Combining Immunotherapy and Radiotherapy Shows Good SynergyImmunotherapy, Web Exclusives
As the number of patients receiving immune checkpoint blockade grows, the combination of radiation and immunotherapy has become increasingly relevant, particularly in the palliative care setting, where radiation therapy is used to treat painful lesions or brain metastases.
At the 2017 Palliative and Supportive Care in Oncology Symposium, Jonathan D. Schoenfeld, MD, MPhil, MPH, Director, Melanoma Radiation Oncology, Dana-Farber and Brigham and Women’s Cancer Center, Boston, MA, presented preclinical data that show promise for radiotherapy plus immunotherapy combinations. He discussed adverse reactions associated with both treatments and ongoing clinical trials evaluating numerous combination therapies.
Radiation’s Contribution to the Immune Response
Evidence that the immune system contributes to local effects of radiotherapy dates back to the 1970s, when it was demonstrated that radiation was not very effective in immunosuppressed models.
Driven by a deeper understanding of antitumor immune response, more recent studies have shown that radiation is not very effective locally in melanoma models with depleted CD8-positive T-cells. However, targeted radiation can also result in immunogenic cell death, leading researchers to hypothesize that radiation may help contribute to a systemic antitumor immune response, reported Dr Schoenfeld.
Researchers have observed synergy between radiation and immunotherapy in preclinical models, specifically in combination with PD-1 pathway inhibitors. Furthermore, this synergy occurs across multiple cancer types, including breast, colorectal, melanoma, and pancreatic cancers, said Dr Schoenfeld.
“There’s a local benefit and potential systemic benefit where radiation is helping immunotherapy, protecting mice from rechallenge, and, in some cases, resulting in this abscopal or out-of-field effect, and these data go beyond PD-1 pathway inhibitors,” he explained.
“The hope is that under normal circumstances, if you have a tumor that’s not recognized by the immune system, you can cause immunological cell death through ionizing radiation and get tumor antigen release in a stimulatory environment that can then stimulate a broad antitumor immune response,” he said.
Radiation and Immune Checkpoint Inhibitors
Although many patients receiving immune checkpoint blockade could potentially benefit from palliative radiation at some point in their care, whether for painful lesions, brain metastases, or oligoprogression, the concern is that radiation and immune checkpoint blockade have overlapping toxicities, especially with radiation fields that include the lung or bowel, explained Dr Schoenfeld.
However, data from more than 130 patients at the Palliative Care Radiation Service at Brigham and Women’s Hospital who received palliative radiation as standard of care and immune checkpoint blockade suggest that the combination is generally well-tolerated. More than 40% of these patients received radiation within 14 days of receiving immune checkpoint blockade.
“Oncologists have become more comfortable giving radiation therapy concurrent with checkpoint blockade,” said Dr Schoenfeld.
Although researchers observed a nonsignificant increase in the incidence of pneumonitis in patients who received radiation to the lung, no other association between the site, dose, and timing of radiation was found, and the overall rates of adverse events were similar to historical data. More prospective data are needed, and clinicians should monitor for associations with rare, but potentially severe, adverse reactions (eg, myocarditis), delayed side effects (eg, pneumonitis), and enhanced radiation effects (eg, radionecrosis), Dr Schoenfeld emphasized.
Immunotherapy After Radiation
Recent data also suggest that immunotherapy may be particularly effective after radiation. A subset analysis of the KEYNOTE-001 clinical trial that assessed patients with non–small-cell lung cancer who received pembrolizumab (Keytruda) showed that those who had previously received radiation fared better than those who had never received radiation before starting immune checkpoint blockade with pembrolizumab.
In addition, analysis of patients at Brigham and Women’s Hospital who received radiation before immunotherapy showed that more than 40% were able to continue using checkpoint blockade for a median of 179 days following palliative radiation.
“As a result of preclinical and clinical data, there are an increasing number of prospective trials studying this combination of therapies,” said Dr Schoenfeld, adding that there are at least 80 ongoing trials of such combinations of immunotherapy with radiation.
“These trials are testing the addition of immunotherapy to radiation standard of care approach, the addition of radiation to immunotherapy standard of care, or exploring synergy observed in preclinical models,” Dr Schoenfeld concluded.
There are 4 isoforms of phosphatidylinositol 3-kinase (PI3K) with distinct functions and expression patterns; among those 4 isoforms, PI3K-alpha and PI3K-beta are ubiquitously expressed and involved in a range of cellular functions.1 Both PI3K-gamma and PI3K-delta are expressed predominantly in normal and malignant hematopoietic cells within the bone marrow.1 PI3K-Delta [ Read More ]
In the cell nucleus, DNA is maintained in a tightly coiled state around proteins called histones.1 During the process of DNA replication for cell division or during the synthesis of RNA and proteins, histone acetyltransferase adds acetyl groups onto the histones, enabling DNA to uncoil.1 By contrast, histone deacetylases (HDACs) [ Read More ]