Immunotherapy drugs are revolutionizing the treatment of many cancer types, but not all patients treated with these new drugs respond. To enhance the efficacy of immunotherapy, researchers at The University of Texas MD Anderson Cancer Center are exploiting a rare phenomenon of radiation therapy in clinical trials for patients with lung cancer and other solid malignancies.
“Radiation has been used for a hundred years to do one thing: achieve local control,” said James Welsh, M.D., an associate professor in the Department of Radiation Oncology. “We are now combining it with immunotherapy for systemic control, and that’s pretty exciting.”
Alone, drugs that inhibit immune checkpoints—CTLA-4 (cytotoxic T lymphocyte antigen 4), PD-1 (programmed cell death protein 1), or PD-L1 (the PD-1 ligand)—can elicit impressive responses in some cancer patients, even in those with metastatic disease. However, immunotherapy eliminates distant disease in perhaps only 20% of patients with metastatic cancer; Dr. Welsh hopes to use radiation to push that rate to 30% or even 40%.
At first glance, the logic of combining radiation therapy with immunotherapy to fight cancer seems obvious. Radiation, which kills cancer cells by damaging their DNA, is given locally; immunotherapy is given to ramp up the immune system to attack the disease systemically. But this is only a partial explanation of how the combination might assault the disease. Rather than one treatment providing just local disease control and the other providing just systemic control, the therapies may work synergistically. One area of synergy is that radiation can stimulate immunogenic cell death and sensitize cancer cells to immunotherapy by promoting the expression of major histocompatibility complex (MHC) class I molecules and other apoptosis-mediating proteins.
“We developed a model of resistance to PD-1 inhibition in my lab. Tumor cells lose the expression of MHC class I molecules, which present antigens to cytotoxic T cells,” Dr. Welsh said. “Radiation can make tumor cells express those molecules and respond to immunotherapy. We’ve shown that in mice and a few humans so far.”
In addition to sensitizing irradiated tumor cells to immunotherapy, radiation can cause the cells to release tumor antigens that prime T cells to attack other tumor cells in the body, including those at distant, non-irradiated sites.
“Effectively, radiation can turn the tumor into a vaccine,” Dr. Welsh said.
This phenomenon of radiation shrinking the tumor locally while inducing an immune response systemically is known as the abscopal effect. The addition of immunotherapy, the thinking goes, helps maintain the effect by preventing T cell activation from becoming downregulated by CTLA-4 or PD-1/PD-L1.
The key to exploiting the abscopal effect to kill tumor cells systemically with radiation, Dr. Welsh said, is fractionation. Conventionally fractionated radiation therapy, in which the radiation dose is given in many small fractions over 6 or 7 weeks, doesn’t work well with immunotherapy because the long-term, almost constant delivery of radiation exhausts the T cells that, given the chance, would go on to attack non-irradiated tumors. Hypofractionated radiation therapy, in which the radiation dose is given in a few large doses over just a week or two, gives those T cells that chance and may prove to have advantages when combined with immunotherapy.
“We need to hit the tumor and then get out of the way,” Dr. Welsh said. “We need to disrupt the tumor with radiation to turn it into a vaccine, and then we need to stop treating it and let the T cells come in and do their work.
“What we’ve previously done for patients with multiple sites of metastatic disease is to hit one site with radiation to try to turn it into a vaccine and then see if the other sites respond,” Dr. Welsh continued. “But now, we’re hitting four or five disease sites with radiation to make the tumor a better vaccine, so to speak, and combining radiation with immunotherapy.”
Immunotherapy is also being added to radiation to help improve local control in patients with stage I disease. “If you can’t get the radiation dose high enough to eradicate the tumor, adding immunotherapy can help with local control,” Dr. Welsh said. “So we’re using the combination for almost all stages of cancer, because almost every patient could benefit from either better local or better distant control.”
Dr. Welsh is heading up several clinical trials to investigate the potential use of the immunotherapy–radiation therapy combination across the cancer spectrum, with a focus on metastatic disease. Enthusiasm for the studies has been strong. The first such trial—a large one looking at the CTLA-4 inhibitor ipilimumab plus radiation in patients with any cancer type who have metastatic or primary lesions in the lungs or liver—has accrued almost all of its nearly 100 planned participants.
In that trial (No. 2013-0882), Dr. Welsh said, “We’ve definitely had some interesting cases where it seems that radiation has really added a benefit.”
One case was particularly striking. One of the early patients enrolled in the trial had anaplastic thyroid cancer, a highly aggressive disease associated with a median survival time of only about 2 months. “The patient had about five metastases in the lung; I treated one with radiation, and all the others just went away for a year,” Dr. Welsh said. “That’s remarkable; it’s something we’ve never seen in anaplastic thyroid cancer. Now there are several trials looking into the combination of immunotherapy and radiation therapy for anaplastic thyroid cancer.”
Although initial results of Dr. Welsh’s study have been promising, some questions remain.
“We can’t yet prove that the radiation caused or helped cause the responses we’ve seen. The patients were receiving both the immunotherapy drug and the radiation, and their disease might have responded to the drug alone,” Dr. Welsh said. “In some of our newer studies, we’re randomly selecting patients to receive either immunotherapy alone or immunotherapy plus radiation to see if we can prove the value of adding radiation.”
For example, the phase II portion of an ongoing trial of the PD-1 inhibitor pembrolizumab plus conventional wide-field or stereotactic radiation therapy for patients with non–small cell lung cancer (No. 2014-1020) includes two treatment arms in which patients receive concurrent pembrolizumab and radiation (conventional in one treatment arm and stereotactic in the other) and two in which patients receive only pembrolizumab for 5 weeks; conventional or stereotactic radiation therapy, depending on the treatment arm, is added for patients whose disease progresses. The 3-month progression-free survival rates of the patients treated with pembrolizumab alone will be compared with those of patients in the concurrent radiation arms.
Other ongoing or upcoming trials of immunotherapy combined with radiation therapy at MD Anderson include a trial in which patients with small cell lung cancer will receive immunotherapy plus standard-of-care chemoradiation (No. 2014-1003); a trial in which patients receiving any immunotherapy drug whose disease is progressing will receive salvage radiation therapy while continuing maintenance doses of their immunotherapy drug if appropriate (No. 2015-0936); and a trial in which patients with brain metastases will receive immunotherapy plus stereotactic radiation to the brain. Studies of immunotherapy combined with radiation therapy in patients with prostate, breast, head and neck, and other cancers also are being planned or are underway.
Increasing interest in cancer immunotherapy has led to a flood of new immunotherapeutic agents. Identifying which agents work well with radiation therapy—and which don’t—and determining how to best sequence combinations of the agents with radiation therapy to elicit an optimal tumor-destroying immune response will be research focuses moving forward.
“We want to make the synergy between immunotherapy and radiation therapy reproducible, so it doesn’t just happen once in a while; and we want to make sure we can do this in a safe manner,” Dr. Welsh said. “We think future studies will help us refine our technique and find the optimal sequencing, doses, and combination of agents.”
Tang C, Wang X, Soh H, et al. Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res. 2014;2:831–838.
Schoenhals JE, Seyedin SN, Tang C, et al. Preclinical rationale and clinical considerations for radiotherapy plus immunotherapy: going beyond local control. Cancer J. 2016;22:130–137.
For more information, contact Dr. James Welsh at email@example.com.
OncoLog, January 2017, Volume 62, Issue 1