What is an Immunotherapy?
Immunotherapies are a class of therapies which, through the use of cell transfers and biologics such as monoclonal antibodies, are able to modulate the immune response. These therapies target specific regulatory pathways in order to leverage the knowledge gained through basic research. As a therapeutic its primary goal is to help ameliorate or completely reverse a given disease phenotype of autoimmunity and cancers.
Checkpoint inhibitors: anti PD-1 therapy
Cancer surveillance is maintained in the body through a variety of mechanisms and circulating lymphocytes, which are constantly surveying the antigenic environment in their surroundings. In order for a naïve T lymphocyte to become activated, the T cell receptor and the costimulatory signals must be activated. The T cell receptor is able to recognize neoantigens which are often displayed by proliferating cancer cells due to altered metabolism. To suppress T cell activation, cancer cells may upregulate negative costimulatory receptors such as PD-1L which ordinarily serve to establish tolerance in healthy tissues 1. These findings led to the development of an anti PD-1 monoclonal antibody also known as nivolumab. Clinical trials of Nivolumab started in 2006 and has demonstrated response rates of 28% for melanoma and 27% for renal carcinomas2.
Chimeric Antigen Receptor T cell therapy
Another immunotherapy approach to target cancers was developed using a so called chimeric antigen receptor T cells. A chimeric antigen receptor is made up of an extracellular domain composed of an antibody variable region, an IgG spacer domain, CD8 derived transmembrane domain and an intracellular signalling domain composed of multiple chains3. The intracellular domain contains the 2 signals required for TcR signal transduction namely the CD3 signalling domain and intracellular costimulatory CD28 signalling domain. These T cells are generated through retroviral modification of patient derived lymphocytes, to express the CAR T cell receptor specific for the cancer antigen and infused back into the patient3. CAR T cell therapy has undergone many iterations and has now been showing clinical promise with clinical trials in acute lymphoblastic leukemia patients showing a cancer remission rate of up to 90% 3.
Interferon therapy and Multiple sclerosis
Biology of Interferons
Interferons fall into two classes, type 1 and type 2 interferons. Type 1 interferons include IFN-a and IFN-b and IFN-y is a type 2 interferon. Type 1 interferons are first responders during acute viral infection and are produced by many different cell types during an ongoing infection. Viral infection is detected by the host cell through recognition of a class of molecules called pathogen-associated molecular patterns or PAMPs. PAMPs are recognized by a class of cellular receptors called pattern recognition receptors or PRRs which are categorized according to structural homology and subtype of PAMPs they are able to ‘sense’. Toll-like receptor family (TLRs) and RIG I-like receptor family (RLRs) are the main responders which recognize viral PAMPs. Viral single stranded RNA leads to the activation of a TLR7/8 complex which through downstream signalling activates the interferon regulatory factor 7 otherwise known as IRF74. IRFs are a set of transcription factors which are responsible for the activation of interferon genes. TLR activation by ssRNA also leads to the activation of other transcription factors like JNK and NFkB which together with IRFs are able to upregulate the IFN-a and IFN-b genes4. Interferons are able to exert their function as autocrine and paracrine signals to spread the word about an ongoing viral infection and prepare cells to deal and limit viral replication. Type 1 interferons bind to their appropriately named cognate receptor the IFN-aR 1 and 2c, which upon dimerization is able to autophosphorylate and begin a signalling cascade culminating in the activation of a powerful antiviral gene cluster called ISG such as Mx genes, IFITM genes, viperin and many more5.
Multiple Sclerosis
Multiple sclerosis is a complex inflammatory neurodegenerative disorder of the central nervous system. The first case of multiple sclerosis was documented in 1395, where a saint was described in a story to have fallen while ice skating at the age of 16 and later developed the well known symptoms of multiple sclerosis such as muscle weakness, pain and vision loss due to optic neuritis. Later in the first half of the 19th century, neurologists from around the world such as Carswell, Cruveilhier, Rokitansky described multiple sclerosis as a medical phenomenon. Later Jean Charcot was able to identify through post-mortem examination the central nervous system lesions seen in patients with multiple sclerosis. Charcot also identified clinical indicators of multiple sclerosis known as Charcot’s triad of nystagmus (involuntary eye movement), staccato speech (pausing between syllables) and intention tremor (due to cerebellar lesions)6. In the present time, the prevalence of multiple sclerosis varies widely from continent to continent, being the highest in North America at 140 cases per 100,000, followed by Europe at 108 cases per 100,000. Interestingly East Asian and Sub Saharan African regions show the lowest rates at just 2.2 and 2.1 cases per 100,000 respectively7. Some risk factors for multiple sclerosis include smoking, low vitamin D, Epstein-Barr virus infection and shows a female sex bias7. The exact etiology of the disease remains to be elucidated, it has been difficult to pinpoint since the lesions that occur can mostly be silent until a clinical significance threshold is reached, by when the initial trigger maybe long gone8 9. The genetic contribution in multiple sclerosis is the HLA-DR and DQ genes specifically the HLA-DR15 which are predominant in Caucasian populations, perhaps contributing to the geographic differences around the world in particular the north south gradient of multiple sclerosis prevalence8. The initial insult which may trigger immune activation may be explained by two theories, the bystander activation of autoreactive myelin specific T cells in response to non-specific inflammation OR molecular mimicry resulting in the activation of myelin specific T cells8. Most of the knowledge on the etiology of MS derives from animal models that have been developed throughout the years. The most famous of which is experimental autoimmune encephalomyelitis (EAE) is produced in mice by subcutaneous immunization with MOG/MBP/PLP emulsified in Complete Freund’s Adjuvant. Advantages of this model are ease of induction and reproducibility however disadvantages are inability to study MS progression and risk factors. Viral models of MS have also been generated, particularly picornavirus, coronavirus and hepatitis virus models of MS. These models are useful in comparing it to the role of Epstein-Barr virus and development of multiple sclerosis in the context of viral infections. Toxicity based models of MS involve cuprizone feed, which elicits mitochondrial toxicity which preferentially targets oligodendrocytes. This model is useful for studying the effects of demyelination and effects on functional outcomes in mice as well as understanding the role of the immune system in mediating oligodendrocyte repair10.
IFN-b immunotherapy in multiple sclerosis: first success story
IFN-beta 1b therapy was the first treatment for multiple sclerosis to be approved by the FDA in 1993. The therapy had a long research history with the first pioneering human clinical trials conducted by Larry Jacobs in 19819,11. The initial rationale for the clinical trial was the evidence for partial involvement of CNS viral infection which acts as a trigger for MS12. Prior to this study the only intervention was the administration of corticosteroids such as prednisone during acute attacks of MS12. The clinical trial run by Larry Jacobs used intrathecal injections of interferon beta eight times over four weeks followed by monthly injections over five months in 10 patients12. The clinical trial outcomes had shown that IFN-b therapy had an overall 30% decrease in the relapse rate of patients13. Although the trial turned out to be a success, the scientific community was not convinced and criticisms followed, such as the death of a patient in the interferon group, statistical and mathematical errors and lack of significance14. This however inspired more research into the usage of interferons as a therapeutic in treatment of patients with multiple sclerosis.
Mechanisms
Although the initial assumption for the IFN therapy was flawed it sparked a series of research papers looking to elucidate the mechanisms of action of IFN-b-1b therapy. In vitro investigation of interferon beta-1b treatment of activated T cells shows decreased efficiency of migration through a fibronectin network, which is an integral component of the blood brain barrier15. Metalloproteases are able to cleave the thick fibrin network which allows lymphocytes to efficiently traffic through, however the authors found that IFN-b-1b treatment decreased the activity of the metalloprotease MMP-9 thereby decreasing the migration capacity of T cells and NK cells15. Another study examining the ratio of MPP-9 to a metalloprotease inhibitor TIMP-1 in multiple sclerosis patients found a correlation between decrease in MPP-9/TIMP-1 ratio and number of active lesions as monitored by gadolinium MRI imaging16. These findings strongly support the notion that IFN-b-1b treatment reinforces the blood brain barrier integrity thereby decreasing leukocyte infiltration and neuronal and oligodendrocyte injury. A secondary mechanism which was explored was the reduction in the levels of adhesion molecules in patients on interferon-beta treatment. Specifically the increase in soluble vascular adhesion markers such as vascular cell adhesion molecule-1 was correlated to a decrease in lesion load, implicating IFN-b based disruption of the cell extraversion may be contributing to the improved clinical outcomes of IFN-b therapy by limiting central nervous system inflammation and damage 17. The importance of blood brain barrier integrity in multiple sclerosis is further supported by the monoclonal antibody treatment Natalizumab, which binds to integrin a4 and blocks leukocyte extraversion across the blood brain barrier, particularly CD4+ T cells 18 13. The clinical trial examining its therapeutic role found that treatment with Natalizumab reduced the risk of exacerbations at 2 years by 40% and risk of progression by 25%18.
Efficacy
Today we are fortunate to have at our disposal many new therapies for multiple sclerosis such as Natalizumab, anti-CD52 Alemtuzumab, numerous anti-CD20 monoclonal antibodies all of which have shown highly efficacious in treating multiple sclerosis through a variety of different mechanisms13. IFN-b therapy however remains a first line treatment for relapsing remitting multiple sclerosis due in part to its safety and the ability to significantly delay the progression of disease in some patients (particularly RRMS) if the started on the treatment immediately. Long term subcutaneous administration of IFN-b was shown to improve patient outcomes in a dose dependent manner, showing the feasibility of significantly delaying the progression of disease and disability that results from neurodegeneration in multiple sclerosis19. IFN-beta treatment of patients with secondary progressive multiple sclerosis has been shown in a randomized double blind placebo controlled clinical trial to significantly decrease the number of active lesions as imaged by gadolinium MRI 20.
Safety
Currently there are a number of different interferon beta based medications available on the market. In some patients anti-IFN-b antibodies can form and neutralize drug thereby rendering it ineffective, in those cases the patients should seek other treatment options21. the In 75% of patients treated with interferon beta has been associated with symptoms such as fever, chills, headaches, allergic reactions, neutropenia, leukopenia and fatigue, however these symptoms are short lived and resolve within 24 hours of drug administration21. Interferon beta therapy has not been found to have negative impacts during or on pregnancy22. Interferon beta therapy is a well-established treatment with mild to moderate efficacy and is a first line therapy for multiple sclerosis patients with little health risks13 21.