Dendritic cells are immune cells which circulate in the blood, whose main function is to process and present antigens to T-cells, which may then target any cell bearing the antigen.
Dendritic cell based vaccine therapies require sufficient fresh tumour material from the patient receiving the vaccine, as well as the collection of dendritic cells from the patient, by leukapheresis. The dendritic cells are multiplied and co-cultured with the tumour lysate and later the DC cells, now capable of presenting tumour antigens to immune effector cells, are re-injected into the patient intra-dermally.
A personalized dendritic cell vaccine therapy called DCVax-L, developed by Northwest Biotherapeutics (based in Bethesda, Maryland, USA), is currently being tested in a phase III trial for glioblastoma, with estimated primary completion date of September 2014. This trial is recruiting at 54 study locations across the United States and one in London, UK, with an estimated enrollment of 300 patients. Patients joining this trial must have sufficient tumor material available from surgery to create the vaccine, and must undergo standard radiochemotherapy. Patients are randomized into two groups: one group receives injections of their own peripheral blood mononuclear (white blood) cells following radiochemotherapy (control arm); the other group receives the DCVax-L vaccine, in which the patient’s dendritic cells pick up tumor antigens by co-culture with tissue from the patient’s tumor.
In a small preliminary trial including 23 newly diagnosed and recurrent glioblastoma patients, the vaccine showed excellent results, with the 15 newly diagnosed patients having a median survival time of 35.9 months, which is roughly double the median survival time for glioblastoma patients receiving the standard radiation and TMZ protocol.
In a March 10 2014 press release, Northwest Biotherapeutics announced that the Paul Ehrlich Institute in Germany (PEI, with a comparable role to the US FDA) has approved a “Hospital Exemption” early access program for DCVax-L. This means that the company may provide DCVax-L for treatment of any glioma patient (glioblastoma or lower grades, newly diagnosed or recurrent)outside of their clinical trial, and charge full price. Patients may be from anywhere. Additionally, the German Reimbursement Authority (InEK) is allowing hospitals to apply for reimbursement for DCVax-L treatments from the Sickness Funds (health insurers) of the German healthcare system. Six major hospitals in Germany had already applied for this reimbursement as of the press release in March 2014. While the reimbursement terms and amount were still being negotiated, patients were allowed to self-pay for the treatment in the meantime.
The treatment is not likely to be cheap. One business report by an outside company published in September 2013 was assuming a price of $14,000 per dose of DCVax-L, or $154,000 for 11 doses over 3 years, although this is dependent on the amount of tumour tissue available to manufacture the vaccine.
A similar business report by a different company published in October 2013 contains some technical details of the DCVax-L manufacturing process. It is revealed that 2 grams of tumor is required to produce enough vaccine for 3-5 years. Manufacturing facilites are located in Memphis, Tennessee and Leipzig, Germany. Manufacturing is a 7 day process: first the patient undergoes a 4-hour leukapheresis procedure to harvest mononuclear cells from the blood. This is followed by a 90 minute “tangential flow filtration” which removes non-leukocyte blood components. Five days of dendritic cell culturing with granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) follows. The dendritic cells are then cryopreserved (ie cooled to sub-zero temperatures) until ready for use. Prior to actual patient vaccination, the dendritic cells are pulsed with tumour peptides from the patient’s tumour sample. This report also expects a possible market launch in late 2015 or early 2016, and forecasts a price per patient of $120,000.
March 31, 2015
Northwest Biotherapeutics released preliminary data on 51 newly diagnosed GBM patients treated with DCVax-L. These patients were not included in the ongoing phase 3 DCVax-L trial due to evidence of disease progression on the baseline MRI scan following chemoradiation. 20 of these patients were classed as rapid progressors, another 25 were classed as indeterminate (evidence of early progression followed by a period of stability or modest regression. One patient was a clear case of pseudo-progression, and the remaining 5 patients were unclassified, due to a lack of available images. Rapid progressors had a median survival ~50% better than expected based on historical data, with one patients still alive at 37 months. The indeterminate group had a median survival of 21.5 months, with 9 patients still alive today. Six of these patients have survived for at least 30 months, and four of these have reached 35-40+ months. These outcomes are better than expected as this group of patients was considered ineligible for the phase 3 trial due to early disease progression. Watch a youtube video of the presentation and read the press release here.
Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Prins et al. 2011.
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