Efficacy of CAR-T cell Therapy in Patients with Hodgkin lymphoma who Relapse or Experience Primary Refractory Disease

Background

Chimeric antigen receptor (CAR) T-cell therapy is a novel form of treatment for primarily blood cancers. CAR-T cell therapies involve engineering individual patients’ T-cells to target specific cancer cells. First, blood is taken from a patient to acquire their T-cells. Secondly, CAR-T cells are produced in the lab where the CAR genes are inserted into the T-cells. Afterward, CAR proteins appear on the surface of the T-cells and they are then reproduced millions of times so that they can be infused into the patient. Then the goal for the CAR-T cells becomes binding to cancer cells to kill them (National Cancer Institute, 2019). This is as illustrated below in figure 1:

Figure 1: How CAR-T cell therapies work (National Cancer Institute, 2019).

Hodgkin’s lymphoma (HL) is a type of cancer that manifests itself in the lymphatic system and the cancer presents itself with supra-diaphragmatic lymphadenopathy meaning swollen lymph nodes above the diaphragm. The cancer cells are characterized as Hodgkin and Reed-Sternberg (HRS) cells. 

Additionally, it is one of the most prevalent cancer types in adolescents. The B-cell lymphoproliferative disorder can be divided into classical HL (cHL) and nodular lymphocyte-predominant HL (NLPHL), however, cHL accounts for over 90% of the cases, which is why it will be the main focus of this article. Though, one thing that all HL subtypes have in common is that they all share an immunophenotypic pattern of CD15+, CD30+ as well as CD45-, antigens that indicate Hodgkin’s lymphoma.

HL has various treatment options ranging from chemotherapy to radiotherapy. The treatments have high rates of curability, even in cases of a patient advancing through the stages of HL (Shanbhag & Ambinder, 2017).

When CAR-T cell therapy should be considered the favorable treatment option

Most cases of HL are sufficiently cured with first-line therapy. However, 15% of HL patients relapse or acquire primary refractory disease, which means they do not go into complete remission. The usual first-line therapy alternative is high-dose chemotherapy and autologous stem cell transplantation (aSCT). aSCT refers to capturing stem cells before going into treatment and injecting them back into the body following the treatment. Around 50% of individuals going through this treatment relapse after transplantation. The issues with the alternative treatment to aSCT are that allogeneic stem cell transplantation (alloSCT) results in high morbidity as well as mortality, even though it provides the most optimal chances for achieving sustained remission. alloSCT shares similarities with aSCT, however the difference in alloSCT is that stem cells are extracted from a donor instead to replace damaged stem cells as a result of radiation or chemotherapy (Ramos et al., 2020).

In July 2021 in America, the treatment for early-stage cHL was comprised of doxorubicin (or adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD), a series of chemotherapies. The former is the most common front-line therapy there is, but this form of treatment does not come without side effects. Generally, cHL patients will be at risk for long-term complications such as cardiopulmonary toxicities, secondary malignancies, and quality of life (QoL) impairment. The latter is, among other things, why the spotlight has been on improving the side effects of being treated with front-line therapy. The first, second, and third line of treatment is shown below in figure 2 (Mohty et al., 2021). 

Figure 2: Lines of treatment for cHL in advanced stages (Mohty et al., 2021).

When the time finally comes to consider CAR-T cell therapy for treating cHL the potential side-effects and the efficacy of CAR-T cell therapy must be taken into consideration.

CAR-T cell therapy has one significantly dangerous side effect, which is cytokine release syndrome (CRS) (National Cancer Institute, 2019). CRS is a condition where an abundance of cytokines are released as a result of immunotherapies like CAR-T cell therapy. The danger lies in the cytokines’ function. They are meant to maintain a healthy amount of blood cells and immune cells, but this becomes difficult when the body is overloaded with cytokines (Cleveland Clinic, 2022). The more cancer cells there are in the body the more likely it is to experience CRS when treated with CAR-T cells. Mild courses of CRS are mostly controllable with first-line therapies and more serious cases of CRS are becoming easier to treat as well, as more experience with CAR-T cell therapies is gained through research. CAR-T cell therapy becomes ineffective when it has to deal with solid tumors. This is especially true for tumor heterogeneity, which is the diversity of cancer cells in a tumor. The latter is due to the fact that solid tumors can vary a lot when it comes to the individual person and sometimes this applies to one patient’s body itself. The molecular diversity in the solid tumors makes it incredibly difficult to treat because the molecular diversity can contribute to the CAR-T cells being unable to function properly (National Cancer Institute, 2019).

The magic of CAR-T cell therapy in cHL shines through when the patient has relapsed or has experienced primary refractory diseases. A study shows that responses to Anti-CD30 CAR-T cell therapies are superior to bendamustine in patients who have previously been treated with bendamustine. In addition to this, when the CAR-T cell therapy was used following fludarabine-containing lymphodepletion regimens it resulted in 59% of complete responses out of 32 patients. The most prevalent toxicities were grade 3 or higher hematologic adverse events. The overall response rate of patients that received fludarabine-based lymphodepletion was 72% (Ramos et al., 2020).

The bottomline is that CAR-T cell therapy should be done when patients are relapsing or experiencing refractory diseases in relation to cHL, because the safety of use is incredible while also maintaining high response rates.

Daniel Godiksen, Youth Medical Journal 2022

References

Cleveland Clinic. (2022, April 7). Cytokine Release Syndrome: Symptoms, What It Is & Treatment. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/22700-cytokine-release-syndrome

Mohty, R., Dulery, R., Bazarbachi, A. H., Savani, M., Hamed, R. A., Bazarbachi, A., & Mohty, M. (2021). Latest advances in the management of classical Hodgkin lymphoma: the era of novel therapies. Blood Cancer Journal, 11(7), 1–10. https://doi.org/10.1038/s41408-021-00518-z

National Cancer Institute. (2019, July 30). CAR T Cells: Engineering Immune Cells to Treat Cancer. National Cancer Institute; Cancer.gov. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

Ramos, C. A., Grover, N. S., Beaven, A. W., Lulla, P. D., Wu, M.-F., Ivanova, A., Wang, T., Shea, T. C., Rooney, C. M., Dittus, C., Park, S. I., Gee, A. P., Eldridge, P. W., McKay, K. L., Mehta, B., Cheng, C. J., Buchanan, F. B., Grilley, B. J., Morrison, K., & Brenner, M. K. (2020). Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma. Journal of Clinical Oncology, 38(32), 3794–3804. https://doi.org/10.1200/jco.20.01342

Shanbhag, S., & Ambinder, R. F. (2017). Hodgkin lymphoma: A review and update on recent progress. CA: A Cancer Journal for Clinicians, 68(2), 116–132. https://doi.org/10.3322/caac.21438

Sterner, R. C., & Sterner, R. M. (2021). CAR-T Cell therapy: Current Limitations and Potential Strategies. Blood Cancer Journal, 11(4), 1–11. https://doi.org/10.1038/s41408-021-00459-7

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The Negative Influence of Coronary Heart Disease on the World

Background

Coronary heart disease (CHD) is an illness that is caused by constrictions of the coronary arteries due to plaque build-up (atherosclerosis). It has become one of the deadliest illnesses in the world, as described in the following sections. In some cases, it is also referred to as ischemic heart disease. (CDC, 2019). 

CHD is normally caused by an unhealthy way of life. Unhealthy lifestyle habits include smoking, obesity, high cholesterol, and lack of exercise. (Torpy, 2009)

How the causes of coronary heart disease impact the world

As CHD stems from atherosclerosis, it is classified as myocardial infarction and ischemic cardiomyopathy, which are severe conditions.

Nevertheless, CHD is found in approximately 126 million people worldwide and that corresponded to roughly 1.72% of the world’s population in 2020. Thus, it is no surprise that CHD further resulted in 9 million fatalities around the world during the same year. 

Despite this, it is predicted that the incidence rate of CHD will accelerate to about 1,845 cases per 100,000 people in 2030, while it lies at 1,655 occurrences per 100,000 individuals in 2020. Thus, CHD incidents are growing worldwide, year by year. This can be put down to growing rates of conditions such as obesity, metabolic syndrome, and diabetes. Further contributing to this is the aging of the global population – CHD is more prevalent in older people.

It is also apparent that both males and Eastern Europeans are more likely to be affected by CHD than other people. This is evidenced by 264 additional occurrences in males compared to females. In the same way, Eastern Europeans have more cases, as opposed to other areas, as illustrated in figure 1.

Figure 1: The global distribution of CHD, where blue displays low rates of cases, while red demonstrates areas with high rates of cases in 2017. Colors express rates per 100,000 humans (Source: Khan et al., 2020)

Interestingly, the majority of persons (~70%) that are at risk for CHD suffer from, not one, but several factors that increase their chances of getting the disease.

Furthermore, from a financial standpoint, it is important to reduce the amount of CHD incidents since treatment comes at a high cost. This is demonstrated by the fact that the cost of treating CHD will require 1 trillion USD in 2030, while 863 billion USD was sufficient in 2010. (Khan et al., 2020)

Ultimately, all of the aforementioned indicates that CHD is a global issue and results in many fatalities and also economic impairment as a consequence of treatment.

How to minimize the effect of CHD

The best way to avoid experiencing CHD is to adopt a healthier lifestyle. A healthy lifestyle, according to the National Health Service, contains the following components. 

First of all, blood pressure should be managed. Blood pressure can be negatively affected by consuming a diet that consists of highly saturated fats, living a sedentary lifestyle, and not taking blood pressure medication when it is necessary. 

Second of all, it is recommended to refrain from smoking and drinking alcohol as they both contribute to CHD. Smoking strengthens the chances of atherosclerosis, while alcohol heightens the risk of encountering a heart attack. 

Some of the previously mentioned facts also call for an improved diet. A good diet is varied, and such a diet is made up of mainly high-density lipoproteins boosting foods (HDL), large quantities of fiber as well as fruits, vegetables, and whole grains.

It is essential to know the difference between “good” and “bad” cholesterol. HDL is known as “good” cholesterol since it prevents the build-up of plaque. It does this by transporting low-density lipoproteins into the liver where they are broken down. Conversely, LDL is “bad” cholesterol since a surplus of LDL causes deposits of plaque in the arterial walls of blood vessels. This slows the flow of blood, therefore, resulting in conditions such as angina, which may lead to heart attacks further down the line. Consuming excessive volumes of sugar is not advised either, as this increases the likelihood of contracting diabetes, which could potentially lead to CHD too. Exercise and a healthy diet are recommended since a healthy heart can endure pumping more blood than an unhealthy heart. A strong diet and exercise both keep blood pressure at a reasonable level. (National Health Service, 2020)

Considering all of the above, CHD is costly, which is demonstrated in patients through life-degrading lifestyles. From an economical perspective, CHD claimed 863 billion USD in treatments in 2010 and is expected to rise to 1 trillion USD in 2030. However, the damages of CHD can be diminished by people at risk adhering to a better lifestyle to avoid risk factors.

Daniel Godiksen, Youth Medical Journal 2022

References

CDC. (2019, December 9). Coronary artery disease: Causes, diagonosis & prevention. Centers for Disease Control and Prevention. https://www.cdc.gov/heartdisease/coronary_ad.htm

Khan, M. A., Hashim, M. J., Mustafa, H., Baniyas, M. Y., Al Suwaidi, S. K. B. M., AlKatheeri, R., Alblooshi, F. M. K., Almatrooshi, M. E. A. H., Alzaabi, M. E. H., Al Darmaki, R. S., & Lootah, S. N. A. H. (2020). Global Epidemiology of Ischemic Heart Disease: Results from the Global Burden of Disease Study. Cureus, 12(7). https://doi.org/10.7759/cureus.9349

National Health Service. (2020, March 10). Prevention – Coronary heart disease. NHS. https://www.nhs.uk/conditions/coronary-heart-disease/prevention/

Torpy, J. M. (2009). Coronary Heart Disease Risk Factors. JAMA, 302(21), 2388. https://doi.org/10.1001/jama.302.21.2388

What causes stuttering, how it is treated and how it may affect people

Background

Stuttering, also known as speech dysfluency, is a condition that involves involuntary verbal expressions. Often stuttering is characterised by repetitions of words, letters or sounds, however, it may also be prolongations of the latter. In other instances speech dysfluency is demonstrated through tension in one’s speech while pronouncing words. A person who stutters may also use circumlocutions, which is substituting a problematic word with one that is easier to pronounce. While symptoms present themselves verbally, symptoms may also present themselves physically which is comprised of involuntary physical expressions such as eye blinking, jaw jerking and jerking movements in general. (Prasse & Kikano, 2008)

There are two different types of stuttering. The first one is developmental stuttering, which is a result of children that are developing their communication skills rapidly. The second is stuttering that manifests itself later in life due to fx head injuries, strokes or progressive neurological conditions. However, the second type of stuttering may be caused by emotional or psychological trauma, medicine or specific drugs. (NHS, 2019)

Causes of stuttering

Why stuttering occurs is not completely clear but there are contributing factors involved. For developmental stuttering this includes both developmental and inhertied factors. Usually, children develop their speech through speech and langauge with the correct rhythm and pronunciation. For this to happen it is required that the child gets sufficient practice in doing so, so that the neural pathways are constructed, and thus, function properly. If this is not the case, the child may incorporate behaviors such as repetitions and blockings, which specifically may present itself when the child wants to say something, feels pressured or when the child is excited. After a while these behaviors should disappear as the brain grows. 

Furthermore, the stuttering may also be of genetical concern as people with speech dysfluencies can potentially have inherited it from their parents and for some only their risk of developing speech dysfluency is increased genetically. (NHS, 2019)

However, research suggests that stuttering may be due to the central nervous system failing to develop stable, basic motor programs and muscle synergies  (Smith & Weber, 2017)

Treatment

There are a variety of different treatment options but generally, a speech therapist will be involved in order to construct an appropriate plan for treating the stutter. The treatment can be comprised of developing strategies that prevent dysfluency and improve communication overall. Another form of treatment would be exploring fear and anxiety related to the stutter and processing these feelings. Additionally, it may be beneficial to adjust the child’s environment in such a way that it is easier for the child to feel relaxed and confident about their speaking abilities. Statistically, boys are more likely to stutter than girls are and genetically there are 2 out of 3 people who stutter that have family members who also have a history of stuttering. (NHS, 2019)

Treatment plans mainly depend on the person’s age and circumstances. These treatment plans are divided into indirect therapy, direct therapy, psychological therapies, and feedback devices.

Indirect therapy builds on focusing less on the speech of the child but rather on how the parents talk with their child and changing the environment at home. Indirect therapy usually recommends the parents to speak in a slow and calm way to their child, avoiding interrupting the child as well as criticizing it. The parent(s) could also optimize the environment in a way that makes it comfortable too. Although, it may also be helpful to identify the things that assist the child in improving speech fluency and focusing on amplifying these things. The parent(s) should also make family members take turns in conversations.

This type of therapy is suitable in the case of the child being older than 5 and hasn’t been stuttering for any more than several months, while also getting worse at communicating.

Direct therapy is different for younger and older children. 

For younger children, the Lidcombe Program is prevalent in behavioral therapy for stuttering in children. It is a program that is made for the parent(s) that is supervised by a speech therapist. The fundamentals of the program rely on regular feedback that is not harmful but constructive and sympathetic. 

For older children (late-onset stuttering) it is more challenging to treat. This is due to the fact that with time the child will acquire various problems associated with stuttering such as being anxious about and afraid of speaking because of the potential to stutter at any time. In addition, this may cause embarrassment and thus, the child will associate stuttering with it. For this reason, the direct therapy for older children pays attention to the social, psychological, and emotional perspectives in regard to stuttering.

In most cases with children old enough to attend school, direct therapy is used to better communication abilities and make the child process its feelings that are linked to stuttering while also aiding increased fluency and understanding of speech dysfluency. Moreover, direct therapy assists in being open about stuttering experiences as well as in gaining self-confidence and more positive attitudes toward stuttering.

However, direct and indirect therapy are not the only solutions as psychological therapy and feedback devices exist.

Psychological therapy is not a direct treatment, although, this type of therapy is meant to combat unfavorable feelings connected to stuttering. It consists of several subtypes of psychological therapy such as solution-focused brief therapy, personal construct therapy, neurolinguistic programming, and cognitive behavioral therapy.

Feedback devices are auditory-based electronic devices that modify the way a child hear their own voice. These feedback devices can have different features like delayed auditory feedback, frequency-shifted auditory feedback, and combined delayed and frequency-shifted auditory feedback.

The following general guidelines for speaking to someone who stutters should be followed with respect to lowering the demands and the risk of overwhelming the child. The children have to be given time in order to process and think about everything being said and their own responses. (NHS, 2018b)

Effects of stuttering

As a result of stuttering as a person, they may make ways of trying to disguise their stutter. For this reason, they may adopt behaviors that make them hide from social interactions, differ in the way they speak, being fearful, frustrated, shameful, or embarrassed of their stutter. In addition to this, they may also try to get past saying specific words that are hard for them to pronounce without stuttering.

All of this may contribute to being self-conscious in certain situations, such as when they have to speak to an authoritative person like a teacher, reading a text in class, answering in front of the class, or having a conversation over the phone. (NHS, 2018a)

Conclusion

In conclusion, it is clear that stuttering is caused by various things in terms of both developmental stuttering and late-onset stuttering. Stuttering is mostly caused by social pressure that has been put on a child in developmental stuttering. However, it is different for late-onset stuttering as its causes are incredibly situational and generally get caused by accidents. Sometimes stuttering happens because of being inherited from parents.

The treatments for stuttering are also shockingly situational as it depends on what type of stuttering it is as well as the roots the stuttering stems from. Although, if the stuttering is not treated the affected individual may avoid certain social situations and therefore limiting their fx academic potential.

References:

NHS. (2018a, October 3). Stammering – How it can affect you. National Health Service. https://www.nhs.uk/conditions/stammering/symptoms/

NHS. (2018b, October 3). Stammering – Treatment. National Health Service. https://www.nhs.uk/conditions/stammering/treatment/

NHS. (2019). Overview – Stammering. NHS. https://www.nhs.uk/conditions/stammering/

Prasse, J. E., & Kikano, G. E. (2008). Stuttering: an overview. American Family Physician, 77(9), 1271–1276. https://pubmed.ncbi.nlm.nih.gov/18540491/

Smith, A., & Weber, C. (2017). How Stuttering Develops: The Multifactorial Dynamic Pathways Theory. Journal of Speech, Language, and Hearing Research, 60(9), 2483–2505. https://doi.org/10.1044/2017_jslhr-s-16-0343