Glioblastoma is the most common and lethal primary brain cancer and clinical outcomes for treating the disease remain poor.  Glioblastoma has a nearly 100% recurrence. Despite advances in early diagnosis and some advances in the standard of care and adjuvant therapy, the current treatment has been virtually unchanged for nearly 20 years.

Treatment for newly diagnosed glioblastoma includes surgery, designed to debulk the tumor, radiotherapy, and chemotherapy with temozolomide (Temodar®; Merck & Co). However, following initial treatment, tumors typically recur in 6 to 8 months, median overall survival (mOS) is 15 to 17 months after diagnosis, and 5-year survival is generally less than 5%. As a result, there is a major unmet medical need. [1][2]

A complex diseased
The poor prognosis of patients with glioblastoma may be caused by various factors, including the unique interaction of the disease with the immune system such as the immunosuppression that glioblastoma causes in its microenvironment.  This complexity is attributed to the ability of the disease to secrete glioma-cell-derived transforming mediators like factor-β, interleukins, and prostaglandin E2, resulting in functional compromise of T-cell responsiveness. [3][4]

Another aspect adding to the complexity of the disease is that it is generally located in the immunologically “difficult to access” central nervous system (CNS), which is efficiently isolated from the peripheral immune system by the blood-brain barrier (BBB). As a result, glioblastoma is mostly found in areas with highly selective accessibility of the CNS to the immune system, predominantly to activated T lymphocytes, which are the only cells that can cross the BBB. [3][4]

Another reason why finding a treatment approach for glioblastoma is so complex, is that the disease is characterized by a genetic profile that is highly diverse both in the pediatric and adult populations. Tumors can, for example, express a wide variety of tumor-associated antigens (TAAs), which vary not only between different patients but within the same individual as well, leading to different biological behaviors that respond differently to a treatment.

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A novel approach
One novel treatment approach involves DCVax® a personalized immune therapy for the treatment of solid tumors being developed by Northwest Biotherapeutics.  DCVax® is a platform technology that uses activated dendritic cells, considered the master cells of the immune system, and is designed to reinvigorate and educate the immune system to attack cancers.

Unlike conventional cancer drugs, which use one active agent to hit just one target, DCVax is designed to ‘hit’ many active agents to hit many targets on the tumor.

In a phase 3 clinical study with autologous tumor lysate-loaded dendritic cell vaccination (DCVax-L) median survival and “long tail” of extended survival were increased in both newly diagnosed and recurrent glioblastoma.

The study met both the primary and the secondary endpoint under the Statistical Analysis Plan for the trial. The outcome of this study was published online in JAMA Oncology [5]

First time in 20+ years
Researchers involved in the development of this new approach believe this is the first time in nearly 20 years that a Phase III trial of a systemic treatment has shown such survival extension in newly diagnosed glioblastoma, and the first time in nearly 30 years that a Phase III trial of any type of treatment has shown such survival extension in recurrent glioblastoma.

Linda F. Powers, Chief Executive Officer of Northwest Biotherapeutics.

“We are excited to see the meaningful survival extensions in glioblastoma patients treated with DCVax®-L in this trial – particularly in the “long tail” of the survival curve, where we see more than double the survival rates as with existing standard of care. With well over 400 clinical trials for glioblastoma having failed over the last 15 years, it is gratifying to be able to offer new hope to patients who face this devastating disease,” said Linda F. Powers, Chief Executive Officer of Northwest Biotherapeutics.

“It is especially encouraging to see these survival extensions with a treatment that has such a benign safety profile,”  Powers continued.

“Over 2,100 doses of DCVax-L were administered during the trial, and we found that the adverse event profile was not meaningfully different than with standard of care alone.  DCVax-L is also quite simple for the physician and patient:  just an intradermal injection in the upper arm, 6 times over the course of year 1, and then twice a year for maintenance thereafter,” she added

Dat supports the claim
In the Phase III trial of DCVax®-L, median Overall Survival (mOS) for newly diagnosed GBM patients (n=232) was 19.3 months from randomization (22.4 months from surgery) with DCVax-L vs. 16.5 months from randomization in the controls (HR=0.80, p=0.002).  Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%.  For recurrent GBM (n=64), mOS was 13.2 months from relapse vs. 7.8 months (HR = 0.58, p<0.001).

Survival at 24 and 30 months post-recurrence was 20.7% vs. 9.6%, and 11.1% vs 5.1%, respectively. In newly diagnosed GBM patients with methylated MGMT, mOS was 30.2 months from randomization (33 months from surgery) with DCVax-L (n=90) vs. 21.3 months in controls (n=199) (HR=0.74, p=0.027).

From a safety perspective, out of more than 2,100 doses of DCVax-L administered during the Phase III trial, there were only 5 serious adverse events that were deemed at least possibly related to the treatment.  There were 3 cases of intracranial edema, 1 case of nausea, and 1 case of lymph node infection.

Manufacturing challenge
DCVax-L is a fully personalized immune therapy made from a patient’s own immune cells (dendritic cells) and antigens (biomarkers) from a sample of the patient’s own tumor.  This means that the treatment is automatically tailored to targets that are present in that patient’s cancer.[6]

However, this approach also creates a manufacturing challenge because DCVax-L is essentially manufactured by fusing the patient’s own glioblastoma cells with the patient’s own dendritic cells. During the initial surgery, a part of the excised tumor is collected and sent for pathological studies. The remaining part of the cancer cells is procured and added to a digestion buffer containing enzymes. After approximately two weeks the patient undergoes a session of leukapheresis, during which peripheral blood mononuclear cells are obtained. Then these cells get ex vivo differentiated into dendritic cells with the addition of interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF).[6]

After this step, the manufacturing process involves combining the two ingredients, the tumor tissue and dendritic cells, to manufacture the vaccine. Then, whole tumor lysate is used to potentially pulse dendritic cells with the entire spectrum of available tumor antigens. The last step of the process, incubation, lasts 16 hours.[6]

If sufficient tumor lysate has been extracted, a multi-year set of doses (generally 5 doses are required) is produced in a single manufacturing batch, which takes 8 days.  The final product is harvested and centrally stored in individual doses under cryopreservation and is available “off the shelf” throughout the treatment regimen. [6]

“The DCVax-L trial, at 94 hospitals in 4 countries, involved the teamwork of a large number of dedicated investigators.  Publication of the results in the prestigious, peer-reviewed journal JAMA Oncology honors this teamwork and demonstrates how the field can move forward with novel therapies and innovative clinical trial designs,” concluded Marnix L. Bosch, MBA, Ph.D., and Chief Technical Officer of Northwest Biotherapeutics.

Northwest Biotherapeutics is currently working on preparations for applications for regulatory approval of DCVax®-L.

Clinical trial
Study of a Drug [DCVax®-L] to Treat Newly Diagnosed GBM Brain Cancer (GBM) – NCT00045968
Expanded Access Protocol for GBM Patients With Already Manufactured DCVax®-L Who Have Screen-Failed Protocol 020221 (DCVax-L EAP) – NCT02146066
Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen Vaccine and Nivolumab in Treating Patients With Recurrent Glioblastoma – NCT03014804

Highlights of prescribing information
Temozolomide (Temodar®; Merck & Co) [Prescribing Information]

[1] Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent glioblastoma–are we there yet? Neuro Oncol. 2013 Jan;15(1):4-27. doi: 10.1093/neuonc/nos273. Epub 2012 Nov 7. PMID: 23136223; PMCID: PMC3534423.
[2] Poon MTC, Sudlow CLM, Figueroa JD, Brennan PM. Longer-term (≥ 2 years) survival in patients with glioblastoma in population-based studies pre- and post-2005: a systematic review and meta-analysis. Sci Rep. 2020 Jul 15;10(1):11622. doi: 10.1038/s41598-020-68011-4. PMID: 32669604; PMCID: PMC7363854.
[3] Smyth MJ, Godfrey DI, Trapani JA. A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol. 2001 Apr;2(4):293-9. doi: 10.1038/86297. PMID: 11276199.
[4] Ochs K, Sahm F, Opitz CA, Lanz TV, Oezen I, Couraud PO, von Deimling A, Wick W, Platten M. Immature mesenchymal stem cell-like pericytes as mediators of immunosuppression in human malignant glioma. J Neuroimmunol. 2013 Dec 15;265(1-2):106-16. doi: 10.1016/j.jneuroim.2013.09.011. Epub 2013 Sep 20. PMID: 24090655.
[5] Liau LM, Ashkan K, Brem S, Campian JL, Trusheim JE, Iwamoto FM, Tran DD, Ansstas G, Cobbs CS, Heth JA, Salacz ME, et al.  Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial. JAMA Oncol. 2022 Nov 17. doi: 10.1001/jamaoncol.2022.5370. Epub ahead of print. PMID: 36394838.
[6] Polyzoidis S, Ashkan K. DCVax®-L–developed by Northwest Biotherapeutics. Hum Vaccin Immunother. 2014;10(11):3139-45. doi: 10.4161/hv.29276. Erratum in: Hum Vaccin Immunother. 2015;11(7):1881. PMID: 25483653; PMCID: PMC4514134.

Featured image: Glioblastoma (GBM), Photo courtesy: © 2016 – 2022 Fotolia/Adobe. Used with permission.

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