A severe calorie-restriction regimen, known as the “fasting-mimicking” diet (FMD), is safe, tolerated by cancer patients, and leads to positive changes in metabolism and the immune system that could prove to be key in anticancer therapies, Italian researchers report.
Studies of tumor-bearing mice have shown that FMDs “enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity,” write Claudio Vernieri, MD, PhD, a medical oncologist at the National Cancer Institute of Milan and director of the metabolic reprogramming in solid tumors program at the FIRC Institute of Molecular Oncology, and his colleagues.
To evaluate the effects of similar dietary regimens in humans, they studied 101 patients being treated for different types of cancer who were asked to follow an FMD regimen in which 1800 kilocalories were consumed in 5 days (600 on the first day and up to 300 in the subsequent 4 days). “The cycle was repeated every 3 to 4 weeks. Between cycles, patients were not subjected to specific dietary restrictions but were recommended to adhere to international guidelines for a healthy diet and lifestyle,” Vernieri and his colleagues explain in their report.
In contrast to previous studies, almost all patients were able to follow the dietary regimen; the compliance rate was 91.8% over all FMD cycles. “In addition, the FMD regimen was able to modify both systemic and intra-tumor metabolism and immune response,” the researchers write.
From the perspective of metabolism response, the FMD regimen reduced median plasma glucose concentrations by 18.6%, serum insulin levels by 50.7%, and serum IGF-1 levels by 30.3%, and these modifications remained stable over several cycles.
The data on loss of body weight, which could present a problem for these patients, was also reassuring: weight loss was reversible during the healthy-eating periods between FMD cycles.
However, the greatest news from a biologic perspective and the most relevant news from a translational perspective was that the FMD regimen had a broad immunomodulation effect. “Our results provide the first actual evidence that this regimen produces systemic immunomodulatory effects in humans associated with the activation of numerous anti-cancer programs at the tumor level,” the team writes.
“With a view to achieving the desired biological effects, whether metabolic or immune, it is critical to define the optimal duration of cyclic fasting or FMD regimens. This is ultimately still an ongoing discussion,” they conclude.
“Severe calorie restriction generated a metabolic shock that activated several populations of immune cells that could boost the antitumor activity of standard antineoplastic treatments,” according to Licia Rivoltini, MD, head of the immunotherapy of human tumors unit at the National Cancer Institute in Milan, who was on the research team.
To investigate the effects of the FMD diet on intra-tumor immunity, the researchers performed an interim analysis of the ongoing DIgesT trial, testing a 5-day FMD cycle 7 to 10 days before surgery in patients with early-stage breast cancer or melanoma. Specifically, they evaluated tumor-infiltrating immune cells and transcriptomic immune profiles in 22 breast cancer patients from whom enough tumor tissue was collected before and after the calorie-restriction period.
The analysis revealed a significant increase in tumor-infiltrating CD8+ T-cells and indicated a functional switch toward an antitumor immune microenvironment after an FMD cycle. The desirable immunomodulatory effects induced by the dietary regimen were observed both at the systemic and the tumor level, indicating a systemic immune response.
Could it be already feasible, then, to start moving toward the clinical use of this strategy? Not quite, as the main limitation of this study is that it did not allow the researchers to draw conclusions about the antitumor effect of calorie restriction. Because study participants were a heterogeneous group of patients with different tumor types and different anticancer therapies, a proper assessment of the therapeutic impact of calorie restriction in patients was not possible. As a result, the researchers have recently initiated new clinical trials, including the BREAKFAST trial, which will be the next step in understanding whether the metabolic and immunologic effects induced by calorie restriction have clinically relevant consequences.
This study was funded by the Italian National Cancer Institute, the Italian Foundation for Cancer Research (AIRC), and the Horizon 2020 European Union Framework Program. Vernieri, Rivoltini, and their colleague Filippo de Braud, MD, director of the Oncology and Hematology Department at the National Cancer Institute of Milan and professor of medical oncology at the University of Milan , were inventors of the FMD regimen used in this study (patent pending).
Cancer Discov. Published online November 17, 2021. Abstract
This article originally appeared in the Italian edition of Medscape.
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