Two new studies by researchers at the US National Cancer Institute add to the growing evidence of the promise of a new type of cancer immunotherapythat uses infrared light to trigger the rapid and selective death of cancer cells.
One of the studies, presented last week at the American Association for Cancer Research (AACR) annual meeting in New Orleans, showed that this method, called near-infrared photoimmunotherapy (NIR-PIT), could trigger immune activity against tumors in mice by decreasing the tumor microenvironment of certain immune cells that act to limit the immune response against tumors.
The other study, published on March 10 in Oncotarget, demonstrated that, in both cultured cells and mice,NIR-PIT specifically targets cancer cells or tumors that express mesothelin, a cell surface protein that is present at high levels in several aggressive human cancers, including mesothelioma, pancreatic cancer, and ovarian cancer.
A clinical trial with NIR-PIT is already underway in people with early-stage recurrent head and neck cancer who overexpress the epidermal growth factor receptor EGFR1.
Near-infrared photoimmunotherapy uses a conjugated photoabsorbent antibody that binds to cancer cells. When near-infrared light is applied, the cells swell and then rupture, causing the cancer cell to die. Photoimmunotherapy is currently in clinical trials in patients with inoperable tumors.
The new studies were led by Dr. Hisataka Kobayashi of the Cancer Research Center (CRC), who developed the NIR-PIT method. NIR-PIT uses a specific antibody chemically linked to a photoabsorbent, a molecule that absorbs light of a specific wavelength. The photoabsorbent used in NIR-PIT, called IR700, absorbs light in the near-infrared part of the spectrum. Dr. Kobayashi designed the antibody-photoabsorbent conjugate combination so that it is activated by near-infrared light only when it binds to its target molecule. Infrared light is used because it can penetrate living tissue without causing damage.
When the antibody-photoabsorbent conjugate is injected into a mouse or human, it binds to cancer cells [that overexpress the target for the antibody]. When near-infrared light is applied, the cells begin to swell rapidly and then burst, causinga form of rapid cell death called necrotic (or immunogenic) cell death," explained Peter Choyke, MD, head of the CCR Molecular Imaging Program and a collaborator on the studies. Dr. Kobayashi has developed conjugates with many antibodies, opening up the possibility of treating a wide variety of cancer types.
For example, Dr. Choyke said that since mesotheliomas are notoriously difficult to remove surgically, "one possible use (of the mesothelin antibody conjugate 'IR700') would be to use NIR-PIT after surgery to treat residual cancer that was missed during the operation."
The study presented at the AACR meeting builds on another finding by Dr. Kobayashi and his team. When tumor cells break down and die in response to NIR-PIT, the cells release their contents into the extracellular space. The healthy immune system adjacent to the dying tumor cells detects these cellular debris as "foreign," resulting in the activation of an immune response that further aids in the destruction of the cancer.
"We know that there are (immune cells called) T cells capable of destroying cancer in the cancer microenvironment itself, " said Dr. Kobayashi, "but they are suppressed by other immune cells called regulatory T cells (Tregs)."
To try to eliminate these immunosuppressive cells, researchers attached IR700 to an antibody that targets regulatory T cells. The conjugate was injected into mice with healthy immune systems that had tumors formed from mouse colon cancer or lung cancer cells implanted under the skin. When the tumors were exposed to NIR light, the Treg cells were rapidly and selectively removed from the microenvironment. This, in turn, led to rapid activation of T cells, destruction of tumor cells within an hour, tumor reduction within a day, and prolonged survival of the mice. Tregs in organs that were not exposed to NIR light were not affected by the treatment.
In this study, researchers also observed cell destruction effects in implanted tumors that were distant from the tumor treated with NIR light.
"In other words," explained Dr. Kobayashi, "the activated T cells from the treated tumor traveled to other tumor sites in the mouse and created significant reactions in the tumors."
The advantage of the Treg method is that it is an alternative to developing a series of different antibodies, such as the anti-mesothelin antibody, to target molecules found in certain types of tumors. "There is only one type of Treg in the body, so the same antibody could be used for multiple types of tumors. Furthermore, by eliminating immunosuppressive Tregs in one place, killer T cells can be obtained that become active throughout the body." Normal tissues in mice are not damaged because NIR-PIT triggers only T cells that are programmed to kill cancer.
Like all cancer therapies, the NIR-PIT approach has limitations. The most obvious is the inability to deliver near-infrared light to all parts of the body. Although near-infrared light penetrates tissue, it cannot penetrate deeply. One possible solution is to expose tumor tissue, such as mesothelioma, to near-infrared light during surgery. The light could also be applied to some tumors, such as lung cancer, through a thin, tube-shaped device called an endoscope, or even through ultra-thin light fibers implanted into a tumor with a special surgical instrument.
Another limitation of these studies is that the mouse mesothelioma model that researchers used in the first study, as well as the models they have used in NIR-PIT studies for other types of cancer, was created by implanting human tumor tissue under the skin of mice with a greatly suppressed immune system. This type of model "is not representative of human cancers, " the researchers wrote in Oncotarget.
However, Dr. Kobayashi said,"We found that when NIR-PIT was performed on animals with healthy immune systems, we got much better responses. Therefore, we believe that the responses will be much better in people with intact immune systems than what we saw in mice."
Phase I clinical trials currently underway with NIR-PIT may help answer that question. The trial, which is testing a conjugate of IR700 and cetuximab (Erbitux), an EGFR1 antibody, for patients with recurrent head and neck cancer, is being conducted by San Diego-based Aspyrian Therapeutics, which licenses the technology from the NCI.
NCI researchers are hopeful that the trial will provide more definitive information about the promise of this new treatment method. In the meantime, additional research is needed to better understand the mechanism by which NIR-PIT destroys tumor cells, said Dr. Choyke, a path that is currently being pursued.
