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Developing new vaccines for lung cancer

Institution: University of California, Los Angeles
Investigator(s): Michael Roth, M.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7RT-0040 Award: $398,511
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Tobacco smoking is the primary cause of lung cancer. Unfortunately. this disease is usually diagnosed at a late stage when conventional treatment with surgery, chemotherapy and radiation are of limited value. Despite some advances in these areas, 86% of lung cancer patients still die from their disease - making lung cancer the number one cause of cancer-related death for both men and women. The goal of this proposal is to develop a new approach for using a patient's own immune system to fight lung cancer. We know that the immune system is capable of curing cancer, but that it is actively suppressed from doing so by the presence of the tumor. Our hope is that by using immune-enhancing hormones we can restore a patient's natural ability to detect and fight their own cancer.

In the past 2 years we have developed a better understanding of how we might use these hormones. When they are mixed with a patient's blood in the laboratory we can increase the number and function of important immune-stimulating cells, called dendritic cells (DC) up to 100-fold. We are just beginning studies in which these hormones are being given as a treatment to lung cancer patients. Our preliminary results suggest that this approach is restoring their immune function. However, in order to develop the best treatment, we need to establish a model system in which we can rapidly study and optimize important factors such as the dosing and timing for administering these hormones, and how to best combine them with an active cancer vaccine. To accomplish these goals, we propose to treat mice with a similar regimen of immune-enhancing hormones and carefully evaluate the effects of this treatment on the number of immune cells, on their capacity to detect and respond to an immune challenge, on the interaction of this treatment with new types of genetically-produced vaccines, and on their ability to resist the growth of implanted lung cancer cells. By the time we finish this work, we hope to have a definite plan on how to treat patients with a new form of immune therapy. If successful, this approach would be widely applicable to patients with cancer; would target only their cancer with little effect on the organs and tissues to which the cancer has spread; could be self-administered at home (without need for hospitalization); and would not require any surgery or chemotherapy.

Final Report
Lung cancer is the leading cause of cancer-related death for both men and women in California and conventional treatment is rarely effective for individuals with advanced disease. Our goal was to develop a model for evaluating new medications that will boost the immune system to react against lung cancer. Our first aim was to test two immune stimulating drugs, GM-CSF and IL-4, for their ability to increase the number and function of special white blood cells called dendritic cells. Dendritic cells are essential for stimulating the immune system and appear to be turned off in patients with cancer. The second aim was to determine whether these dendritic cells enhance the immune response to a genetically-engineered vaccine, and to develop and test new forms of the vaccine that might enhance the immune response even further. Our third and final specific aim was to combine GM-CSF and IL-4 therapy with genetically-engineered vaccines in a manner that boosts the immune response against lung cancer.

Different combinations of the two immune stimulating hormones, GM-CSF and IL-4, were given to mice by a special continuous infusion pump. Mice treated with GM-CSF alone demonstrated a marked increase in the number of dendritic cells as well as other immune cells. The response to GM-CSF and IL-4, in combination, was more specific for generating dendritic cells and produced cells with greater stimulating activity. In theory, having more dendritic cells, and ones with greater function, should increase one’s ability to respond to a vaccine. To evaluate this, we tested the response to new genetically-engineered vaccines. These vaccines are made from a common cold virus called adenovirus. The infectious nature of the virus is deactivated and the virus is used as a carrier to transport the vaccine inside cells. In order to evaluate the usefullness of this approach against cancer, mice were first injected with tumor cells. In the absence of any treatment these cells grow rapidly and ultimately kill the mouse. To boost their immune response, the number of stimulatory dendritic cells was first increased by administering GM-CSF and IL-4. Mice were then vaccinated with either of two adenovirus vaccines – one capable of targeting the immune system against the cancer cells and one control virus. Treatment with GM-CSF and IL-4 alone had little impact on tumor growth. Similarly, an injection of the vaccine itself had no effect on tumor growth. However, the tumors in mice that were treated with the immune stimulating drugs and then vaccinated grew at a much slower rate. The pre-treatment with GM-CSF and IL-4 was found to increase the response to the gene-therapy vaccine by 10 fold. A newer form of this virus was also evaluated and boosted the immune response another 10-fold.

We are currently working to understand the mechanisms involved in this treatment and how to better optimize it for use in patients. Treatment of cancer patients with GM-CSF and IL-4 has shown promising results, similar to our animal studies, and it is hoped that the combination of immune stimulating therapy and gene therapy will result in a safe and effective treatment for lung cancer.
Publications

Systemic murine GM-CSF and IL-4 in the development of dendritic cell (DC) subsets and their localization in spleen of mice
Periodical: Cancer Research Index Medicus:
Authors: Basak S, Trejo DT, Stolina M, Dubinett SM, Roth MD ABS
Yr: 2000 Vol: 41 Nbr: A11 Abs: Pg:

Increased dendritic cell number and function following continuous in vivo infusion of GM-CSF and IL-4.
Periodical: Blood Index Medicus:
Authors: Basak SK, Harui A, Stolina M, Sharma S, et. al. ART
Yr: 2002 Vol: 99 Nbr: 8 Abs: Pg: 2869 - 2879

Helper-dependent adenoviral vectors efficiently express transgenes in human dendritic cells but still stimulate antiviral immune responses.
Periodical: Journal of Immunology Index Medicus:
Authors: Roth MD, Cheng Q, Harui A, et. al. ART
Yr: 2002 Vol: 169 Nbr: 8 Abs: Pg: