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Liposome complex holds great potential
The research team at National Jewish Medical and Research Center was investigating gene therapy options for cancer treatment, but things were not going as planned. The liposomal complex they were using as a delivery vector to introduce therapeutic genes into the target cells, was eliciting a very strong immune response and muddying the waters of their investigation. The research team tried to work around the immune response, keeping their focus on gene therapy, but to no avail – until it occurred to the team that they might just have something more here, not gene therapy, but a powerful immunostimulant with many potential uses in medicine.
“The immune response was a side effect of the gene therapy delivery system we were working with,” said Dr. Steven Dow, a Professor in the Department of Clinical Sciences and in the Department of Microbiology, Immunology and Pathology at Colorado State University, and a former director of the National Jewish research team. “We were taught that the gene delivery vectors were inert, but we found that instead they were very stimulating to the immune system. We realized that instead of working around what we thought was a problem, the delivery system might be ideal as an adjuvant for vaccines and for use as an immunotherapeutic. It was pure serendipity – most discoveries in science are not made because they are thought through, but because someone is a good observer.”
In 2001, Dr. Dow left National Jewish to join the faculty at the College of Veterinary Medicine and Biomedical Sciences, but his research partnerships as a result of his work with the cationic liposome DNA complex (CLDC) continue to expand, particularly in the use of cationic lipid adjuvant systems to increase the efficacy of vaccines and immunotherapeutics. Adjuvants are critical components of vaccines, helping to stimulate the innate immune response which in turn activates the adaptive immune response. The innate immune system is comprised of cells and mechanisms that defend the host from infection in a general manner without conferring long-lasting immunity. The adaptive immune response is put into play by the innate immune system and enables the host to recognize and remember specific pathogens, conferring protective immunity and preparing the body for future challenges.
The adaptive immune response builds immunity over time to multiple challenges which is why, in normal situations, young children do not have protective immunity to the degree that adults do. Vaccines help to build that immunity by challenging the immune system with attenuated or killed pathogens, generating a protective immune response without harming the host. Adjuvants such as CLDC activate the innate immune response by mimicking natural infection, triggering a low level of inflammation, and an improved T-cell and B-cell response.
“We’ve been using adjuvants for over 100 years, but are just now figuring out exactly how they work,” said Dr. Dow. “Aluminum salts, including aluminum hydroxide and aluminum phosphate, are the most common adjuvants used. The problem is that these adjuvants stimulate primarily an antibody response, which is fine when you’re protecting against agents like the tetanus toxin. But if you’re trying to protect against complex antigens such as tuberculosis, cancer, and HIV, you need more than an antibody response, you need an adjuvant that will elicit a T-cell response as well which is what we are seeing with CLDC.”
In addition to using CLDC as a vaccine adjuvant, researchers are investigating the complexes for use in immunotherapy. The first human clinical trials started in June with flu vaccines incorporating the new adjuvant. In October, researchers will begin a study in hepatitis C patients using the complex as an immune system stimulant and in patients with acute myelogenous leukemia. The potential uses for the complexes are varied, as evidenced by the current number of research projects and clinical trials.
Dr. Dow works with colleagues at: National Jewish on cancer and asthma vaccines; University of Colorado Health Sciences Center on formulation development; University of California at Davis and Stanford University on flu studies (which, if successful, could help to dramatically increase the country’s flu vaccine stores); National Institutes of Health on a herpes vaccine study; Penn State University Medical Center on a cancer study in humans with AML; University of Utah on immunotherapy for viral infections; and CSU’s Rocky Mountain Regional Center of Excellence for Biodefense and Emerging Infectious Diseases on a number of agents including arboviruses, Eastern and Western equine encephalitis viruses, and West Nile virus, LaCross virus, Francisella tularensis, and Mycobacterium tuberculosis. He works with colleagues in his own lab on bacterial diseases including Burkholderia mallei and pseudomallei, Yersinsia pestis, and Francisella tularensis.
Dr. Dow also is a member of the Animal Cancer Center, where CLDC complexes are being investigated for use in tumor immunotherapy and tumor vaccines. In addition, he collaborates with Dr. Michael Lappin and other colleagues in the Department of Clinical Sciences on studies of CLDC immunotherapy for feline and canine viral and fungal diseases.“We are doing a lot of translational research here and working at the Veterinary Teaching Hospital provides a tremendous advantage in advancing these studies rapidly,” said Dr. Dow. “We can quickly move from the laboratory into clinical trials, and from there take the next step into human medicine, benefiting both animals and humans.
”The CLDC technology serves as the core technology for the start-up company Juvaris Biotherapeutics based in San Francisco. Juvaris is pursuing the use of CLDC as both a vaccine adjuvant and as a stand-alone immunotherapeutic. Recently, Bayer Animal Health licensed the CLDC technology from Juvaris Biotherapeutics for use in animal health applications. Since coming to CSU, Dow and his research partners have had numerous patents filed through the Colorado State University Research Foundation.
“It appears that there are many possible applications for the CLDC immunotherapy technology,” said Dr. Dow. “All these partnerships allow a fuller exploration of the biomedical applications of CLDC, ultimately benefiting human and animal patients with improved preventive and therapeutic care.”