A clinical trial in cancer patients has demonstrated that a diet involving cycles of short-term, severe calorie restriction—referred to as a fasting-mimicking diet (FMD)—can be safe, feasible, and may boost the antitumor activity of standard anticancer therapies. The trial, reported in Cancer Discovery, found that cyclic fasting resulted in a decrease in blood glucose and growth factor concentrations, reduced peripheral blood immunosuppressive cells, and enhanced intratumor T-cell infiltration, in cancer patients receiving standard-of-care therapy.
“Our results from a first-in-human clinical trial showed that a scheme of severe short-term calorie restriction was safe and biologically active in patients, and that its activity likely involved the activation of immune responses,” said Claudio Vernieri, MD, PhD, a medical oncologist at Fondazione IRCCS Istituto Nazionale dei Tumori and the director of the Metabolic Reprogramming in Solid Tumors program at IFOM (the FIRC Institute of Molecular Oncology). “Since calorie restriction is a safe, inexpensive, and potentially effective approach that could be easily combined with standard antineoplastic therapies, we think these findings might have relevant implications for cancer therapy.”
Vernieri and colleagues reported on the study in a paper titled, “Fasting-mimicking diet is safe and reshapes metabolism and antitumor immunity in cancer patients,” in which they concluded, “Cyclic FMD is well tolerated and causes remarkable systemic metabolic changes in patients with different tumor types and treated with concomitant antitumor therapies … the FMD reshapes systemic and intratumor immunity, finally activating several antitumor immune programs.”
Co-corresponding authors on the study are first author Vernieri, together with Filippo de Braud, MD, director of the oncology and hematology department of Fondazione IRCCS Istituto Nazionale dei Tumori and professor of medical oncology at the University of Milan; and Licia Rivoltini, MD, head of the Immunotherapy of Human Tumors Unit at Fondazione IRCCS Istituto Nazionale dei Tumori.
Preclinical research has shown that severe calorie restriction in the form of cyclic fasting or a fasting-mimicking diet has potent anticancer effects when combined with standard drug-based anticancer therapy, the authors wrote. “In tumor-bearing mice, cyclic fasting or calorie-restricted, low-carbohydrate, low-protein diets, collectively referred to as FMDs, have convincingly demonstrated additive or synergistic antitumor activity in combination with cytotoxic chemotherapy (ChT), immunotherapy or endocrine therapies.” But despite this preclinical evidence, the investigators continued, the safety and biological effects of calorie restriction in cancer patients haven’t been well investigated so far.
Vernieri and colleagues carried out a first-in-human study to investigate the safety, feasibility, metabolic, and immunomodulatory effects of a severely calorie-restricted, five-day FMD regimen in cancer patients. The trial enrolled 101 patients with various tumor types, who were also treated with different standard anticancer therapies.
The study participants were administered with a five-day, low-carbohydrate, low-protein, plant-derived diet, which provided up to 600 Kcal on day 1, and up to 300 Kcal on days 2, 3, 4, and 5, for a total amount of up to 1,800 Kcal in five days. The cycle was repeated every three or four weeks for up to a maximum of eight consecutive cycles. Calorie restriction was followed by a refeeding period of 16 to 23 days, during which patients were not subjected to any specific dietary restrictions, but were recommended to adhere to international guidelines for a healthy diet and lifestyle.
The investigators evaluated the effects of the FMD on patient metabolism, and immune responses in their peripheral blood. To investigate the effects of the FMD diet on intratumor immunity, Vernieri and colleagues separately carried out an interim analysis of patients enrolled in another trial (DigesT), which is testing a five-day FMD cycle seven to 10 days before surgery in early-stage breast cancer (BC) and melanoma patients. Specifically, they evaluated tumor-infiltrating immune cells and transcriptomic immune profiles in 22 breast cancer patients for whom enough tumor tissue had been collected before and after the FMD.
The authors’ reported trial achieved an overall compliance rate of 91.8% when considering all FMD cycles, and met its primary safety endpoint. The incidence of severe FMD-related adverse events was 12.9%, with the most common being fatigue, which was rarely severe. These results demonstrated that short-term severe calorie restriction was safe, feasible, and well tolerated by the majority of patients, regardless of the tumor type and the type of antitumor therapies they were also receiving.
Importantly, the loss of body weight that occurred during the five days of severe calorie restriction was reversible in most of the patients during the refeeding period. Commenting on the reversibility of FMD-related body weight loss, De Braud said, “This is an especially important finding because it excludes the risk that patients might undergo progressive weight loss and/or malnourishment, which are associated with reduced efficacy of anticancer therapies and reduced survival.”
The investigators’ analysis of 99 evaluable patients showed that the FMD regimen reduced median plasma glucose concentration by 18.6%, serum insulin by 50.7%, and serum IGF-1 by 30.3%. These changes remained stable over the course of eight consecutive cycles. “Of note, FMD-induced metabolic changes were independent of the type of primary tumor (BC, colorectal cancer, lung cancer, others), concomitant anticancer treatments (ChT, other therapies), and tumor stage (limited, advanced),” they wrote. “Similar metabolic modifications occurred in nine healthy volunteers undergoing the same five-day FMD regimen.”
Importantly an analysis of 38 patients at the end of a five-day FMD cycle showed a significant decrease of circulating immunosuppressive myeloid subpopulations and an increase of activated CD8+ T cells. Both of these effects occurred independently of concomitant antitumor therapies, and were also seen in a small group of healthy volunteers. “Interestingly, the observed modifications in myeloid sub-populations were similar in patients undergoing the FMD in combination with ChT or with other standard antitumor therapies,” the investigators further commented.
The interim analysis of the DigesT trial also revealed a significant increase in tumor-infiltrating CD8+ T cells, among other changes, indicating a functional switch toward an antitumor immune microenvironment following FMD. “IHC analysis revealed a statistically significant increment of tumor-infiltrating CD8+ T cells in post-FMD surgical tumor samples when compared to pre-FMD tumor biopsies,” the team commented.
To investigate the functional relevance of FMD-induced changes in tumor-infiltrating immune cell populations, the team also used RNA-seq technology to evaluate any modulation of immune transcriptomic signatures that have prognostic relevance, or are associated with the functional status of tumor-infiltrating immune cells. “Overall, the FMD induced profound changes of intratumor transcriptional programs,” they wrote. “Single gene level analysis revealed a dramatic increase in the expression of several immune-related genes … Notably, the interferon gamma (IFNγ) activating signature (IFNG.GS), which is selectively activated in tumor-infiltrating immune cells and is associated with favorable clinical outcomes, was enriched in post-FMD tumor samples …”.
Further analysis showed that the FMD induced an enrichment of 13 immune-related gene expression signatures (including IFNG.GS) previously associated with favorable prognosis in cancer patients, including BC patients.” The authors pointed out that desirable immunomodulatory effects induced by the experimental dietary regimen were observed both at the systemic and at the tumor level, indicating a coherent immune response that originates in the blood and then propagates to the tumor.
The main limitation of the study was that it did not allow the researchers to draw conclusions on the antitumor efficacy of calorie restriction because it enrolled a heterogeneous cohort of patients with different tumor types and different concomitant anticancer therapies. This precluded a complete assessment of the therapeutic impact of calorie restriction in patients.
Nevertheless, as Rivoltini stated, “Severe calorie restriction generated a metabolic ‘shock’ that activated several populations of immune cells that could boost the antitumor activity of standard antineoplastic treatments.” The authors concluded, “We have shown that a severely calorie-restricted, low-carbohydrate, low-protein, five-day dietary regimen that mimics fasting is safe and feasible when repeated every 21–28 days in combination with standard antitumor treatments, and it reshapes systemic metabolism and antitumor immunity in cancer patients.”
The authors have recently initiated new clinical trials, including the BREAKFAST trial, to investigate the antitumor effects of the FMD approach in cancer patients. These studies should further help scientists understand if the metabolic and immunological effects induced by calorie restriction have clinically relevant consequences improving the efficacy of antineoplastic therapies and prolonging the life expectancy of cancer patients.