Call for a holistic framework for cancer immunotherapy

Abstract

Cancer immunotherapy using immune checkpoint blockers (ICBs) has revolutionized clinical oncology. In exceptional responders, checkpoint inhibition enables long-term remission and potentially a cure, even in the metastatic setting, whereas there is still a significant proportion of patients without prolonged benefit. The complexity regulating the likelihood of ICB response can at least in part be explained by baseline variables such as tumor mutational burden, 1 immune checkpoint molecule expression levels (e.g., PD-1/PD-L1) 2 and tumor T-cell infiltration. 3 Unfortunately, these factors cannot be deliberately modulated therapeutically and therefore play only a minor role when envisioning treatment-enhancing strategies. Alternatively, emerging variables may easily be amenable to manipulation to optimize ICB response rates and durability. In this regard, nonpharmacological approaches such as specific health interventions and treatment timing have recently gained momentum, proposing a more holistic framework for cancer immunotherapy and management within an interdisciplinary, cross-functional environment.Because diet influences the host microbiome, 4 which in turn affects ICB efficacy, 5,6 targeted dietary interventions represent a promising strategy to specifically modulate the microbial landscape and optimize cancer immunotherapy. 7 This concept is underscored by recent work in melanoma demonstrating an association of high fiber intake (i.e., ≥20 g/d) with improved progression-free survival under ICB therapy. 8 Mechanistically, a high-fiber diet promotes tumor T-cell infiltration as well as the expression of genes related to T-cell activation and effector function in murine models. 8 The concept of modulating ICB efficacy by dietary habits is further supported by prospective data from 101 patients with cancer on a fasting-mimicking diet (FMD) (NCT03340935). 9 The cyclic, 5-day dietary intervention was not only safe but also induced distinct metabolic changes and extensively reshaped the cancer immunome. 9 More specifically, FMD reduced blood glucose, insulin, and IGF1 levels, contracted circulating suppressive myeloid-and T-cell compartments, and enhanced intratumoral T-cell activation and cytotoxicity. 9 Notably, many of these effects were independent from the underlying tumor type and the particular cancer therapy used. This suggests that ICB-treated patients may also benefit from fasting/FMD. Importantly, because many cancer patients are cachectic or otherwise weak, the immune-modulatory and metabolic effects of fasting/FMD may, in the future, be more appropriately modeled by calorie restriction mimetics. 10 In fit or only mildly impaired patients, physical activity, generally known to reduce cancer risk and cancer-specific morbidity and mortality, 11 may promote anticancer immunity and potentiate ICB efficacy. In preclinical models, aerobic exercise fosters systemic immune mobilization and induces the accumulation of activated, tumor-infiltrating T cells expressing IL-15Rα, finally leading to tumor growth ret...

Non-pharmaceutical interventions to optimize cancer immunotherapy

“…Therefore, prospective clinical trials of NPIs as a catalyst for ICB efficacy and QoL are warranted and may constitute the next generation of cancer immunotherapies optimized and conducted within a patient-centric, holistic framework engaging also social networks. 4 …”

“…Recently, we advocated a holistic approach to cancer immunotherapy, also embarking on lifestyle- and biorhythm-related factors to support treatment efficacy. 4 We made this proposition based on data showing that the efficacy of ICB is mechanistically linked to various factors, including diet/microbiome, physical activity, stress, and circadian rhythmicity. In contrast to drug development and the establishment of new ICB combinations, tackling these factors often requires nothing more than behavior change on patient side (which may, however, not be easily achievable especially when the social system around the target person is unsupportive).…”

“…Shared decision-making and management within multidisciplinary, inter-professional teams including psychological expertise, 4 , 172–174 will be essential for tackling healthification in the setting of ICB. Next to CCCs, patient organizations such as cancer societies and peer support groups could strongly promote healthification in cancer patients.…”