July 9, 2007

Bringing the Heat
By Beth W. Orenstein
For The Record
Vol. 19 No. 14 P. 32

By cranking up the temperature, a treatment technique hopes to attack tumors in a highly specific manner.

Heat can be an effective cancer treatment—either alone or combined with radiation and/or
some types of chemotherapy. The clinical challenge has been how to deliver the right amount of heat to the tumor without damaging nearby healthy tissue.

A spin-off of a military technology development company in Chelmsford, Mass., has developed a potential solution to the nonspecific heating problem. Triton BioSystems, Inc. (TBS) emerged in early 2002 from Triton Systems, Inc., which developed a method for battlefield repairs of body armor and other composite materials. The battlefield repair uses resin saturated with nanoparticles that become heated when exposed to a magnetic field. The heated resin can be molded to patch composite materials before it cools and hardens. The spin-off company was formed after researchers wondered whether such nanoparticles could be used to deliver targeted heat sufficient to kill cancer cells.

Researchers at TBS further developed the concept using cell cultures of human breast cancer and nanoparticles labeled with antibodies specific to the breast cancer cells. In those lab studies, the researchers found breast cancer cells were killed when the culture dishes were exposed to antibody-labeled iron oxide nanoparticles and an alternating magnetic field (AMF). This combination proved a specific and effective treatment technique when antibody targeting and the AMF were appropriate, says Robert Ivkov, PhD, senior director of research and development at TBS.

TBS then approached researchers from the Radiodiagnosis and Therapy Program at the University of California (UC)-Davis Cancer Center in Sacramento to develop the concept into preclinical animal studies. For the past five years, the company has been working with a group led by Sally J. DeNardo, MD, a professor of internal medicine and radiology at UC-Davis Medical Center. TBS approached DeNardo and her husband, Gerald L. DeNardo, MD, professor emeritus, because of their experience in biological targeting. Using human breast cancer implanted in mice, “we were able to show that our method for delivering thermal ablation is feasible,” says Ivkov, a coauthor of the study.

In March, the Journal of Nuclear Medicine (JNM) published a study demonstrating the UC-Davis group’s success with their ablation method in animals.

The researchers took an antitumor monoclonal antibody called Chimeric L6, known to effectively target breast cancer, and attached it to the surface of miniscule iron oxide nanoparticles. The antibody contains a human portion on its molecular structure to reduce its visibility to the immune system. Likewise, the particles were made of clinically safe polymers that allowed them to remain circulating in the blood long enough for efficient uptake in the tumor. Unavoidably, Ivkov says, the properties of the iron oxide nanoparticles and the body’s own immune system resulted in some particle uptake by the liver, spleen, and other organs. However, if the particles are not activated by the AMF, they are harmlessly processed and cleared from the body, he says.

The nanospheres are so tiny that 10,000 can fit on the end of a straight pin. The researchers injected trillions of the iron oxide nanoparticle conjugates into the bloodstream of immune-deficient female mice. The particle-antibody conjugates then sought out and latched onto receptors on the cancer cells’ surface.

In 2005, the researchers had looked at particle concentration in tumors as a function of time (hours vs. days), and that information was published in Clinical Cancer Research.

In the most recent study, the research team waited 72 hours, which it had calculated as the optimal time for this particular antibody-particle combination, Ivkov says. After three days, the researchers applied an AMF to the tumor region. The magnetic field caused the nanospheres that had attached onto the tumor cells to change magnetic polarity thousands of times per second, instantaneously generating significant localized heat. The heat killed the cancer cells, and the nanoparticle bioprobes cooled as soon as the AMF was turned off, so there was no residual damage.

“We have engineered the treatment coil so that only the particles in the tumor get treated,” Ivkov says. “The particles elsewhere do not get heated at all, or certainly heated to a much lower extent, and do not cause noticeable damage.”

The magnetic field treatment lasted for 20 minutes—a time previous TBS studies showed to be effective. The mice had been positioned in the magnetic device so their tumors were located over the highest power region of the magnetic coil, Ivkov notes.

In all cases, the researchers found that the tumor growth was severely delayed in the treated mice compared with the mice in the control groups. Tumor treatment effects were analyzed by the Wilcoxon rank sum comparison technique. This method allows for a statistical comparison of the time it takes for a treated tumor to double, triple, or quadruple its volume with the time it takes an untreated one to reach the same volumes.

The research protocol had three control groups. One group was not treated. Another group received a particle injection but no magnetic field treatment, while the third group did not receive particles but was exposed to the magnetic field, which was turned on with the same parameters as for the mice injected with antibody-labeled particles. “We found that if the particles were injected but not activated, or if the animals were placed in the activated coils with no particles, the growth rate of the tumors was the same as if we had done nothing,” Ivkov says. By having the three control groups, the researchers were able to determine that “the only treatment which had an effect was the simultaneous use of particles and an alternating magnetic field.”

No particle-related toxicity was observed nor was any treatment-related toxicity observed unless the AMF power was delivered at a level much higher than necessary. These extreme levels produced an unacceptable level of hyperthermia in the mice. Only at these extreme levels did some of the mice die, a finding consistent with earlier observations published in Clinical Cancer Research, Ivkov says. “So one can extrapolate and say that because the side effects here are minimal, one can envision longer or even multiple treatments in short periods of time to really bring a tumor under control,” he says.

Since the research that led to the JNM publication was completed, researchers at TBS have advanced the manufacturing process for the particles so that they are able to produce between five and 10 times more heat, Ivkov says. “We have some early results in mice that these work very well and, in fact, better than what we observed in our previous studies.”

The company, which he notes is planning to pursue FDA approval for the technique, says the next step will be clinical testing in patients.

In the published study, Ivkov says, approximately 50 mice were injected with human breast cancer cells. However, the researchers believe their method is not limited to treating breast carcinoma. TBS has licensed a human engineered antibody from XOMA Ltd. of Berkeley, Calif., that “is selective to a number of cancers, including breast, prostate, non–small-cell lung, colorectal, ovarian, and we believe, head and neck cancers,” Ivkov says.

The combination of Triton’s new particles and this antibody is the product currently in development for eventual clinical trial testing. Ivkov says the company has yet to decide what cancer its first human trial will attempt to treat.

“It can be complicated,” Ivkov says. “Part of the issue is that one has to carefully choose where an unmet need exists. Most oncologists would agree that for primary disease, breast cancer therapies that exist now do a pretty good job. Most women diagnosed with breast cancer have a fairly good prognosis. The challenge is for women with metastatic disease or recurrence and if the breast cancer is advanced when diagnosed.”

Ivkov says the new technology could prove beneficial if it can be used with existing therapies to reduce the size of tumors or treat lymph node metastases. “Because the combination of heat and radiation, and even some chemotherapy agents, is extremely potent, one can envision where heating is combined with lower doses of radiation and the result is a synergistic effect. If the radiation doses can be reduced, the patient gets the benefit of the therapy, but the toxicity from the treatment is reduced,” he says.

Also, Ivkov says, by imaging the tumors—a possibility inherent with this approach—researchers can measure the concentration of bioprobe in the tumor and use that information to predict how much of the tumor will be destroyed, as described in the JNM publication. “The measurements could be critical for calculating the right dose of [nanoparticle] bioprobes to give a patient undergoing treatment,” he says.

Like Ivkov, Sally DeNardo is hopeful that the technique could join other cancer therapies, especially for cancers that are hard to treat, such as metastatic breast cancer and melanoma.

However, Ivkov notes that “the regulatory process is one that takes several years,” and it will likely be that long until the nanotechnology is available in clinical settings.

P. Jack Hoopes, DVM, PhD, an associate professor of surgery and medicine at Dartmouth Medical School in Hanover, N.H., and an adjunct professor of engineering at Dartmouth’s Thayer School of Engineering, also sees promise in the developing nanotechnology medical field.

Hoopes, who has been working with TBS for roughly 18 months, says the nanoparticle cancer treatment concept could be extremely beneficial because it has the ability to deliver treatment to tumors in a highly specific manner.

“If this works as envisioned,” he says, “the treatment could be used to safely treat tumors anywhere in the body, as long as the circulating antibody-nanoparticle conjugate could get there. Since there is blood flow to all tumors, it should not matter where the cancer [is] located.”

Hoopes says the major problem with radiation and chemotherapies is that they are toxic to normal tissues as well as tumors, thereby limiting the dose that can be delivered to a tumor. “This treatment could successfully address that issue,” he says. “Although a number of important details must be worked out, such as optimization of antibody [to] tumor cell binding, highly specific systemic therapies, such as this one, are very exciting and hold the great promise for future cancer treatment success.”

— Beth W. Orenstein is a freelance medical writer who writes from her home in Northampton, Pa.