Status: approved in Switzerland, Germany

Organizations involved:

Northwest Biotherapeutics, Inc. – Manuf.; R&D; Tech.; Germany and Switzerland mark.

Gerald P. Murphy Cancer Foundation – R&D; Tech.

Pacific Northwest Cancer Foundation – Former

Lonza Biologics plc –Patent dispute

Cross ref.: See also the entry below for BiovaxID, a similar personalized dendritic call cancer vaccine, and the entry for Tumor Antigen-KLH Vaccine, rDNA (#271), another personalized dendritic cell-type vaccine, but using recombinant patient antigens to sensitize dendritic cells.

Description: DCVax-Brain is a personalized (patient’s own) immunotherapeutic vaccine for treatment of glio-blas-toma multiforme (GBM; brain cancer). Dendritic cells derived from the patient’s blood by leukapheresis are cultured to maturity; “activated through a series of proprietary steps,” then mixed with (exposed to; sensitized by) tumor antigens (tu-mor biomarkers) derived from the patient’s own tumor; and the sensitized/activated T-cells are injected back into the patient through a simple intradermal injection in the arm or thigh, consisting of just a few drops. The TFF-Cell Separation System, a closed and automated device based on tangential flow filtration is used for manufacturing dendritic cells from patient leukapheresis material.

[Note, although the company claims this to be the first personalized vaccine to receive approval. In many respects, DCVax does not appear that much different from similar personalized vaccines that have long been in use, with physicians (in the U.S., at least) not needing FDA approval to perform most individualized or autologous cellular therapies].      

Nomenclature: Dendritic Cell Vaccine, Personalized/DCVax [BIO]; DCVax-Brain [TR; ‘DCVax” is the reg. TR]

Biological.: DCVax anticipated to be a platform technology applicable to most cancers. “DCVax works by mobilizing the full spectrum of immune response, both innate and adaptive, rather than just single immune agents such as antibodies alone or T cells alone. As such, DCVax mobilizes the patient’s immune system to function in its normal, natural way. This leads to both improved efficacy and lack of problematic toxicities.”

Companies.: DCVax-Brain was developed, is manufactured and marketed by Northwest Biotherapeutics, Inc.

Manufacture: Unlike many personalized therapies in development, DCVax is claimed to be cost-effective. A proprietary batch manufacturing process is used, with a single manufacturing run producing at least 3 years of personalized treatments for a particular patient. DCVax-Brain is stored frozen in single-dose vials, ready for use on an off-the-shelf basis for that patient. By doing only one manufacturing run, and having the product available off-the-shelf, the costs can be in a range comparable to other cancer therapeutics.

Status: In Feb. 2007, Northwest Biotherapeutics (NWBT) applied for approval in Switzerland. On July 8, 2007, Authorization for Use (approval) from the Swiss Institute of Public Health (Bundesamt für Gesundheit; BAG) was granted for DCVax-Brain for treatment of brain cancer patients in Switzerland. The company claims, “As such, DCVax-Brain is the first commercially available therapeutic vaccine for such cancers.” The product will be launched in 3rd quarter 2007. The Company is authorized to manufacture DCVax-Brain in the U.S. and make it available for the treatment of patients with brain cancer at select centers in Switzerland. Approval “was based upon the Company’s clinical data to date, and upon an extensive inspection by Swissmedic (the Swiss Agency for Therapeutic Products) on behalf of the BAG.”

In March 2014, Paul Ehrlich Institute ("PEI"- the FDA of Germany) approved a "Hospital Exemption" early access program under Section 4b of the German Drug Law. Under this Hospital Exemption, NW Bio may provide DCVax-L to patients for the treatment of any glioma brain cancers (both Glioblastoma multiforme and lower grade gliomas), both newly diagnosed and recurrent, outside of the Company's clinical trial and charge full price. The patients may be from Germany or elsewhere. This approval has a term of five years, and can be re-applied for and re-issued at the end of that period.

Tech. transfer: DCVax-related U.S. patent applications include 20030175247, “ Method to increase class I presentation of exogenous antigens by human dendritic cells,” currently unassigned but with one of Northwest Biotherapeutics’ founders as an inventor, with claims for activation of cryopreserved dendritic cells for immunotherapeutic responses against primary and metastatic cancer using tumor antigens in combination with bacillus Calmette-Guerin (BCG; see related entries), a bacterium known to induce potent cellular immune responses and used as an adjuvant. U.S. 20050059151, “Compositions and methods for priming monocytic dendritic cells and T cells for th-1 response,” similarly unassigned but with a company founder as sole inventor further claims use of BCG, interferon-gamma GM-CSF, IL-4 and other immune modulators to induce maturation of dendrtic cells (to T-lymphocytes or T-cells). An application assigned to Northwest Biotherapeutics, Inc., 20050173315, “ Tangential flow filtration devices and methods for leukocyte enrichment,” concerning the TFF-Cell Separation System.

An international filing, WO9704802, “Isolation and/or Preservation of Dendritic Cells for Prostate Cancer Immunotherapy,” assigned to the Pacific Northwest Cancer Foundation, now the Gerald P. Murphy Cancer Foundation (with Dr. Murphy the inventor of the PSA test), and the prior affiliation of Dr. Boynton, a company founder and current President, with the associated Northwest Hospital (Seattle, WA), suggests that the Foundation/Hospital is an assignee or holds an interest in DCVax-related intellectual property (or, at least, DCVax-Prostate).

In Aug. 2007, Northwest Biotherapeutics (NWBT) reported that Lonza Group AG had filed a federal suit alleging infringement of its patented GS System (glutamine synthetase) gene amplification/selection technology. NW responded that it (o its contract manufacturers) does not use and never has used this gene expression or any other recombinant methods with DCVax-Brain (with this suit more likely involving DCVax-Prostate). In Dec. 2007, Lonza withdrew most of its allegations against NW, including all claims related to DCVax-Brain. However, Lonza then filed a second suit alleging that DCVax(R)-Prostate and "other infringing products or technologies" of NWBT infringed Lonza's gene expression patents. Lonza subsequently removed all allegations of infringement by NWBT products other than DCVax-Prostate (so DCVax-Brain is not affected).

The only use of any gene expression system ever connected in any way, even indirectly, with any NWBT product has been the use by an unrelated third-party manufacturer of a gene expression system to produce two batches of recombinant PSMA protein for NWBT in 1999 and 2001. The manufacturer chose the gene expression system it used, and was the only party who used that expression system in any connection with NWBT's product. NWBT did not use, nor has it ever used, Lonza's expression system. NWBT contracted to receive, and did receive, two batches of recombinant PSMA protein from the manufacturer. The PSMA protein that NWBT received was used in the manufacture of only one NWBT product: DCVax-Prostate as used in its early trials. No other recombinant protein has ever been used to manufacture any other DCVax(R) product..

Trials: In its trials, both newly diagnosed and recurrent glioblastoma multiforme (GBM; brain cancer) patients treated with DCVax-Brain have more than doubled their survival time compared to patients who did not receive DCVax-Brain. Clinical trial data to date in brain cancer patients have shown that DCVax-Brain delays disease recurrence by nearly 3-fold, from 6.9 months to 18.1 months for newly diagnosed patients. DCVax-Brain also extended patients’ survival from 14.6 months to more than 33 months (and continuing – median not yet reached). Brain cancers are among the most rapidly lethal cancers. With limited treatments available, even newly diagnosed patients have a median survival of only 14.6 months. Unlike chemotherapy, DCVax-Brain does not cause any debilitating side effects.

Adverse events are those seen with other strong immune responses, such as pain or itching at the injection site, mild fevers and malaise, muscle pain and headaches. After more than 250 injections given in clinical trials, the side effects related to receiving DCVax were generally mild. Some patients had moderate injection site reactions, some severe injection site reactions have been observed (but the adverse effects are relatively minimal compared to most other therapeutic regimens).

Northwest Biotherapeutics is currently conducting a pivotal Phase II trial in 141 glioblastoma multiforme (GBM) patients in the U.S. The trial began enrolling patients in Dec. 2006, and is anticipated to conclude around the end of 2008. The company plans to seek DCVax-Brain approval in both the U.S. and EU in early 2009, based upon the results of this trial.

A related vaccine, DCVax-Prostate is currently in a pivotal Phase III trial for prostate cancer, and has also received FDA clearance for clinical trials in five other cancers (including lung cancer). “Clinical trial data to date in hormone independent prostate cancer patients have shown striking results similar to the results in brain cancer.”

DCVax may be particularly useful as an adjuvant treatment in patients with low tumor burden.

Medical: Since 2005, the Standard of Care for patients with GBM has been surgery followed by a combination of radiation and daily Temodar chemotherapy, and then 6 monthly cycles of Temodar chemotherapy. The studies defining this Standard of Care achieved a median time to progression of 6.9 months and a median overall survival of 14.6 months (N Engl J Med, 352:987, 2005).

Market: Besides its indigenous population, Northwest Biotherapeutics notes that Switzerland is increasingly noted for medical tourism, indicating that the company may recruit patients from throughout Europe and, perhaps, the U.S. and rest of the world. Brain cancers can strike all ages, and are the leading cause of cancer deaths in children under the age of 20, suggesting that children and adolescents will be a major market for DCVax-Brain.