May 10, 2000 UCSD School of Medicine scientists report in the May Nature Biotechnology a potentially powerful new approach to vaccine protection against cancer, infectious disease and allergy, based on immune response-boosting DNA technology derived from microorganisms linked to tuberculosis.
A century ago, physicians noted that patients whose TB had invaded their bladders seemed to develop a protection against bladder cancer. This observation led to clinical treatment using cell extracts from mycobacterium Bacille Calmette-Guerin (BCG), a strain of TB-like bacteria that does not cause disease. Patients with bladder cancer treated with BCG extract experienced lower rates of cancer recurrence.
In 1984, a Japanese group isolated the "active ingredient" responsible for the anti-tumor effect of BCG extract--a specific class of previously unknown DNA sequences that restrict tumor growth. Subsequent studies have shown that these immunostimulatory DNA sequences (ISS) act by stimulating immune response.
The UCSD team has now demonstrated in mice that a new class of vaccines consisting of ISS chemically conjugated to protein (protein-ISS conjugate or PIC) can be used as a powerful immune enhancing agent, directly targeting the cellular switch that turns on the body's defensive reaction against foreign invaders. The successful use of this new vaccine technology not only clarifies how ISS works at the molecular level, it also opens doors for a new approach to clinical therapy for cancer, infection and allergic reaction.
The study's senior author, Eyal Raz, M.D., associate professor of medicine at UCSD and a member of UCSD's Sam and Rose Stein Institute for Research on Aging (SIRA), says that this is the first demonstration that ISS conjugate can effectively be used as a Trojan horse. An ISS-based vaccine carrying an antigen protein bypassed key steps in the normal chain of events leading to immune response, interacting directly with the immunological "on" button to muster the system's army of killer cells to launch a potent and lethal attack on the foreign protein.
According to co-author Hearn Jay Cho, M.D., Ph.D., a research fellow with UCSD and the SIRA, when mice with tumors were vaccinated with this ISS-based vaccine, a "remarkably high level of cytotoxic T-lymphocyte response was achieved." The overall increase in immune response was dramatic and effective in preventing new tumor growth and in slowing the growth of existing tumors in the mice.
Besides the vaccine's impact on tumor growth, the team reported a significant finding involving a key step in the communication cascade leading to immune response.
The vaccine conjugate combined ISS with an antigen--a class of proteins recognized by the immune system's patrolling lymphocytes as foreign. Normally, when these surveillance cells, called cytotoxic lymphocytes (CTL), encounter cells carrying antigen, they latch onto the cells, attempt to disable the invader and signal for other components of the immune system to join the attack. A successful interaction requires the intervention of linking cells called CD4+ helper T cells that activate and license CTL to kill the antigen. In most cases, the absence of this licensing link will stop the immune response in its tracks.
The UCSD team reports that the PIC vaccine bypassed this licensing step completely, and directly initiated a powerful CTL response without T cell help. When genetically altered mice lacking CD4+ helper T cells were vaccinated, the CTL response was a strong as the activation seen in normal mice. These mice have a severe immune deficiency similar to AIDS in humans.
This could be of importance in development of new vaccines against HIV and other immunodeficiencies, characterized by reduced or absent CD4+ helper T cells, leaving the patient extremely vulnerable to opportunistic infections. A vaccine that is not dependent on CD4+ as an activator could potentially beef up a disabled immune system and provide protection against the infections that further weaken the AIDS or immunodeficient patient, the authors speculate. Studies addressing these issues in primates have already been initiated.
Finally, the researchers indicate that this vaccine technology has potential as a tool to treat allergic diseases, caused by over-response of the immune system to various environmental factors. Rather than stimulating and enhancing immune response against an insidious protein associated with illness, it might be possible to introduce an allergenic protein directly into the patrolling cell and trick the cell into recognizing the protein as something it has created itself, inhibiting the allergic response.
"This is a platform technology that elicits an incredible immune response, and potentially gives unprecedented power to the physician to treat a number of clinical diseases," said Raz.
Co-authors of the paper are Kenji Takabayashi, Pei-Ming Cheng, Minh-Duc Nguyen and Maripat Corr of UCSD and the SIRA, and Stephen Tuck of Dynavax Technologies Corp. of Berkeley, CA, which licensed this technology from UCSD. The work was funded by grants from the NIH and Dynavax Technologies and a research fellowship from the Sam and Rose Stein Institute for Research on Aging.
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