Targeting Glucose Metabolism to Enhance Immunotherapy: Emerging Evidence on Intermittent Fasting and Calorie Restriction Mimetics

Question
Does evidence currently support the use of metabolic therapies (including caloric restriction, intermittent fasting, and a ketogenic diet) as an adjuvant treatment to improve the effectiveness of immunotherapy?
Takeaway
Currently, preliminary evidence from in vitro and animal trials suggests metabolic therapies may increase the effectiveness of existing cancer therapies including immunotherapy, chemotherapy and radiotherapy by slowing tumor growth and increasing tumor vulnerability. There is little human trial data at present, which indicates efforts to enhance the effectiveness of cancer therapies by exploiting cancer metabolism remain preliminary but promising.

This 2019 article summarizes research that indicates various metabolic therapies may improve clinical outcomes in cancer patients treated with immunotherapy.

Immunotherapeutics, particularly immune checkpoint blockade (ICB) therapies, have recently become an approved treatment option for patients with certain advanced cancers. Currently, fewer than half of patients receiving ICB experience objective, durable responses (1), which has led to a search for combinatorial therapies that increase the effectiveness of immunotherapy and/or the durability of remission. As previously explored on CrossFit.com, glucose-limiting therapies — a category that includes caloric restriction, intermittent fasting, and the ketogenic diet — are thought to slow cancer growth and increase the vulnerability of cancer cells to treatment by depriving highly glycolytic cancer cells of a necessary fuel source. Recent research has indicated this occurs without compromising tumor-infiltrating T-cells and so may be applicable to immunotherapy. The authors of this paper review the data supporting the use of each of the above glucose-limiting therapies in cancer patients.

Calorie-restriction (CR) — that is, chronically restricting calories by 10-20% — consistently reduces cancer incidence and progression in animal models (2). Researchers have suggested this may be due to the effects of CR on plasma glucose and insulin levels, IGF-1 signaling, or activity through the PI3K/Akt/mTOR pathways (3). Preclinical data suggests energy-deprived (i.e., calorically restricted) tumor cells downregulate antiapoptotic pathways, which increases their vulnerability to radiotherapy and chemotherapy. As yet, this therapy has not been tested in humans, and the fact that CR may lead to weight loss and exacerbate cachexia is cause for concern.

Intermittent fasting (IF) produces similar reductions in plasma glucose, IGF-1, and related signaling pathways to caloric restriction but with reduced risk of weight and/or muscle loss. IF therefore may be a more tolerable and effective therapy in cancer patients (4). Animal research suggests IF reduces tumor proliferation rates and cancer treatment outcomes (5), with these effects potentially moderated specifically by glucose suppression. There is no human data on whether IF improves clinical outcomes in cancer patients alongside standard-of-care treatments, though two ongoing trials are testing whether IF improves response to chemotherapy (6).

The potential impact of the ketogenic diet on cancer has been explored on CrossFit.com. Preclinical evidence suggests the ketogenic diet may improve the effectiveness of radiotherapy and/or chemotherapy through mechanisms related to either the suppression of glycolytic pathways or the direct effect of elevated ketone levels (7). A recent review argued these therapies are promising (8), but as with the other therapies, there is no human trial data demonstrating a clear impact on improving cancer outcomes.

Overall, the lack of human trial data means there is not currently evidence to support the direct claim that metabolic therapies can improve cancer outcomes. Despite this, a variety of animal and in vitro models suggest this hypothesis remains promising and deserves further investigation.

Notes

1. Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape; Cancer immunotherapy using checkpoint blockade
2. Selectively starving cancer cells through dietary manipulation: Methods and clinical implications; Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: A systematic review and meta-analysis; Effect of intermittent versus chronic calorie restriction on tumor incidence: A systematic review and meta-analysis of animal studies
3. Caloric restriction — a promising anti-cancer approach: From molecular mechanisms to clinical trials; Calorie restriction and cancer prevention: Metabolic and molecular mechanisms; Dietary and pharmacological modification of the insulin/IGF-1 system: Exploiting the full repertoire against cancer; Effects of intermittent and chronic calorie restriction on mTOR and IGF-1 signaling pathways in mammary fat pad tissues and mammary tumors; The role of the insulin/IGF system in cancer: Lessons learned from clinical trials and the energy balance-cancer link; Insulin-like growth factor 1 signaling is essential for mitochondrial biogenesis and mitophagy in cancer cells
4. Reduced levels of IGF-1 mediate differential production of normal and cancer cells in response to fasting and improve chemotherapeutic index
5. Dose effects of modified alternate-day fasting regimens on in vivo cell proliferation and plasma insulin-like growth factor-1 in mice; Alternate-day fasting reduces global cell proliferation rates independently of dietary fat content in mice; A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance and healthspan; Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer and cardiovascular disease; Metabolic effects of intermittent fasting; Caloric restriction mimetics enhance anticancer immunosurveillance; Fasting-mimicking diet reduces Ho-1 to promote T-cell mediated tumor cytotoxicity
6. Fasting-mimicking diet with chemo-immunotherapy in non-small cell lung cancer (NSCLC); Intermittent fasting accompanying chemotherapy and gynecological cancers (FIT2)
7. Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts; Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet; Ketogenic diet in cancer therapy; Anti-tumor effects of ketogenic diets in mice: A meta-analysis; Inhibition of neuroblastoma tumor growth by ketogenic diet and/or calorie restriction in a CD1-Nu mouse model
8. The emerging role of ketogenic diets in cancer treatment