Vagal nerve stimulation in cancer: latest data for a potential new treatment approach
Latest advancements in cancer therapies
Cancer's insidious onset and potentially devastating outcomes have made it one of the most feared diseases of the 21st century. Despite major advances in early diagnosis and treatment for many of around 200 tumor histotypes identified, cancers are still a major contributor to disease burden worldwide, second only to cardiovascular diseases, and projections forecast that global cancer burden will continue to grow for at least the next 2 decades (GBD 2019).
According to the simplest definition, cancer is a group of diseases characterised by uncontrolled growth and spread of abnormal cells (American Cancer society).
The first line of defence against tumors is constituted by our innate immune system which routinely recognizes and kills atypical cells.
Tumor cells can however escape the immune system via numerous mechanisms and ultimately the installation of an immunosuppressive tumor microenvironment (TME) constituted by immune cells, stromal cells, blood vessels, and extracellular matrix which supports cancer cell survival, local invasion and metastatic dissemination.
While much of the research in cancer pathogenesis has focused on the genetic basis of cancer cells, there is now increasing interest in common characteristics of the TME and, parallelly, on new avenues for treatments that target the TME as opposed to the neoplastic cells.
Unlike traditional cancer treatments, such as radiotherapy and chemotherapy, which directly target cancer cells through exogenous agents, immunotherapies dynamically modulate the endogenous immune system to attack cancer cells.
This strategy, centered on removing the breaks of the immune system to attack tumor cells, has proved to be so promising that “cancer immunotherapy” was named in 2013 “Breakthrough of the Year” by Science and resulted in James P. Allison and Tasuku Honjo’s winning of the 2018 Nobel Prize of Physiology or Medicine.
Next to immunotherapy, there is increasing evidence that approaches directed toward the sympathetic and parasympathetic system may provide a novel therapy to inhibit cancer progression.
The autonomous nervous system and tumorigenesis
Although the function of the autonomic nervous system (ANS) in mediating the “flight-or-fight” response was recognized decades ago, the crucial role of peripheral innervation in regulating cell behavior and response to the microenvironment has only recently emerged.
New data suggest that cancer progression can be influenced by local ANS innervation directly, as a means for tumor cells migration, and indirectly, through actions on the immune, endothelial and stromal cells of the TME that express receptors for some neurotransmitters.
Preclinical studies have consistently indicated that sympathetic nerves increase the progression of any cancer type investigated, while parasympathetic nerves may exert different effects on cancer progression– i.e. increase tumor progression by M1 receptor stimulation in prostate cancer and M3 receptor stimulation in gastric and colorectal cancers, while suppress cancer progression by M1 receptor stimulation in breast and pancreatic cancers.
It is well established that the vagus nerve, the longest cranial nerve with the largest territory of innervation in the human body, exerts a crucial homeostatic role through inhibition of oxidative stress, inflammation and sympathetic activity, and its index, heart rate variability (HRV), has prognostic roles in various chronic conditions.
Epidemiological studies showed that high vagal activity, indexed by heart rate variability (HRV), predicts longer survival not only in metabolic and cardio-vascular chronic conditions, but also in cancer patients, specifically in patients with colon cancer, prostate cancer, breast cancer and non-small-cell lung cancer (NSCLC).
These data suggest that vagus nerve activity may have a prognostic and protective role in cancer and hence it may be usefully modulated for treatment purposes.
Vagal nerve neuromodulation for cancer treatment
As we have shown, therapies directed at modulating the TME could provide an effective approach to harness cancer progression and, in this regard, the neuromodulation of the vagal nerve has the potential to be one of the key treatment strategies among cancer neural therapy.
Adding to the good results that non-invasive neuromodulation of the vagus nerve has already shown in diabetes, stroke, depression, and myocardial infarction, some preclinical and clinical data suggest potential use of non-invasive vagal nerve stimulation (nVNS) in cancer treatment.
Recently, Parasym technology was used in a pilot clinical study to provide nVNS to patients diagnosed with locally advanced non-small cell lung cancer (NSCLC) and receiving standard-of-care radiation therapy with concurrent chemotherapy. The study (published in Frontiers in Immunology) provided promising results for nVNS as an adjunct immunotherapy for NSCLC patients.
Lung cancer is the leading cause of global cancer incidence and mortality and NSCLC accounts for approximately 85% of the lung cancer cases currently observed worldwide. Although there are many ways to treat NSCLC, such as radiotherapy, chemotherapy, surgical resection and targeted molecular therapy, the 5-year survival rate of patients with NSCLC is less than 18%.
The recent introduction of immune-checkpoint inhibitors therapy based on inhibiting negative immunomodulation signalling (i.e. Programmed Cell Death Protein 1 PD-1 and Programmed Cell Death Ligand 1 PD-L1) has shown a benefit in a subset of patients. However, additional strategies aimed to reinforce antitumour immunity need to be explored to harness the effects of radio(chemio)therapy.
Given that radiotherapy can induce local immunosuppression and that the immunoprofile of the TME remains a key determinant for lung cancer patient prognosis, combination strategies that curtail the immunosuppressive myeloid compartment and reinforce T-cell immunosurveillance could crucially advance treatment efficacy.
Recent preclinical and clinical pilot studies conducted in mice and in patients with NSCLC, respectively, showed a potentially immunostimulatory effect of nVNS in the TME, with the capability to stimulate lung tumor infiltrating lymphocytes.
The preclinical study showed that transcutaneous VNS alters RT-induced immunosuppression in favour of more functional antitumor effector cells, decreasing T reg cells and increasing the functional orientation of tumor infiltrated CD8+T.
This combined effect was associated with a modest reduction in tumor burden using a VNS monotherapy. However, the same effect could potentially have very beneficial synergistic effects when VNS is used in combination with checkpoint inhibitors since the induction of intratumoral Tregs has been found to contribute to the development of resistance to anti-PD-1 therapy.
Importantly, these results revealed that the impact of nVNS treatment was restricted to immune subsets in the spleen and in the lung TME with no effects observed in peripheral blood. This suggests that nVNS has a targeted action and that future clinical monitoring of nVNS effects should be implemented at the tumor site.
The pilot clinical study conducted using Parasym technology in patients diagnosed with locally advanced NSCLC, showed lower levels of neutrophils and elevation of Natural Killer cells, both key actors of anti-tumor immunity, in the cohort administered with nVNS. These promising data should be replicated in bigger and well-defined samples.
Although larger clinical trials will need to be performed to clarify the optimal doses and combination strategies, these preclinical and pilot clinical data suggest that VNS holds potential in patients who qualify for radiotherapy in combination with immunotherapy.
Increasing evidence suggests how targeting tumor microenvironment could be a key determinant in cancer prognosis. Assessing possible synergies between cancer neural therapy, and specifically VNS, and immunotherapies, such as ICIs, should be the next step towards novel effective strategies in cancer therapy.
About the author
Dr Elisabetta Burchi, MD, PhD, MBA
Dr Burchi is a clinical psychiatrist, expert in Neuromodulation and leads translational research at Parasym. Her postdoctoral work focused on innovative neuromodulatory treatment approaches, conducted at the Albert Einstein College of Medicine, NY, USA.
Global Burden of Disease 2019 Cancer Collaboration. Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019. JAMA Oncol. 2022;8(3):420–444. doi:10.1001/jamaoncol.2021.6987
Hanoun M, Maryanovich M, Arnal-Estape A, Frenette PS (2015) Neural regulation of hematopoiesis, inflammation, and cancer. Neuron 86:360–373
Kamiya A, Hiyama T, Fujimura A, Yoshikawa S. Sympathetic and parasympathetic innervation in cancer: therapeutic implications. Clin Auton Res. 2021 Apr;31(2):165-178. doi: 10.1007/s10286-020-00724-y. Epub 2020 Sep 14. PMID: 32926324.
Gidron Y, Deschepper R, De Couck M, Thayer JF, Velkeniers B. The Vagus Nerve Can Predict and Possibly Modulate Non-Communicable Chronic Diseases: Introducing a Neuroimmunological Paradigm to Public Health. J Clin Med. 2018 Oct 19;7(10):371. doi: 10.3390/jcm7100371. PMID: 30347734; PMCID: PMC6210465.
Reijmen E, De Mey S, Van Damme H, De Ridder K, Gevaert T, De Blay E, Bouwens L, Collen C, Decoster L, De Couck M, Laoui D, De Grève J, De Ridder M, Gidron Y, Goyvaerts C. Transcutaneous Vagal Nerve Stimulation Alone or in Combination With Radiotherapy Stimulates Lung Tumor Infiltrating Lymphocytes But Fails to Suppress Tumor Growth. Front Immunol. 2021 Dec 1;12:772555. doi: 10.3389/fimmu.2021.772555. PMID: 34925341; PMCID: PMC8671299.
Fois SS, Paliogiannis P, Zinellu A, Fois AG, Cossu A, Palmieri G. Molecular Epidemiology of the Main Druggable Genetic Alterations in Non-Small Cell Lung Cancer. Int J Mol Sci. 2021 Jan 9;22(2):612. doi: 10.3390/ijms22020612. PMID: 33435440; PMCID: PMC7827915
Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current research in cancer. American journal of cancer research. 2020;10(3):727.
Dr Elisabetta Burchi, MD, MBA
Translational Research Lead at Parasym