Anti-integrin antibody inhibits radiation-induced lung fibrosis

LOS ANGELES—New drugs on the horizon could reduce the adverse effects of radiation to the lung, allowing higher doses for lung cancer patients, according to studies presented at the 49th ASTRO annual meeting.

In studies at New York University, mice given radiation to the lungs had a sharply reduced incidence of radiation-induced fibrosis when treated with an antibody to integrin-b-6, a molecule central to signaling in the transforming growth factor-beta (TGF-b) pathway (ASTRO plenary abstract 1). [See also article on page 42.]

"Previous research has shown that TGF-b, a potent cytokine that is upregulated after radiation exposure, is an acute mediator of radiation-induced lung injury," commented presenting author Simon K. Cheng, MD, PhD, a resident at the NYU Cancer Institute. He and his colleagues evaluated the role of integrin-b-6, a key activator of TGF-b that has been implicated in fibrosis.

"As seen in our mouse model of radiation-induced fibrosis, integrin-b-6 is strongly upregulated starting 18 weeks postradiation. Then 2 weeks later, the onset of fibrosis can be seen histologically," Dr. Cheng explained.

The investigators, led by John Munger, MD, and Silvia Formenti, MD, of the NYU School of Medicine, first assessed the impact of a single 14-Gy fraction of radiation to the lungs in wild-type mice and in integrin-b-6 knockout mice. Between 24 and 28 weeks after radiation, most wild-type mice had marked alveolar remodeling of the lung relative to their nonirradiated counterparts; in contrast, irradiated knockout mice had essentially normal lung architecture relative to their nonirradiated counterparts.

In addition, the irradiated wild-type mice had a roughly 65% increase in collagen deposition, as assessed by measurement of hydroxyproline, whereas the irradiated knockout mice had levels similar to those of nonirradiated knockout mice.

"These results taken together show that integrin-b-6 is required for radiation-induced fibrosis," Dr. Cheng said.

Since integrin-b-6 is only strongly upregulated at 4 months after radiation exposure, "a tempting question to ask was what would happen if we blocked TGF-b and integrin-b-6 only during a short period before the onset of fibrosis," Dr. Cheng commented.

To test this hypothesis, the team used two approaches to block TGF-b signaling: an anti-integrin-b-6 monoclonal antibody (6.3G9, Biogen Idec) and a soluble TGF-b type 2 receptor, which sequesters active TGF-b.

Irradiated wild-type mice were injected with a control antibody, with the anti-integrin antibody 6.3G9 (0.3, 1, or 10 mg/kg per week), or with the soluble receptor, starting 16 weeks after radiation.

Late inhibition

At 26 weeks, the control mice had marked fibrosis; fibrosis in mice treated with the anti-integrin antibody was reduced in a dose-dependent manner, and fibrosis in mice treated with the soluble receptor was lower as well.

"Taken together, these findings suggest that inhibiting late TGF-b signaling can prevent the formation of radiation-induced fibrosis," Dr. Cheng said.

The investigators next evaluated the safety of TGF-b inhibition. "One concern about inhibiting TGF-b is that the total, complete loss of TGF-b function and integrin-b-6 function can cause lymphocytic inflammmation in the lung," Dr. Cheng explained.

To assess this outcome, broncho-alveolar lavage was performed in treated mice at 28 weeks to measure lymphocytes and neutrophils.

Results showed that the 10-mg dose of the anti-integrin-b-6 antibody was associated with lymphocytic inflammation, but the 1-mg dose and the soluble receptor were not.

No survival increase

Finally, reasoning that reduced fibrosis might translate into improved survival, the investigators compared lifespans between treated and untreated mice.

They found that mice treated with the anti-integrin antibody or the soluble receptor did not live significantly longer than control mice.

"One possible explanation for this is that these mice were given whole-thorax radiation, with a large percent of the dose to both lungs and heart," Dr. Cheng said, noting that such radiation has adverse vascular effects.

"It will be interesting to repeat these experiments with more limited lung radiation fields, such as only one lung, and this will be closer to real-life clinical lung cancer radiation therapy," he said.

Paradigm shift

The results support a "paradigm shift" in our understanding of late radiation injury, Dr. Cheng concluded.

"The immediate effect at the time of radiation may not be the irreversible cause of late radiation injury," he said. "This means that if transferred to humans, these interventions may not have to be given upfront at the time of radiation but can be given later—maybe many months later, perhaps at the onset of symptoms of these injuries—and they still may be therapeutic."

At an ASTRO press conference, Dr. Cheng noted that fibrosis is a very serious side effect of radiation therapy (see box on this page).

"The toxicity of pulmonary fibrosis limits the radiation dose that can be safely given to patients," Dr. Cheng said. "Doctors may fear that the serious problems caused by fibrosis will outweigh the good done by the radiation. If further studies conclude that this drug can indeed prevent fibrosis, it could lead to more effective radiation therapies for advanced lung cancer."

A biological approach

"Dr. Cheng and his colleagues presented data showing the importance of TGF-b and integrin in radiation-induced lung fibrosis," commented Stephen M. Hahn, MD, chairman of radiation oncology at the University of Pennsylvania. "If these preclinical data are subsequently confirmed, clinical trials of clinically relevant compounds might be helpful in preventing lung fibrosis from radiation therapy."

Dr. Hahn concluded that "such a biological approach to preventing a serious late effect from radiation would be a major advance."