 2)
Future strategies to ameliorate the efficacy of immunotherapy and facilitate clinical translation will be provided to address the unmet medical needs of GBM 3).
With the 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 4).
Immunotherapy, has become a promising strategy with the ability to penetrate the blood-brain barrier since the pioneering discovery of lymphatics in the central nervous system.
The anti-tumoral contribution of Gamma delta T cells depends on their activation and differentiation into effectors. This depends on different molecules and membrane receptors, which conditions their physiology. Belghali et al. aimed to determine the phenotypic characteristics of γδT cells in glioblastoma (Glioblastoma) according to five layers of membrane receptors.
Among ten Glioblastoma cases initially enrolled, five of them who had been confirmed by pathological examination and ten healthy controls underwent phenotyping of peripheral γδT cells by flow cytometry, using the following staining: αβTCR, γδTCR, CD3, CD4, CD8, CD16, CD25, CD27, CD28, CD45, CD45RA, CD56, NKG2D, CD272(BTLA) and CD279(PD-1).
Compared to controls, the results showed no significant change in the number of γδT cells. However, they noted a decrease of double-negative (CD4- CD8- ) Tγδ cells and an increase of naive γδT cells, a lack of CD25 expression, a decrease of the expression of CD279, and a remarkable, but not significant increase in the expression of the CD27 and CD28 costimulation markers. Among γδT cell subsets, the number of Vδ2 decreased in Glioblastoma and showed no significant difference in the expression of CD16, CD56, and NKG2D. In contrast, the number of Vδ1 increased in Glioblastoma with overexpression of CD16, CD56, and NKG2D.
The results showed that γδT cells are prone to adopt a pro-inflammatory profile in the Glioblastoma’s context, which suggests that they might be a potential tool to consider in T cell-based glioblastoma immunotherapy. However, this requires additional investigation on a larger sample size 5).
A limited number of phase III trials have been completed for checkpoint inhibitor, vaccine, as well as gene therapies, and have been unable to show improvement in survival outcomes. Nevertheless, these trials have also shown these strategies to be safe and promising with further adaptations. Further large-scale studies for chimeric antigen receptors T cell therapies and viral therapies are anticipated. Many current trials are broadening the number of antigens targeted and modulating the microtumor microenvironment to abrogate early mechanisms of resistance. Future Glioblastoma treatment will also likely require synergistic effects by combination regimens 6).
As the pioneer and the main effector cells of immunotherapy, T cells play a key role in tumor immunotherapy.
For glioblastoma, immunotherapy has not been as effective 7) , the T cells in Glioblastoma microenvironment are inhibited by the highly immunosuppressive environment of Glioblastoma, (cold tumor microenvironment) posing huge challenges to T cell-based Glioblastoma immunotherapy 8) 9) 10).
As these tumors do not attract and activate immune cells, approaches based on educating immune cells on killing tumor cells, utilized in “hot” immuno-activating cancers, have not been successful in brain tumor clinical trials. In this context, the use of immune-stimulatory approaches, like therapy with oncolytic viruses (OV), is promising 11)
Xu et al. detailed the management of gliomas and previous studies assessing different immunotherapies in gliomas, despite the fact that the associated clinical trials have not been completed yet. Moreover, several drugs that have undergone clinical trials are listed as novel strategies for future application; however, these clinical trials have indicated limited efficacy in glioma. Therefore, additional studies are warranted to evaluate novel therapeutic approaches in glioma treatment 12).
Earlier forms of immune-based platforms have now given way to more current approaches, including chimeric antigen receptor T-cells, personalized neoantigen vaccines, oncolytic viruses, and checkpoint blockade 13).
Critical to mapping a path forward will be the systematic characterization of the immunobiology of glioblastoma utilizing currently available, state of the art technologies. Therapeutic approaches aimed at driving effector immune cells into the glioblastoma microenvironment as well as overcoming immunosuppressive myeloid cells, physical factors, and cytokines, as well as limiting the potentially detrimental, iatrogenic impact of dexamethasone, will likely be required for the potential of anti-tumor immune responses to be realized for glioblastoma 14).
Patients with glioblastoma (Glioblastoma) exhibit a complex state of immunodeficiency involving multiple mechanisms of local, regional, and systemic immune suppression and tolerance. These pathways are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing immunotherapy for Glioblastoma 15).
Progress in the development of these therapies for glioblastoma has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas.
Trials have revealed promising trends in overall survival and progression free survival for patients with glioblastoma, and have paved the way for ongoing randomized controlled trials 16) 17)
Some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of glioblastoma multiforme and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature 18).
A recurrent theme of this work is that immunotherapy is not a one-size-fits-all solution. Rather, dynamic, tumor-specific interactions within the tumor microenvironment continually shape the immunologic balance between tumor elimination and escape. High-grade gliomas are a particularly fascinating example. These aggressive, universally fatal tumors are highly resistant to radiation and chemotherapy and inevitably recur after surgical resection. Located in the immune-privileged central nervous system, high-grade gliomas also employ an array of defenses that serve as direct impediments to immune attack. Despite these challenges, vaccines have shown activity against high-grade gliomas and anecdotal, preclinical, and early clinical data bolster the notion that durable remission is possible with immunotherapy. Realizing this potential, however, will require an approach tailored to the unique aspects of glioma biology 19).
Clinical experiences with active specific immunotherapy demonstrate feasibility, safety and most importantly, but incompletely understood, prolonged long-term survival in a fraction of the patients. In relapsed patients, Van Gool et al developed an immunotherapy schedule and categorized patients into clinically defined risk profiles. He learned how to combine immunotherapy with standard multimodal treatment strategies for newly diagnosed glioblastoma multiforme patients. The developmental program allows further improvements related to newest scientific insights. Finally, he developed a mode of care within academic centers to organize cell therapy for experimental clinical trials in a large number of patients 20).
Immunostimulating oligodeoxynucleotides containing unmethylated cytosine–guanosine motifs (CpG-ODN) have shown a promising efficacy in several cancer models when injected locally. A previous phase II study of CpG-ODN in patients with Glioblastoma recurrence (Glioblastoma) has suggested some activity and has shown a limited toxicity. This multicentre single-blinded randomised phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with de novo glioblastomas.
Patients with a newly diagnosed glioblastoma underwent large surgical resection and CpG-ODN was randomly administrated locally around the surgical cavity. The patients were then treated according to standard of care (SOC) with radiotherapy and temozolomide. The primary objective was 2-year survival. Secondary outcomes were progression free survival (PFS), and tolerance.
Eighty-one (81) patients were randomly assigned to receive CpG-ODN plus SOC (39 patients) or SOC (42 patients). The 2-year overall survival was 31% (19%; 49%) in the CpG-ODN arm and 26% (16%; 44%) in the SOC arm. The median PFS was 9 months in the CpG-ODN arm and 8.5 months in the SOC arm. The incidence of adverse events was similar in both arms; although fever and post-operative haematoma were more frequent in the CpG-ODN arm.
Local immunotherapy with CpG-ODN injected into the surgical cavity after tumour removal and followed by SOC, although well tolerated, does not improve survival of patients with newly diagnosed Glioblastoma 21).
Epidermal growth factor receptor 3 (EGFRvIII) is present in approximately one-third of glioblastoma (Glioblastoma) patients. It is never found in normal tissues; therefore, it represents a candidate target for glioblastoma immunotherapy. PEPvIII, a peptide sequence from EGFRvIII, was designed to represent a target of glioma and is presented by MHC I/II complexes. Dendritic cells (DCs) have great potential to sensitize CD4+ T and CD8+ T cells to precisely target and eradicate Glioblastoma.
Li et al. show that PEPvIII could be loaded by DCs and presented to T lymphocytes, especially PEPvIII-specific CTLs, to precisely kill U87-EGFRvIII cells. In addition to inhibiting proliferation and inducing the apoptosis of U87-EGFRvIII cells, miR-326 also reduced the expression of TGF-β1 in the tumour environment, resulting in improved efficacy of T cell activation and killing via suppressing the SMO/Gli2 axis, which at least partially reversed the immunosuppressive environment. Furthermore, combining the EGFRvIII-DC vaccine with miR-326 was more effective in killing U87-EGFRvIII cells compared with the administration of either one alone. This finding suggested that a DC-based vaccine combined with miR-326 may induce more powerful anti-tumour immunity against Glioblastoma cells that express a relevant antigen, which provides a promising approach for Glioblastoma immunotherapy 22).
