Timing of radiation plus immunotherapy could be key to antitumor response in kidney cancer

Reuters Health – 15/09/2020 – Appropriate timing of radiation and immunotherapy likely will improve the antitumor response in kidney cancer, a high-throughput analysis suggests.

“We are still learning how radiation… alters existing patient immune responses,” Dr. Jason Muhitch of Roswell Park Comprehensive Cancer Center in Buffalo, New York told Reuters Health by email. “We are also finding that the factors that influence patient responses to treatment can be specific for tumor types. Therefore, additional work is needed to show if the endpoints utilized in our study are reliable indicators for the specific forms of immunotherapy used in kidney cancer.”

As reported in Proceedings of the National Academy of Sciences of the United States of America (PNAS), Dr. Muhitch and colleagues analyzed kidney cancer cell samples from patients treated with stereotactic body radiation therapy (SBRT).

Pathway analysis showed that SBRT is an effective immune-sensitizing agent in kidney cancer, and T cell receptor sequencing revealed increased clonality (expansion) in the radiation-treated tumors.

Longitudinal tracking of the expanded clonotypes showed an increased abundance of these cells at two weeks post-radiation compared with pretreatment levels; however, the expansion was not sustained, and levels contracted toward baseline by four weeks.

“Taken together,” the authors state, “these results indicate robust intratumoral immune remodeling and a window of tumor-resident T cell expansion following radiation that may be leveraged for the rational design of combinatorial strategies.”

Dr. Muhitch said, “Our effort was the first to utilize patient tumors to study the effects of radiation on the T cell repertoire over time…We are eager to investigate how radiation impacts other malignancies using a similar approach, but it may take some time before we have access to sufficient numbers and types of patient tumor samples.”

“A major question in the field is which dosing regimen should be used to promote immune responses,” he added. “There is evidence from preclinical studies that the selected dose can have a considerable impact on tumor growth control when used with immunotherapy. The optimal dose can also vary between tumor models. Depending on the desired effect, it is likely that dosing will be specific for a particular tissue as well.”

Dr. Scott Gerber, Co-Director, Center for Tumor Immunology Research at the University of Rochester Medical School in New York, commented in an email to Reuters Health, “This work further supports the concept that radiotherapy can stimulate a potential antitumor immune response.”

“A key finding is that antitumor T cells may be stimulated early, but this stimulation is not sustained,” he said. “This could have important implications clinically; especially as combinatorial approaches have gained traction as a means for treating cancer. The data presented here suggest there may be an optimal window where additional therapies, such as immunotherapies, could be combined with radiotherapy to bolster and sustain the antitumor response.”

“It would be intriguing to know whether this is a true ‘contraction’ of these T cells or whether they have migrated out of the blood stream into another compartment such as the spleen, lymph nodes, or liver,” he added.

“The intricate design of the current study sheds light on the kinetics of the antitumor immune response following radiotherapy and suggests that analyzing only one time point could be misleading,” he said. “Furthermore, it suggests that more longitudinal studies examining multiple timepoints are warranted. Future work correlating these findings with patient outcome will help elucidate the clinical ramifications of these results.”

By Marilynn Larkin

SOURCE: https://bit.ly/33xQKtS Proceedings of the National Academy of Sciences of the United States of America (PNAS), online September 8, 2020.