Brain health: Redefining MS Management From CAR T-Cell Therapy to Community Prevention Strategies

In the realm of Multiple Sclerosis (MS) management, significant strides have been made in controlling relapses and new lesion formation. High-potency drugs like Ocrelizumab, Ofatumumab, Natalizumab, Cladribine, and HSCT have marked a turning point in MS treatment. However, a critical aspect of MS still eludes our grasp – the progression of the disease.

The term "smouldering MS" has emerged in contemporary discourse, highlighting our ongoing battle with the non-relapsing attributes of MS – be it Progression independent to Relapses (PIRA), Relapse-Associated Worsening (RAW), secondary progression, or primary progression, enlarging white matter lesions, brain atrophy etc. This underlines a pivotal question in MS therapy: Are we merely addressing the consequences rather than adopting a preventative approach against the abnormal immune response at the heart of MS?

 A promising avenue in this regard is the exploration of small molecules like BTK inhibitors(1) and the innovative CAR T-cell therapy(2). These treatments potentially offer better penetration into the Central Nervous System (CNS), targeting the disease right at the brain tissue. This leads us to ponder a fundamental question: Can we decode and reprogramme the immune cells, designed to defend us, but which paradoxically inflict harm on the CNS in MS?

This inquiry becomes even more intriguing in light of genetic studies. According to research published in 'Nature', MS susceptibility genes were introduced into Europe approximately 5000 years ago, coinciding with migrations from the Pontic Steppe (Eastern Europe and Central Asia). These genes, largely linked to autoimmune functions, were possibly expressed in ancient herder populations to combat animal-borne pathogens, a by-product of pastoral lifestyles. Over generations, these genes have inadvertently increased the risk and prevalence of MS(3).

In ancient populations, the development of diseases like Multiple Sclerosis (MS) could have been influenced by a variety of factors. Genetic drift and the founder effect might have caused certain mutations to become prevalent in small, isolated groups. Natural selection could have favoured genes offering survival benefits, such as resistance to cold climates or infections, in harsh environments like the steppe. Environmental factors, including vitamin D levels affected by sunlight exposure, along with dietary influences from high-fat animal-based diets, might have played a role. Exposure to different infectious diseases could have impacted immune system functioning, particularly in populations with a predisposition to autoimmune diseases like MS. Additionally, the mobility of these groups led to genetic mixing and migration, introducing new genetic variations. Lastly, epigenetic changes, influenced by the environment, could alter gene expression, potentially increasing disease risk and passing these changes to future generations.

 This genetic perspective sheds light on the geographical variance in MS incidence. For example, why are there only a few cases of MS in China country? Can we reverse-engineer the immune cells' genetic makeup to restore their benign nature?

Shifting the MS Treatment Landscape: From BTKi Setbacks to CAR T-Cell Breakthroughs

The journey towards understanding and manipulating the immune system's role in MS is a challenging yet hopeful one. CAR T-cell therapy, with its potential to reprogram immune cells, might be the key to unlocking a more effective and preventative approach in MS treatment. It represents not just a battle against the symptoms but a deeper war against the underlying causes – a true paradigm shift in our fight against Multiple Sclerosis. However, this journey might encounter setbacks, as seen in the case of BTKI. Recent updates reveal that Evobrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor being developed by Merck KGaA/EMD Serono for MS treatment, did not achieve its primary objectives of relapse reduction in the phase 3 EVOLUTION trials. The company intends to thoroughly analyse the complete set of data, with plans to present and publish these findings in the future. Maybe BTKi treatment still very powerful for MS disease progression?

However, recent FDA approval for Phase 2 trials in CAR T-cell therapy for MS marks a significant step forward. This article delves into what this means for MS patients, especially those with limited treatment options. FDA Clears Phase 2 KYSA-7 Study of CAR T-Cell Therapy in Refractory Progressive Multiple Sclerosis (neurologylive.com)

CAR T-cell therapy is a type of treatment that involves reprogramming the patient's own immune cells to fight certain diseases, like cancer (4)or, in this case, multiple sclerosis (MS). Here's a more detailed explanation of the process, tailored for MS patients:

1. Collection of T-Cells: The first step involves drawing blood from the patient. From this blood, T-cells, a type of white blood cell that plays a critical role in the immune response, are isolated.
2. Genetic Modification: Once the T-cells are isolated, they are sent to a laboratory. Here, they are genetically modified to express a specific receptor on their surface, known as a Chimeric Antigen Receptor (CAR). This receptor is designed to recognize and bind to specific proteins (antigens) present on the surface of target cells – in the case of MS, these would be cells involved in the pathological process of the disease.
3. Expanding the T-Cells: The genetically modified T-cells are then cultivated in the lab to increase their numbers. This step ensures that there are enough CAR T-cells to have an effective response when reintroduced into the patient's body.
4. Preparation for Reinfusion: Before the CAR T-cells are given back to the patient, the patient may undergo a process called lymphodepletion. This involves using chemotherapy to clear out some of the existing immune cells. Chemotherapy has fertility implications, more Fertility and chemotherapy | Cancer in general | Cancer Research UK. This step is not always necessary but can help the CAR T-cells work more effectively.
5. Reinfusion: The expanded CAR T-cells are then infused back into the patient's bloodstream. This is usually done through an IV drip, similar to a blood transfusion.
6. Action of CAR T-Cells: Once in the bloodstream, these modified T-cells can seek out and bind to the target cells in the body using their new receptors. Upon binding, they become activated and kill the target cells.
7. Monitoring: Post-infusion, patients are closely monitored for any adverse reactions or side effects. One of the common risks associated with CAR T-cell therapy is an immune response known as cytokine release syndrome, which can range from mild to severe.
8. Long-Term Follow-Up: Patients who undergo CAR T-cell therapy require long-term follow-up to monitor the effectiveness of the treatment and any late-emerging side effects.

 CAR T-cell therapy, while promising, can have significant side effects. These can vary from mild to severe, and not all patients will experience all side effects. Here are some common and serious side effects (5, 6).

1.       Cytokine Release Syndrome (CRS): This is the most common and can be serious. When CAR T-cells are activated, they release large amounts of cytokines into the blood. This can lead to fever, fatigue, headache, rash, low blood pressure, difficulty breathing, and in severe cases, organ dysfunction.

2.      Neurological Toxicities: Patients may experience confusion, difficulty speaking, tremors, seizures, or severe headaches. These symptoms can range from mild to life-threatening.

3.       B-Cell Aplasia and Low Immunoglobulin Levels: Since CAR T-cells can target healthy B-cells, this can lead to a decrease in these cells, resulting in lower levels of immunoglobulins (antibodies). This makes patients more susceptible to infections.

4.       Infection: The treatment process, which may include chemotherapy prior to reinfusion, can weaken the immune system, increasing the risk of infections.

5.       Anaemia and Bleeding: Due to the impact on blood cells, patients may experience anaemia, bleeding, or bruising.

6.       Infusion Reactions: Reactions to the infusion of CAR T-cells can include fever, chills, nausea, headache, rash, and difficulty breathing.

7.       Tumour Lysis Syndrome: This occurs when cancer cells are killed rapidly, releasing their contents into the bloodstream, potentially leading to kidney failure and other issues. It's more common in cancer treatment but can theoretically occur in any disease where cells are rapidly destroyed.

8.       Allergic Reactions to the CAR T-Cell Construct: Some patients might have an allergic reaction to the components of the genetically modified T-cells.

9.       Graft-versus-Host Disease (GVHD): This is more common in treatments using donor cells, but in some types of CAR T-cell therapies, especially if they involve donor cells, the patient's body might react against these foreign cells.

10.   Long-term Effects: There is still much to learn about the long-term effects of CAR T-cell therapy, as it is a relatively new treatment and is under investigations.Looking Ahead: A Vision of Hope and Innovation in MS Treatment

 Looking Ahead: A Vision of Hope and Innovation in MS Treatment and Brain health prevention

The journey of CAR T-cell therapy from a mere concept to a potential game-changer in treating Multiple Sclerosis (MS) reflects the incredible progress in medical science. This path, marked by scientific research, clinical trials, and the real-life experiences of patients, is one of cautious optimism. It involves carefully weighing the potential life-altering benefits against the risks and side effects and it is still not available in clinical practise as yet, but the whole concept of treatment is very promising in the current rapidly evolving MS environment.

However, our quest to conquer MS doesn't end with current treatments. The fight against this complex disease requires continuous searching for a cure and more effective treatments, particularly focusing on halting the progression of MS. In this endeavour, we must never underestimate the importance of a healthy and balanced lifestyle. Living with MS is a multifaceted challenge; there is no single cure or solution. As I embark on my journey as a certified Neurology and Brain Health Ambassador under the European Academy of Neurology (EAN), I am setting a bold and transformative challenge for myself and the community. I am committed to promoting a holistic approach that encompasses early detection, innovative medical treatments, and lifestyle management. My vision extends to revolutionizing MS brain health prevention. Envision a future where "NeuroCheck Stations" would become a cornerstone of community health - innovative brain health check booths situated in business districts and on community high streets. These stations would offer a quick, non-invasive screening for brain health, serving as a beacon for proactive neurological care. Equipped with cutting-edge technology, perhaps even offering rapid MRI scans, these booths would be designed to seamlessly integrate into the daily lives of the public. The "NeuroCheck Station" would not only be a hub for early detection but also a source of education and empowerment, encouraging individuals to take charge of their neurological health. By making brain health assessments as commonplace as checking one's blood pressure, this initiative would aim to transform the societal approach to brain health, emphasizing prevention and early intervention. While still a concept, the potential impact of such NeuroCheck Stations on public health could be profound, paving the way for a future where brain health is both celebrated and vigilantly maintained.

By harnessing artificial intelligence and advanced algorithms, we can identify individuals at high risk for MS and intervene proactively, much like the strategies used in stroke prevention. I envision a community-driven approach, where local businesses and organizations collaborate to set up pre-MS screening Neurocheck stations, let’s set the goal to reduce MS disease prevalence by 10% , or reduce MS disease progression by 10% next year. These stations would conduct vital checks like symptom history, family history assessments, vaccinations and Vitamin D level measurements while educating the public about impactful lifestyle choices. Moreover, the implementation of random MRI screenings in the general population, using standardized and precise protocols, could be ground breaking in early detection and intervention.

This vision extends beyond my personal dreams or individual-led ventures; it represents a global mission. It's about forging a movement that goes beyond conventional medical practices. Merely visiting my Neurology and MS clinics is not sufficient; I seek the involvement of your neighbour too, to assist in early problem identification, to aid in slowing disease progression, and to pinpoint those potentially at risk of MS. By embracing prevention, early detection, and comprehensive care, we chart a course towards a future of possibilities. The journey ahead is uncertain, but by integrating innovative research like CAR T-cell therapy with community involvement and technological advances, we are paving a path towards a future where MS can be effectively managed and, we hope, completely eradicated.

Together, let's strive to make this vision a reality, transforming the lives of those living with MS and shaping a future where this diagnosis is not life-altering but a condition that can be effectively managed and ultimately prevented.

Conclusion and Summary: United in the Fight Against Multiple Sclerosis

 As we stand on the brink of a new era in the management of Multiple Sclerosis (MS), our exploration into the potential of CAR T-cell therapy and other innovative treatments opens a promising path forward. Our journey through the complexities of MS management, while marked by significant progress in controlling relapses and lesion formation, reminds us that the battle against the disease's progression continues.

 In confronting MS, we recognize the need to shift from merely addressing symptoms to pre-emptively targeting the abnormal immune responses at the heart of the disease. The exploration of novel treatments like BTK inhibitors and CAR T-cell therapy represents a beacon of hope, illuminating a path where reprogramming the immune system could cease its unintended assault on the CNS.

 The genetic history of MS, revealing the influences of human migrations and lifestyle changes on the disease's prevalence, challenges us to broaden our perspective. This insight compels us to consider a comprehensive approach that addresses genetic, environmental, and lifestyle factors in managing and preventing MS.

 As a passionate Neurology and Brain Health Ambassador under the European Academy of Neurology (EAN), I am committed to pioneering this transformative approach. My mission is to integrate cutting-edge medical research with proactive community engagement and holistic patient care. By utilizing artificial intelligence and advanced algorithms, we aim to identify individuals at high risk for MS and provide early intervention, mirroring successful stroke prevention strategies.

 Imagine a future where community-led initiatives, such as local pre-MS screening booths ( Neurocheck stations) and widespread MRI screenings, are commonplace. This vision is not a mere dream but a tangible goal that we are actively pursuing – a world where MS and other Neurological conditions can be effectively managed and ultimately prevented. This collaborative effort transcends traditional medical boundaries, combining innovative research with public education and a dedication to comprehensive care.

 In this pivotal moment, I extend an invitation to you all. If the vision outlined in this article resonates with you and you are willing to support this initiative to prevent the onset of MS, I earnestly encourage you to get in touch. This is not a journey I can undertake alone. It requires the collective effort, support, and expertise of each one of us. Together, we can make a substantial difference in the lives of those at risk or living with MS.

 Let us unite in this fight against MS, transforming our collective vision into a reality. This is an opportunity for us to create a world where MS is not a life-defining condition but a manageable challenge. By joining hands, sharing knowledge, and pooling our resources, we can pave the way for a future where MS is a condition met with hope, effective management, and the promise of a better quality of life.

 Your support, expertise, and involvement are invaluable. Together, let's embark on this transformative journey, making a lasting impact in the fight against Multiple Sclerosis. Please reach out if you are ready to be part of this ground-breaking initiative. With your help, we can redefine the future of MS treatment and prevention, making it a reality filled with hope and possibilities for all.

 Note: The infographics and descriptions are fictional suggestions to give you an idea of what visuals might accompany the article. Created by AI under my commands.

If this article resonated with you or if you believe it can inspire someone else on their MS journey, I encourage you to like, comment, and share it with your community.

#Multiplesclerosis #Brainhealth #BeewellwithMS

More fascinating information about New Treatment Horizons in MS - tune in on multiple podcast platforms to listen BeewellwithMS podcast www.beewellwithms.com, new episode is going to be released on 22nd January, 2024. Episode: New Treatment Horizons in MS -Regenerative Neuroimmunology with Cambridge Prof Stefano Pluchino.

© dr Agne Straukiene

 References:

1.           Krämer J, Bar-Or A, Turner TJ, Wiendl H. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol. 2023;19(5):289-304.

2.           Gupta S, Simic M, Sagan SA, Shepherd C, Duecker J, Sobel RA, et al. CAR-T Cell-Mediated B-Cell Depletion in Central Nervous System Autoimmunity. Neurol Neuroimmunol Neuroinflamm. 2023;10(2).

3.           Barrie W, Yang Y, Irving-Pease EK, Attfield KE, Scorrano G, Jensen LT, et al. Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations. Nature. 2024;625(7994):321-8.

4.           Brudno JN, Lam N, Vanasse D, Shen Y-W, Rose JJ, Rossi J, et al. Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma. Nature Medicine. 2020;26(2):270-80.

5.           Chohan KL, Siegler EL, Kenderian SS. CAR-T Cell Therapy: the Efficacy and Toxicity Balance. Curr Hematol Malig Rep. 2023;18(2):9-18.

6.           Li L, Gao J, Sun Z, Li X, Wang N, Zhang R. Effects of CAR-T Cell Therapy on Immune Cells and Related Toxic Side Effect Analysis in Patients with Refractory Acute Lymphoblastic Leukemia. Mediators of Inflammation. 2023;2023:1-7.