Fasting-mimicking diet benefits for cancer patients
Fasting-mimicking diet is safe and reshapes metabolism and antitumor immunity in cancer patients
Evidence for the safety and effectiveness of a special 5-day fasting mimicking diet (FMD) was recently presented in research published in the journal Cancer Discovery. FMD was shown to enhance standard anti-tumor therapies. The anti-tumor immune response and improved glucose regulation. Immune cell suppression was relieved and T cells made more active.
The 5-day fasting mimicking diet is a rigorously researched program that ‘tricks’ the body into activating its beneficial fasting biology while avoiding the harm of crucial nutrient depletion and the hardship of actual fasting.
“Cyclic FMD is well tolerated and causes remarkable systemic metabolic changes in patients with different tumor types and treated with concomitant antitumor therapies. In addition, the FMD reshapes systemic and intratumor immunity, finally activating several antitumor immune programs.
Here we report on the final results of a first-in-human clinical trial (NCT03340935) that investigated the safety, feasibility, metabolic and immunomodulatory effects of a severely calorierestricted, five-day FMD regimen in cancer patients. We also report on results of an interim analysis in which we investigated FMD-induced systemic and intratumor immune responses in 22 breast cancer (BC) patients enrolled in the ongoing DigesT trial (NCT03454282).”
FMD is safe with standard cancer therapy
Cyclic five-day FMD was followed by 16-23 days of refeeding. The duration of the FMD cycles depended on the schedule of concomitant antitumor treatment, and ranged between 21 and 28 days. Fatigue was the most common adverse effect; others, including hypoglycemia, dizziness, and feeling faint were rare.
Key metabolic parameters improve
Glucose and insulin regulation changed markedly, especially important for cancer treatment…
“In 99 evaluable patients the FMD reduced median plasma glucose concentration by 18.6% (range: [-63.1%;+67.8%]), serum insulin by 50.7% (range: [-91.3%;+697%]) and serum IGF-1 by 30.3% (range: [-72.3%;+139.8%]), while it increased average urinary ketones from 0.18 mg/dl to 59.9 mg/dl. 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).”
Immune suppressing cells reduced and cancer-killing cells activated
Immunosuppressive myeloid cells (MDSCs - myeloid derived suppressor cells) were downregulated and activated/cytotoxic cells boosted. ChT (cytotoxic chemotherapy) alone resulted in an increase of immunosuppressive CD14 cells.
“At the end of five-day FMD, we found a significant decrease of total monocytes (CD14+ ) and of two highly immunosuppressive monocyte subsets, i.e., those lacking HLA-DR expression (CD14+ HLA-DRneg ), acknowledged as monocytic myeloid-derived suppressor cells (M-MDSCs) (8,9), and CD14 + cells expressing PD-L1 (CD14+ PD-L1+ ). The FMD also reduced low-density CD15+ granulocytes, which include polymorphonuclear MDSCs (PMN-MDSCs)…Notably, CD14+HLA-DRneg, CD14+PD-L1 +and CD15 +cells were downmodulated in patients receiving the ChT-FMD combination (Fig. 2B), but not in patients treated with ChT alone, which even resulted in a boost of CD14+PD-L1 +cells.
FMD-induced reduction of myeloid cell subsets was paralleled by an increase of activated CD8 + T cells (co-expressing PD1 and CD69) and cytolytic CD3neg CD16+ CD56 dim NK cells (11), while CD3 + T cells expressing the high affinity IL-2 receptor (CD3+ CD25 + cells), which can be associated with Treg activity, were reduced.
Notably, CD8+PD1 +T cells collected after the FMD displayed remarkably increased expression of activation markers…while CD8+ PD1 + T cells not expressing the immune checkpoints LAG-3 and TIM-3 were increased, thus excluding their exhaustion…In addition, we observed an enrichment of CD3+CCR7negCD45RA negcells within CD3 +T lymphocyte , which suggests the acquisition of an effector-memory phenotype.
Together, these data indicate that the FMD, alone or in combination with standard antitumor therapies, down-regulates immunosuppressive myeloid cell subsets, while at the same time increasing effector cells with an activated phenotype. By contrast, ChT alone does not affect most of these cell subsets, and it can even boost highly immunosuppressive CD14+ PD-L1 + cells.”
FMD changes the tumor microenvironment in breast cancer
It’s very desirable to promote the polarization of immune cells to the cytotoxic Th1 lymphocyte and M1 macrophage types. The authors selected 22 consecutive BC (breast cancer) patients participating in their trial for whom enough tumor material was available before and after the FMD.
“In this patient cohort, we first confirmed that the FMD reduces blood glucose, insulin and IGF-1 concentration and increases urinary ketone bodies…Due to the biological relevance of blood IGF-1 reduction in mediating fasting/FMD-induced antitumor effects in preclinical models, we investigated if the observed reduction of blood IGF-1 concentration affects IGF-1 receptor (IGF1R) expression/activation at the tumor level…Notably, we found a significant reduction in total and phosphorylated IGF1R in post-FMD surgical tumor specimens when compared to pre-FMD tumor biopsies, thus indicating that FMD-induced growth factor changes in the blood are reflected by consistent modifications of the corresponding biological pathways at the tumor level.
To assess the impact of the FMD on intratumor immunity, we evaluated tumor-infiltrating CD8 + T cells, CD68 + macrophages and other immune cell subsets. 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…While tumorinfiltrating macrophages (CD68 +cells) were also up-regulated after the FMD , the CD8/CD68 (protein) and CD8A/CD68 (gene transcript) ratios, which were previously associated with better prognosis in cancer patients, were increased in post-FMD tumor specimens.
Notably, the FMD increased total CD8 +T cells and CD8 + T cells with T-helper 1 (Th1) polarization, along with other immune cell populations potentially implicated in antitumor immune response, such as NKT, activated dendritic cells (aDC), and central and effector memory CD4 +and CD8 +T cells (CD4 +Tcm, CD4 +Tem, CD8 +Tcm, CD8+…we detected an increase of M1-like macrophages after the FMD, while M2-like macrophages [suppressive] did not significantly change.
Together, these results indicate a switch of the functional orientation of the tumor microenvironment toward a favorable/cytotoxic Th1/M1-like phenotype.”
Cyclic FMD induces favorable genetic changes
The expression of immune-related genes that activate tumor-infiltrating immune cells and are associated with favorable clinical outcomes was increased, notably promoting the immune activating cytokine IFNγ (interferon-gamma).
“Overall, the FMD induced profound changes of intratumor transcriptional programs. 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 specimens…Consistent with these data, 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.
Together, these results show that five-day FMD is sufficiently potent to broadly reshape intratumor immunity within 7-10 days in patients with limited-stage BC, thus reducing biomarkers associated with immune suppression and promoting tumor-infiltration by activated and cytotoxic immune cell populations.”
The authors additionally noted a reduction in immunosuppressive MDSCs (myeloid-derived suppressor cells and exhausted T cells with an upregulation of central and effector T cell types.
“The FMD also profoundly affected T cells, particularly the CD8 + subset, with a remarkable upregulation of PD-1 and an enhancement of the effector phenotype…Overall, the contraction of peripheral blood myeloid suppressive compartment was associated with an enhanced intratumor T cell cytotoxicity.”
Remarkable benefit when combined with standard treatments
Though caution should be observed when considering patients who are underweight or at higher risk to become malnourished or experience progressive weight loss, the 5-day fasting mimicking diet has a high safety and tolerability profile and yields the benefits of fasting without the hardship and potential harm is highly worthy of consideration in many anticancer regimens. The authors summarize the implications of their results:
“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.
…our experimental FMD regimen reduced median blood glucose, insulin and IGF-1 concentration by 18.6%, 50.7% and 30.3%, respectively, i.e. more than 1-3 days of water-only fasting. Notably, these changes were independent of the type of primary tumor, concomitant anticancer therapy, and were consistently reproduced across subsequent FMD cycles, thus excluding the occurrence of systemic metabolic adaptation.
The most biologically novel and translationally relevant finding of this study consists in the broad immunomodulatory effects of the FMD at both systemic and tumor level. In the blood of cancer patients and healthy volunteers, the FMD reduced total monocytes and several populations of immunosuppressive cells, such as M-MDSCs, PMN-MDSCs and Tregs, while it increased cytotoxic T lymphocytes, cytolytic NK cells, and promoted a switch of CD8 + cells towards an activated/memory phenotype. These changes were paralleled by similar and desirable immunological modifications at the tumor level, where five-day fasting/FMD in BC patients increased total and activated intratumor CD8 + T cells, activated dendritic cells, NK cells and memory T cells, and it resulted in an enrichment of immune signatures previously associated with good prognosis and/or better response to therapies in cancer patients.”
Their research also demonstrated durable benefits:
“In addition, some FMD-induced systemic immunological modifications, such as the modulation of monocyte, MDSC and NK cells, are long-lasting, i.e., they are maintained at least 40 days after the end of FMD. These data indicate potential carryover immunological effects of the FMD, and suggest that in specific clinical contexts (e.g., less advanced tumors, combination with immune checkpoint inhibitors) a few FMD cycles could be sufficiently potent to stably reshape systemic immunity, thus determining the conditions for long-term synergistic antitumor effects of FMD and standard antitumor treatments."
In conclusion, cyclic FMD is a safe, feasible and inexpensive dietary intervention that modulates systemic metabolism and boosts antitumor immunity in cancer patients.”
