Effects of Smoke on Bladder Cancer Treatment

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Last year, our lab team received a grant from the Flight Attendants Medical Research Institute (FAMRI). FAMRI was created from a settlement with tobacco companies over flight attendant exposure to secondhand smoke in their work.

The money is used to fund research into a variety of health effects related to smoking. Our grant, in the amount of $325,000, was given to study the relationship between smoking and responsiveness to bladder cancer treatment.

We will be presenting preliminary data from the study at this year's American Urological Association Annual Scientific Meeting in Chicago.

Anecdotal reports tell us that smokers and people who are routinely exposed to secondhand smoke do not fare as well with immunotherapy for bladder cancer as other patients.

Although patients with regular exposure to smoke seem to have higher rates of recurrence and progression than other individuals, a direct association between smoking and bladder cancer treatment has never been proven.

Our laboratory established a bladder cancer mouse model that allows us to test the effects of smoke on current treatment regimens used in humans, as well as to evaluate novel treatments that may be able to overcome the effect of smoking.

We have demonstrated increased bladder cancer cure rates in mice undergoing intravesical gene therapy with immunocytokines, such as interleukin (IL)-2 and B7.1, which yielded prolonged immunological memory that protected mice from tumor rechallenge.

This approach may be limited by the propensity of a high level of IL-2 to stimulate expansion and proliferation of immunosuppressive regulatory T cells (T reg). Studies have also noted the similar immunosuppressive activity of smoking. Recent investigations demonstrate that the anti-angiogenic tyrosine kinase inhibitor sunitinib malate can attenuate the induction of T reg proliferation by IL-2.

We identified several specific aims for our research. The first is to scientifically determine if animals that are exposed to smoke get more bladder tumors than animals that are not exposed. Also, we are interested in seeing how the two groups vary in their response to intravesical treatment with BCG immunotherapy.

Our second aim is to compare the effects of intravesical liposome-mediated IL-2 gene therapy and the anti-angiogenic role of sunitinib malate with the effects of combined treatments on survival of C3H mice with MBT-2 tumors.

When the optimal combination of IL-2 and sunitinib malate is determined, the regimen will be combined with two different doses of B7.1 gene therapy and compared with B7.1 therapy alone in treating MBT-2 tumor-bearing mice in our third aim.

For aims two and three, survival and treatment efficacy will be assessed by measuring urine levels of IL-2, interferon-γ (immunostimulatory cytokines), and IL-10 and transforming growth factor β1 (immunosuppressive cytokines). In aim four, we will test the best treatments from aims two and three against secondhand smoke exposure by measuring the effects on the immune response.

This project will define the detrimental effect of cigarette smoke exposure on intravesical treatment for bladder cancer and serve a translational basis for a human clinical trial combining sunitinib malate with IL-2 + B7.1 gene therapy for bladder cancer.

Our lab team includes Warren Heston, PhD, lab director; Amit Patel, MD; and Thomas Powell, PhD, the primary grant writer. We see this project as a unique opportunity to categorize and identify immune responses in bladder cancer.
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