Multiple Sclerosis and Cancer: The Ying-Yang Effect of Disease Modifying Therapies.

Esther Melamed,Michael William Lee

doi:10.3389/fimmu.2019.02954

Esther Melamed, Michael William Lee

Open Access

https://doi.org/10.3389/fimmu.2019.02954

Copy DOI

Abstract

Over the past two decades, the field of multiple sclerosis (MS) has been transformed by the rapidly expanding arsenal of new disease modifying therapies (DMTs). Current DMTs for MS aim to modulate innate and adaptive immune responses toward a less inflammatory phenotype. Since the immune system is also critical for identifying and eliminating malignant cells, immunosuppression from DMTs may predictably increase the risk of cancer development in MS patients. Compared with healthy controls, patients with autoimmune conditions, such as MS, may already have a higher risk of developing certain malignancies and this risk may further be magnified by DMT treatments. For those patients who develop both MS and cancer, these comorbid presentations create a challenge for clinicians on how to therapeutically address management of cancer in the context of MS autoimmunity. As there are currently no accepted guidelines for managing MS patients with prior history of or newly developed malignancy, we undertook this review to evaluate the molecular mechanisms of current DMTs and their potential for instigating and treating cancer in patients living with MS.

Highlights

Multiple Sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) and the leading non-traumatic cause of neurological disability in young adults
Many of the available MS disease modifying therapies (DMTs) had been used for years as cancer treatments prior to being re-purposed for MS, such as rituximab, Multiple Sclerosis and Cancer cladribine, and methotrexate, while other DMTs are actively being evaluated for their anti-tumor potential, such as dimethyl fumerate, fingolimod, and teroflunomide
There are a low number of fingolimod associated malignancies that have emerged in clinical trials (Table 1) and in the post-clinical trial era, including melanoma, basal cell carcinoma, breast cancer, squamous cell carcinoma, large B cell lymphoma, ocular lymphoma, Merkel cell carcinoma, cutaneous CD30+ T-cell lymphoma and multiple myeloma

Summary

INTRODUCTION

Multiple Sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) and the leading non-traumatic cause of neurological disability in young adults. Fingolimod has strong immunosuppressive properties against Treg cells [118] that contribute to tolerance of malignant tumor cells [119] indicating fingolimod may have potential in post-transplant malignancies [120] Another potential anticancer mechanism of fingolimod is inhibition or degradation of SK1, which is upregulated in multiple cancers, including CNS (brain), gastrointestinal (colon, stomach, rectum, small intestine), genitourinary (ovary and uterus), pulmonary and breast [121]. Upregulation of B regulatory cells (Bregs) and IL-10 could serve as another mechanism of fueling potential tumorigenesis [123] To this degree, there are a low number of fingolimod associated malignancies that have emerged in clinical trials (Table 1) and in the post-clinical trial era, including melanoma, basal cell carcinoma, breast cancer, squamous cell carcinoma, large B cell lymphoma, ocular lymphoma, Merkel cell carcinoma, cutaneous CD30+ T-cell lymphoma and multiple myeloma. Other analogs of S1PR that are currently in different phases of preclinical and clinical trials, such as TABLE 1 | Summary of disease modifying therapies, their mechanisms of action, incidence of cancer in clinical trials, and studies of DMTs in different cancer types

B Cell Therapies

Findings

CONCLUSIONS AND FUTURE DIRECTIONS