by Sandra Lobo, medcitynews.com
November 4th 2013 7:42 AM
Traditional approaches to for cancer are quite limited in treating late-stage and aggressive cancers. Aduro BioTech, Inc., a clinical-stage immunotherapy company, is using the immune system to fight cancer and provide more options for patients. The immune system defends against the growth and spread of tumors. Cancer develops as a result of multiple changes in the cellular machinery that inhibits this line of defense, thereby allowing the tumor to grow. Once this occurs, a successful treatment could be vaccines that induce a broad and potent immune response to break the immune system’s tolerance of the tumor. Aduro has developed such vaccines, using three complementary immunotherapy platforms, Listeria, GVAX and cyclic dinucleotides (CDNs), with broad applications in cancer and infectious disease.
The Listeria platform uses a live, attenuated strain of Listeria monocytogenes to treat cancer and infectious diseases. The strain is engineered to deliver cancer or microbial antigens into cells to be processed by the host cellular machinery and presented to the immune system, thus inducing a potent immune response. The use of this bacteria as a cancer/microbial vaccine platform has several advantages, such as direct targeting of immune (dendritic) cells, signaling the innate immune system through multiple pathways and an ability to be repeatedly administered without being neutralized.
Using a pathogen such as Listeria to treat disease may seem counter-intuitive, but Aduro’s Listeria platform has been shown to be well tolerated in multiple clinical trials. CRS-207 is Aduro’s lead Listeria -based therapeutic, engineered to express the tumor-associated antigen mesothelin. CRS-207 was evaluated in a Phase 1 trial in 17 end-stage patients with cancers known to express mesothelin: mesothelioma, non-small-cell lung, ovarian and pancreatic. Despite an expected survival of 3-5 months for all subjects treated with CRS-207, six out of 17 lived 15 months or longer.
The GVAX platform utilizes human cancer cell lines that have been genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is a potent cytokine capable of inducing differentiation, proliferation and activation of a variety of immune cells, thus serving as a stimulant for the immune system. The immunostimulatory property of this cytokine has been exploited for use as a vaccine adjuvant to boost the potency of poorly immunogenic cancer antigens as vaccines. The GVAX cell lines have been irradiated to prevent cell division, yet are metabolically active. GVAX products include vaccines for pancreatic cancer, leukemia, myeloma, breast and prostate cancer that are all in the late human clinical stage, with colorectal and melanoma in the early human clinical stage.
Aduro’s strong growth has been led byDr. Stephen T. Isaacs, president and CEO of Aduro BioTech, who initiated the current immunotherapy program. Issacs recruited key members of the current vaccine team with deep expertise in the biology of Listeria. Aduro’s business model is based on leveraging platform technologies to rapidly develop and advance a broad range of new vaccines and vaccine combinations for applications in oncology, infectious diseases and biodefense. Aduro’s future pipeline includes a new Listeria -based therapeutic, ADU-623, that is expected to be advanced in 2013 into an investigator-sponsored Phase 1 clinical trial in patients with glioblastoma. In addition, the company continues to be funded by research grants for the development of new vaccines for prostate cancer, tularemia, hepatitis B virus (HBV) and melanoma.
Isaacs said with three complementary platforms in addition to the Listeria platform, his company is in a good spot to take advantage of the new approach to cancer treatment.
“We are entering the new era of immunotherapy, and what is becoming clear is that combinations are more effective than individual immunotherapies that only activate one part of the immune system,” he said.
Aduro acquired all GVAX assets from BioSante Pharmaceuticals, Inc. (NASDAQ: BPAX), including intellectual property and cell lines. Under its purchase agreement with BioSante, Aduro paid $1 million upfront and has committed to additional milestone and royalty payments after commercialization of GVAX products.
Four GVAX vaccines have been granted U.S. Food and Drug Administration Orphan Drug designation: GVAX Pancreas for the treatment of pancreatic cancer, GVAX AML for the treatment of acute myeloid leukemia, GVAX CML for the treatment of chronic myeloid leukemia and GVAX Melanoma for the treatment of melanoma. Aduro is currently evaluating the sequential administration of the GVAX Pancreas vaccine and its own Listeria -based CRS-207 in a randomized, controlled Phase 2 trial of 90 patients with metastatic pancreatic cancer, and enrollment in the trial has been completed. The company presented abstracts at both ASCO and ESMO, but have not posted the information on its our website yes due to an embargo.
The CDNs platform uses cyclic dinucleotides that are ubiquitous molecules secreted by Listeria and other intracellular pathogens. These molecules signal through STING (STimulator of INterferon Genes), inducing the expression of inflammatory cytokines that are known to induce a potent innate immune response. A principal barrier to the development of effective vaccines is the lack of adjuvants and formulations that can elicit an effective and long-lived immune response. Aduro’s CDNs represent a new class of adjuvants that have been shown to effectively increase vaccine potency. Aduro is now combining CDNs with GVAX into a new vaccine named STINGVAX that has demonstrated superior efficacy over GVAX alone in animal models.
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