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Promising Research for Treatment of Glioma

Human brain scan

Glioblastoma and its variants are, at present, unable to be cured. Once diagnosed the life expectancy is only 15 months or so. They can occur at any age but most are seen in people between the ages of 50 and 70. In just the past two years studies have been moved from animal trials to human trials and are showing promise. No matter what their outcomes, further research is needed.

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Columbia researchers have learned why some glioblastomas, the most common type of brain cancer, respond to immunotherapy. The findings could help identify patients who are most likely to benefit from this treatment. Fewer than one in ten patients with GBM respond to immunotherapy.

This is disappointing when looking at how successful this kind of therapy has been in the treatment of a variety of aggressive cancers. GBM patients are typically treated with surgery to remove as much of the tumor as possible, then followed with radiation and chemotherapy.

Unfortunately even with aggressive therapy average survival is around 14-15 months. Glioblastomas are able to turn off the immune system from attacking the cancer cells. Nonresponsive tumors had a mutation in the macrophages (a form of white blood cell) that rather than attack the tumor cells it produced growth factors that promoted survival and spread of cells instead. The study suggested that tumors who had a mutation in the signaling pathway may benefit if two compounds were used together to treat GBM. This result has identified new targets for the treatment of GBM but more research is still needed (Rabadan et al, 2019).

What is glioblastoma?

Primary brain cancer consists of tumors that originate from the central nervous system and comprise a myriad of different tumor types; benign to malignant. Primary brain cancer patients typically remain asymptomatic until the overt clinical manifestation of tumor presence appears. These include but are not limited to headaches, seizures, dizziness, gait imbalances, sensory loss, personality changes, urinary incontinence, etc. Of the approximately 50,000 newly diagnosed primary brain tumors each year in the US, approximately 50% are classified as gliomas.

The most aggressive form of this is the glioblastoma multiforme. Despite the profound appreciation of molecular drivers of GBM, targeted therapies against them have proven excessively inefficient. Because of the blood-brain barrier, there has been very limited or no pharmaceutical treatment against these growths. Present treatment options include debulking-removal of tumor tissue as much as anatomically possible, then radiation and chemotherapy.

Despite this aggressive treatment regimen, the average survival of GBM patients is about 15 months with less than 3% of patients survive longer than five years post-diagnosis. It is clear that seeking alternative treatment approaches is of high priority for gliomas. Glucocorticoids are an integral part of treatment for glioma. It helps with nausea/vomiting and toxicity induced by chemo-radiotherapy. Tumors are routinely genotyped against an ever-increasing panel of known gene mutations. These steps have shown a glimmer of hope for the usefulness of immunotherapies for gliomas (Boussiotis & Charest, 2018).

Current treatments

Newly diagnosed glioblastoma (GBM) is treated with surgery, radiation, and chemotherapy with an average survival time of approximately 15 months. And despite maximal initial treatment the tumors invariably reoccur. After that happens the average survival time is typically only six months. In this study, tumor reductions were observed in 72% of patients (18 of 25) enrolled in the group. And five patients had a survival period of more than three years with a greater or equal to 95% reduction in the area of the enhanced tumor. Immune response after a single injection of DNX-2401 was noted in human glioma widespread necrosis with infiltration of T-cells was observed in surgical specimens 14 days after DNX-2401 treatment.

The results of this testing have provided the first clinical correlation that DNX-2401 can induce direct oncolytic effect followed by an antitumor immune response. DNX-2401 has shown evidence of being highly efficient because of expanded ineffective and it is capable of enhancing antigen presentation (Lang et al, 2018).

Promising strides in research for therapy

There is a huge need for effective treatment approaches to fight the most malignant brain tumor. Clinical and preclinical studies have greatly expanded the knowledge about molecular aspects of this deadly disease and how it interacts with the hose immune system.

The usual treatment for glioma includes surgical removal-often referred to as debulking-radiation therapy and/or chemotherapy. The side effects of these treatments can be drastic. A patient who receives radiation therapy for glioma faces the risk of being left with a neurologic deficit that significantly impairs daily function.

Studies have shown that due to the disturbance of the blood-brain barrier integrity the immune system is still able to interact with cells from the central nervous system. In animal models, there has been a success noted with immunity-based approaches. The use of CAR T-cells has been shown to be safe with minimal side effects in a first-in-human pilot study. Extensive molecular characteristics of gliomas, coupled with 2016 WHO classification, have been instrumental in improving the understanding of glioma progression and how they respond to new therapeutics. Genetic lesions encountered within the glioma cells also will help in reprogramming immune cells. Glioma is a devastating disease and despite many years of research, the prognosis remains grim (Kamron et al, 2018).

Glioblastoma multiforme is the most common malignant primary brain tumor. Despite aggressive multi-forms of attack, it remains fatal. Current standards of care include surgery to remove as much of tumor as possible, systemic chemotherapy and radiation therapy.

Current research is looking at immunotherapy using T-cells in patients to stimulate their own immune system to attack tumor cells. In an effort to help prolong the lives of those afflicted, several clinical studies were started but few were finished.

One study that was finished was only able to prolong life a mere two months longer. Another trial that is underway is trying a vaccine containing some of the patients own dendrite cells (nerve cells found in the brain) to see if that helped. Unfortunately, only 50% of the chosen group showed immunological response and it also noted the response of each person to the vaccine was different.

GBM remains incurable despite increased understanding of genetic and epigenetic pathways dysregulated in these tumors. Epigenetic is related to changes in gene function that do not involve changes in the actual DNA sequence. Immunotherapy trials have shown minor improvements in overall survival was only increased by a few months. And while it will be difficult to create a blanket treatment for all types of GBM it is still worth dedicating resources into future research toward individual patient treatments (Chin et al, 2018).

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In the past 20 years, dendrite cell vaccination being used for immunotherapy in cancer treatment has taken a rollercoaster ride. While promise was shown in a few initial trials they didn’t translate to larger studies. In the last five years, there has been a resurgence in clinical trials for dendritic cell (DC) vaccination showing more sophisticated approaches reported in the literature. DC vaccination trials have shown promise in the treatment of breast cancer and AML (acute myeloid leukemia) patients leading to five-year remission free for some AML patients. DC vaccinations, when combined with chemotherapy have shown promise against recurrent ovarian cancer by causing their T-cell to attack the tumor growth. This progress is presently being researched for possible application to fighting gliomas. Tumor antigenicity can have a marked impact on immunotherapy including DC vaccination.

Studies currently recruiting or ongoing DC vaccine trials reveal a remarkable diversity of the vaccine formulations and approaches to combination therapy. This suggests that experimental treatments previously confined to mice have finally shown translational promise in the clinic (Cannon et al, 2019).

Hope for pediatric patients with glioma

Numerous studies have been done evaluating peptide-based vaccine approaches for both adult and pediatric brain tumors. Despite frequently eliciting a biologic response, tumor shrinkage is not observed. The recent pilot trial of peptide vaccine immunotherapy involves three immunogenic epitopes that demonstrated complete responses in two of twelve children. These were significantly higher compared with previous experiences with both pediatric and adult high-grade gliomas.

The promising clinical and biologic responses led researchers to implement phase II clinical trial using the peptide vaccine strategy. While the results of work to date are highly encouraging, the pilot trial also demonstrated a clear need for developing approaches to predict which patients will respond to or resist treatment.

A lack of any patients with complete response likely reflects issues of immune escape, lack of antigen processing components, unfavorable immune milieu or up-regulation of immune checks patient molecules. In addition, the response variability prompted researchers to assess biomarkers of response and resistance to the therapy.

The data suggest that future studies should include the analysis of coding and non-coding RNA. Pretreatment biomarkers may assist in determining which patient to treatment. Development of gene-expression analysis could be very important for the trial outcome. A clear limitation of this study was the small sample size. Because of the good response, phase II has started enrolling patients for further study (Müller et al, 2018).

GBM is the most common type of primary brain tumor in adults. One promising way to therapeutically tackle the immunosuppressive GBM is to use engineered viruses that kill tumor cells via direct oncolysis and stimulating the antitumor immune response. Glioblastoma can either arise as a primary tumor or can evolve from a less malignant astrocytoma or oligodroglioma. The current standard of care of GBM includes surgery, chemotherapy and/or radiation therapy.

Unfortunately, this is not curative and survival rate averages 14-15 months. There has been some success with cancer immunotherapy in otherwise untreatable cancers. But much of this was found on mouse models. So it would be easy to overestimate immunotherapy that worked with mouse model would work in clinical studies involving GBM has yet to be seen. A glimmer of hope has been seen in phase I/II clinical studies using cancer cell selectively replicating oncolytic viruses. Then these are used as direct cancer-killing agents and active anticancer vaccines. Therapy with DNX-2401, an adenovirus, has shown an increase in T-cell infiltration along with parvovirus H-1 that showed an increase in cytotoxic T-cell infiltration. In most trials, the virus is given directly into the cavity left from tumor removal.

Some viruses like parvovirus are able to reach the BM tumors in clinical trials indicating an effective systemic delivery of the virus can be achieved in human patients. In addition, the presence of glioma stem cells can render the GBM tissue resistant to effective viral spread. This illustrates the need for robust replicating viruses in order to disrupt the suppression of GBM microenvironment (Martikainen & Essand, 2019).

Cancer researchers at the University of Bonn (Germany) have reported significant progress in the treatment of glioblastoma. About one-third of all patients who suffer from a variant of this most common and aggressive brain tumor with a survival increase noted in those treated with the current combination therapy when compared to those who have undergone standard treatment of surgery, radiation, and chemotherapy. In Germany, 2400 people are diagnosed with GBM each year. Of these, the majority are adults between the ages of 50 and 70. After radiation, these patients currently receive chemo with TMZ that alters the DNA in the cancer cells which die as a result. And while is stops the growth of the tumor for some time it is not a cure. In order to validate their findings, they started a longer patient trial. And while this new treatment only helps one-third of total GBM patients, it is a big step toward personalized cancer treatment of glioblastoma patients (Herrlinger et al, 2019).

Work Cited
Boussiotis, V.A. & Charest, A. (2018). Immunotherapies for malignant glioma. Oncogene, 37(9).

Cannon, M. J. et al. (2019). The evolving clinical landscape for dendritic cell vaccines and cancer immunotherapy. Future Medicine Immunotherapy, 11(2).

Chin, C. et al. (2018). Immunotherapy and epigenetic pathway modulation in glioblastoma multiforme. Frontiers in Oncology,8 (article 521).

Herrlinger, U. et al. (2019). Progress in treatment of aggressive brain tumors. University of Bonn.

Kamran, N. et al. (2018). Current state and future prospects of immunotherapy for glioma. Immunotherapy, 10 (4).

Lang, F.F. et al. (2018). Phase 1 study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: Replication and immunotherapeutic effects in recurrent malignant glioma. Journal of Clinical Oncology, 36(14).

Martikainen, M. & Essand, M. (2019). Virus-based immunotherapy of glioblastoma. Cancers, 11(2).

Müller, S. et al. (2018). Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas. The Journal of Clinical Investigation Insight, 3(7).

Rabadan, R. et al. (2019). Why some brain tumors respond to immunotherapy. Columbia University Irving Medical Center.

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