Supervised by: Yuhui Zhou, BA (Hons). Yuhui is a 5th year medical student at the University of Cambridge. She gained a First class degree in her intercalated year studying Pathology. She has an interest in Cancer & Immunology and has been awarded a Wellcome Trust Biomedical Vacation Scholarship to study host responses to infection.
Introduction
Cancer is generally defined as a malignant process of autonomous, unregulated cell proliferation with the ability to spread or metastasize to distant organs (Young Ok et al. 2018). It starts from the conversion of normal cells into tumor cells in an extensive process that transforms them from a precancerous lesion to a malignant tumor. Cancer cells stimulate angiogenesis or blood vessel growth which supplies nutrients to tumors (CST n.d.). These cells multiply rapidly and require large amounts of nutrients and energy to feed this growth, which can cause fatigue and organ failure. The immune system fights this uncontrolled growth through killer cells, yet even these cells can become cancerous through genetic mutations. Some types of cancers have evolved in a way that makes them imperceptible to these killer cells. Cancer is caused by genetic factors as well as external agents, some of the most common being physical, chemical, and biological carcinogens (WHO 2022). With physical carcinogens, a patient may have been exposed to ultraviolet or ionizing radiation, chemically they may have been exposed to a contaminant such as asbestos or arsenic, and biologically they may have had pre-existing infections from bacteria, viruses, and parasites (WHO 2022).
The body may fight cancer in many different ways and with the help of modern medicine, doctors have been able to come up with numerous treatments to suit a patient’s needs better. Chemotherapy is a medication that uses strong chemicals to kill rapidly growing cells in one’s body and is most commonly used to treat cancer because cancer cells grow and multiply much faster than the rest of the body’s cells (Mayo Clinic 2022). However, because chemotherapy travels throughout your whole body, it kills healthy cells too. Luckily, there are alternatives. For this paper, we will be focusing mainly on immunotherapy, more specifically CAR T-Cell Therapy (CART) and Immune Checkpoint Inhibitors (ICI). Immunotherapy is a highly promising cancer treatment; it uses the immune system’s power to fight cancer cells (John Hopkins Medicine 2020). The way this works is by using substances made by the body or in a laboratory to improve how the immune system works (Cancer.Net 2022). CART, sometimes referred to as cell-based gene therapy, is a type of immunotherapy where T-Cells are given to a patient in order to fight diseases, namely cancer. Usually, T-Cells are taken from a patient’s blood or bone marrow into the laboratory, where they are changed by adding a gene for receptors which helps T-Cells attach themselves to a specific cancer antigen (American Cancer Society 2022). These are then put back into a patient’s body with the hopes of better targeting and killing cancer cells.
On the other hand, ICIs are immunotherapy drugs. Immune checkpoints activate when checkpoint proteins partner with their partner proteins. Immune checkpoint proteins on the surface of T-cells bind to their partner proteins on other cells and send an “off” signal to the T-Cells, which stops the immune system from destroying cancer. ICIs block checkpoint proteins from binding with their partner proteins. This prevents the “off” signal from being sent to the immune system which allows T-Cells to kill the cancer cells (National Cancer Institute 2022). These two treatments are the future of immunotherapy, however, they are also fairly new and in research/trial stages at the time of writing. Before treating patients with these immunotherapies, it is important to identify side effects that may arise and damage patients’ health, to ensure that they are comfortable and want to pursue these treatment routes. In this paper, we hope to provide an overview of unforeseen effects that coincide with CART and ICIs in regard to patients undergoing immunotherapy.
Methodology
To find scientific articles, we used public search engines such as Google Scholar, PubMed, National Library of Medicine, and many more. However, accessing the full text for these articles often brought us to different websites or search engines. For CAR T-Cell Therapy, our searches consisted of “immune issues CAR T-cell therapy”; “autoimmune side effects CAR T-cell therapy”; “CAR T-cell therapy in hematologic malignancies: A voyage in progress”; “CAR T-cell therapy neurological adverse effects”; “cerebral edema CAR T-cell therapy”; “Cytokine release syndrome neurological adverse effects”. For Immune Checkpoint Inhibitors, our searches consisted of “Immune Checkpoint Inhibitors, adverse effects”; “Immune checkpoint inhibitors, thyroid disorders”; “immune checkpoint inhibitors, cardiac disorders, PD-1/PD-L1, CTLA-4, Ipilimumab, cardiac, endocrine system, hematological effects”; “immune checkpoint inhibitors, neurological adverse effects”; “immune checkpoint inhibitors, neurological autoimmunity”; “immune checkpoint inhibitors, nerve disorders”.
Results
CAR T-Cell Therapy
Most T-cells recognize foreign cells though the antigen that the cells have which normal body cells do not have. However, certain cancers have evolved that prevent T-cells from recognizing the cancer’s antigen and therefore letting the cancer alone continue to grow. To combat this issue, CAR T-cell therapy (CARTCT), which is a type of immunotherapy, was created. This is when chimeric antigen receptor (CAR) T cells are harvested either from a donor or the patient and are genetically engineered using CRISPR technology to express a specific CAR (eg, using a retrovirus) that recognizes the neoantigens that are expressed on the cancer cell’s surface (Sterner 2021). As a result, the T-cells are now able to selectively target and kill any cells expressing that antigen (eg, CD19, HER-2) (Grigor et al. 2019). CARs are made of an extracellular antigen-binding domain of an immunoglobulin which is connected via transmembrane domains to the intracellular T-cell receptor signaling parts (Dai 2016), which allows the redirection of lymphocytes, and an intracellular T-cell signaling domain that triggers CAR T-cell activation (Sievers et al. 2020). This structure means that the T-cells are able to recognize unprocessed antigens and be activated in a way independent from the major histocompatibility complex (MHC) (Jackson et al. 2016); this results in powerful anti-tumor responses due to high T-cell activation (Sadelain 2013).
CARTCT has been very successful in treating cancers such as hematological malignancies, particularly B cell malignancies (Holstein et. al 2019, Boyiadzis et al. 2018), but it has not been as effective on solid tumors for various reasons. However, toxicities can occur as a result of CARTCT, regardless of what kind of cancer it is being used to treat. This is because the engineered T-cells die if the CARs antigen binding affinity is too high (Liu et al. 2015, Caruso 2015). The side effects covered in this review include On-target/Off-target toxicity graft versus host disease, cytokine release syndrome (CRS), infection, and neurotoxicity. Antigen escape will also be covered as it is one of the major issues with CARTCT. These toxicies have been limiting the development and research of CARTCT use on solid tumors (Wagner et al. 2020). Furthermore, it has been shown that the design of the CAR, the specific target, and the tumor type most likely determine if the patient experiences side effects and the severity of these toxicies (Roex 2020). Most patients that have received the first FDA approved CARTCT, CD19-directed CARs, have experienced some sort of toxicity (FDA 1 2017, FDA 2 2017). Sometimes these toxicities have proven to be life-threatening in clinical trials (Maude et al. 2015, Schuster et al. 2018, Park et al. 2018). However, many of these toxicities are reversible.
Antigen Escape and “On-Target/Off-Target” Toxicity
Although single antigen targeting CAR-T cells can deliver high response rates initially, in certain cases, the patient’s tumor becomes resistant to single antigen targeting CAR constructs (Sterner et al. 2021). This can happen if a significant portion of the CAR T-cells display partial or complete loss of target antigen expression, which is what antigen escape is. The issue with antigen escape is that when a patient is initially treated with CARTCT, the therapy may work and the cancer is battled, but the patient may relapse. For example, 70–90% of patients with relapsed and/or refractory ALL positively respond to CD19 targeted CARTCT, data has shown that a disease resistance mechanism has developed. Around 30–70% of patients who have recurrent disease after treatment had loss of the CD19 antigen (Majzner et al. 2018, Maude 2015). To combat the relapse rates, some CARTCT are targeting multiple antigens (Sterner et al. 2021). Many of these new strategies use either CAR constructs or tandem CAR, which target multiple target tumor antigens (Sterner et al. 2021). There are several clinical trials that suggest that these strategies may result in prolonged durable remission rates (Rafiq et al. 2020). Unfortunately, many antigens that are often expressed on solid tumor antigens are also expressed on normal tissues, making targeting solid tumors difficult. If the antigens are not selected properly then it can result in the modified T-cell killing too many non-cancerous cells, which can trigger many immune responses. This phenomenon is called “on-target off-tumor” toxicity and is the cause for many toxicities, including the ones discussed later on. More research has to be done on the types of antigens that can be used for CARTCT so that a balance can be struck where therapy is effective, but is not towards either extreme so as to cause antigen escape or “on-target off-tumor” toxicity.
Graft Versus Host Disease (GVHD)
In a meta-analysis of 42 hematologic cancer studies (775 patients) and 18 solid cancer studies (138 patients), graft versus host disease (GVHD) was reported in three of the seven hematologic cancer studies that administered an allogeneic product (44 evaluable patients). The pooled prevalence of GVHD was 23.4% demonstrated among patients treated with CAR-T cell therapy (Grigor et al. 2019). GVHD is almost always a result of a transplant, as the patient’s immune system reacts to the new cells as foregin and attacks them. The immune system recognizes the difference between histocompatibility antigens which activates GVHD (Mansouri et al. 2021). However, there is a lack of knowledge of which cases had GVHD and if they had anything in common. For example, did the patients have GVHD where the T-cells harvested from the patient or a donor? In order to further develop our understanding of CARTCT and its effects, clinical trials should report if any patients experienced GVHD, the severity of GVHD in the patient, and if the GVHD affected the patient’s response to CARTCT. CARTCT could become the first-line treatment for many cancers, but that can only happen if the risks are fully understood and easily treatable.
Cytokine Release Syndrome (CRS)
Cytokine release syndrome (CRS) is the most common adverse effect to CARTCT as the meta-analysis used in the previous section found CRS was experienced by 55.3% of patients with hematologic malignancies (Brudno et al. 2019). As a result of its prevalence, CRS is the most understood and recorded side effect of CARTCT; it is characterized by high fevers, sinus tachycardia, hypotension, hypoxia, depressed cardiac function, and other organ dysfunction. It has been theorized that CRS is caused by a release of inflammatory cytokines from the CAR T-cells as it is associated with supraphysiologic cytokine production and massive in vivo T-cell expansion (Sadelain 2013). Interestingly, CRS is more common in patients with hematologic malignancies, as the meta-analysis found that CRS was only reported in two solid cancer studies and the pooled prevalence was 5.4% (Grigor et al. 2019). Patients at high risk of severe CRS include those with large tumor burdens, those with comorbidities, and those who develop early onset CRS within 3 days of infusion, although occasionally severe CRS can occur outside of these parameters (Maude et al. 2014, Davila et al. 2014). However, inhibition of macrophage activating and monocyte activating cytokine GM-CSF with lenzilumab has decreased CRS and increased CAR T-cell activity (Sterner et al. 2020, Sterner & Kenderian 2019, Sterner, Cox et al. 2019). CRS can be treated, especially if it is mild, but in severe cases, it is difficult to know if and how early steroids should be administered. CRS is the most understood side effect of CARCTC in that the specificities of what causes this reaction is known. The next step to making CARTCT safer for use is to focus on the treatment of CRS at all levels. Since CRS symptoms are displayed within the first week after administering CARTCT, early and effective treatment that does not impact the effectiveness of the CARTCT to cause antigen escape need to be established. Treatments for CRS are available, however, the specificites mentioned earlier must be well established for each grade of CRS. If this adverse effect of CARTCT is able to be managed and without detriment to the patient, then CARTCT will be an option for many more patients than it currently is.
Infection
Infection can be caused by variable factors, however, a patient’s immune system must have not been able to kill the germ early on. This could be a result of the body being overloaded by too many foriegn cells. In the meta-analysis, infection was reported in 14 hematologic cancer studies and the pooled prevalence was 12.2%; infection was assessed in two solid cancer studies and the pooled prevalence was 13.6% (Grigor et al. 2019). Throughout our research, this meta-analysis was the only source that mentioned infection. This is most likely because infection is a rare side effect of CARTCT and is, in the majority of cases, non-lethal and easily treatable. However, one concern may be the fragile state that the patient’s immune system is in during treatment. As for many of these side effects, the biggest worry is making sure that the patient is able to recover from the toxicity and that the patient’s weakened immune system will not cause other issues.
CAR T-Cell Therapy Associated Neurotoxicity
While Adaptive T-Cell Therapy has shown to be effective against leukemia, its successes are offset by its ability to cause neurotoxicity in the brain. It has been reported that 32-64% of patients being treated with CAR T-Cell Therapy have experienced neurological adverse effects (Hay 2018). Neurotoxicity has been shown approximately 5 to 7 days after treatment with CAR T-Cells (Hay 2018). Both cytokine release syndrome and neurotoxicity are the most commonly reported effects from Adaptive T-Cell Therapy (Grigor et al. 2019). Cytokine release syndrome causes a variety of neurological disorders, many of which are poorly understood, especially in relation to CRS. It has been shown that CRS may cause symptoms such as hypoxia (when there is not enough oxygen to supply tissues and organs), fever, hypotension, vascular conditions like cytopenias, coagulopathy, decreased cardiac function, and many more (Bhutta et al. 2022, Adkins 2019). This is because Adaptive T-Cell Therapy enables immune cells to destroy cancer cells by releasing inflammatory cytokines. The danger with this hypersecretion of cytokines is that they don’t specifically target the cancer cells, but rather other surrounding cells and tissues. This phenomenon can explain the variety of adverse effects associated with CARTCT.
The most common neurological adverse effect associated with CARTCT is encephalopathy (Dholaria et al. 2019), which refers broadly to a sudden change in the function of the brain (Malmo 2021). The release of cytokines from CAR T-cells can also cause changes in neuron excitability, production of neurotransmitters, and oxygen delivery to the cerebral tissue of the brain (Galic et al. 2012). Specifically, interleukin cytokines have been shown to increase the ability of neurons to excite themselves and initiate an electrical impulse, causing seizures and strokes. Cytokines from CAR T-cells have also been shown to change the synapses of neurons in the central nervous system, controlling vital functions of the body such as gut and neuroendocrine functions. More specifically, cytokines alter the polarization events occurring at the synapses of these neurons that stimulate impulses. This leads these neurons to release fewer neurotransmitters, ultimately causing effects like fever and malfunctions in the gastrointestinal tract.
In addition, CAR T-Cell Therapy has been associated with cerebral edema (Nehring et al. 2021). While the mechanism of this action is poorly understood, CAR T-Cells and cytokines increase the permeability of the blood brain barrier that supplies nutrients to and from the brain, causing the cerebrospinal fluid to spill in the brain and cause cerebral edema (Tóvolli et al. 2017, Calvo 2019, Cleveland Clinic 2019). Cerebral edema is characterized by swelling of the brain and can sometimes lead to death, but in most cases, it is reversible (Khoja et al. 2017). It can cause declines in language perception and cognition. Another neurological effect associated with CARTCT is cerebral malaria. The central nervous system malfunctions due to the rapid release of cytokines, causing subsequent microvascular malfunctions in the brain (Cleveland Clinic 2021, Stelmachowska-Banaś 2020).
There are no specific patterns of these neurological effects: the effects cannot be traced to one region of the brain and are very diverse in their pathologies. Furthermore, the relationship between CAR T-Cell Therapy and these neurological effects is poorly understood and requires further research in future.
Immune Checkpoint Inhibitors
The immune system is the primary line of defense against the development and spread of cancer. The failure of the immune system to identify and remove malignant cells plays a significant role in cancer progression. Luckily molecules that block immune checkpoint pathways in order to boost the host immune system’s activity against tumors have been developed and become a common treatment for many cancers. Checkpoint proteins, such as programmed cell death ligand-1 (PD-L1) on tumor cells and programmed cell death receptor-1 (PD-1) on T-cells, aid in the regulation of immune responses. The binding of PD-L1 to PD-1 prevents T-cells in the body from killing tumor cells. By inhibiting the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor, T-cells are able to kill tumor cells.
PD-L1 and PD-1 are two of the few Food and Drug Association (FDA) approved ICIs. New pathways and molecules are continuously being investigated in an effort to improve ICI therapy responses and application. It all started with ipilimumab (IPI) in 2011, the first FDA-approved ICI, which was used to treat patients with melanoma (De Filette et al. 2019). IPI is most commonly used with nivolumab as a treatment for non-small-cell lung cancer (NSCLC). In combination, they have resulted in longer progression-free and overall survival than ipilimumab alone (Larkin et al. 2019). Ipilimumab is an anti-cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) monoclonal antibody and nivolumab is an anti-PD-1 agent. CTLA-4 is a molecule that is overexpressed on the surface of active T-cells to dissuade T-cell receptors from being overstimulated (TCR). CTLA-4 competes with TCR co-stimulator receptors for ligand binding, preventing T-cell activation. On activated T-cells, PD-1 is also highly active. When PD-1 binds to its ligand, PD-L1, it sends a negative costimulatory signal that inhibits T-cell activation (Wei et al. 2018). The Blockade of CTLA-4 and PD-1 leads to immune-mediated anti-tumor responses. Anti-CTLA-4 and anti-PD-1 agents have improved the condition of multiple solid and hematologic malignancies (Wei et al. 2018).
In order to improve immune checkpoint inhibition therapy responses and application, new pathways and molecules are being investigated. While immunotherapy with ICIs has revolutionized the treatment of many types of advanced cancers, the majority of patients still do not benefit because only a small percentage of patients respond positively to these treatments.
Cardiac Toxicity
Immune-related adverse events (irAEs) can occur in any organ or tissue during ICI treatment. While cardiac irAEs are less common than irAEs in other organs, they still have a high mortality rate. Myocarditis and pericarditis are the two most common clinical manifestations of immunotherapy-related cardiotoxicity. Cardiomyocytes, like cancer cells, may use the PD-1/PD-L1 pathway to stop T-cell hyperactivation in a physiological state. ICIs, by alleviating tumor suppression of T-cells, can also alleviate cardiomyocyte suppression of T-cells, resulting in hyperactivation of T-cells in the heart. This consequently may result in ICI-associated cardiotoxicity. Furthermore, ICIs may have an effect on pre-existing cardiac disease, such as accelerating or decompensating pre-existing heart failure in affected patients. Many types of cardiac irAEs have been reported, typically myocardial injury, pericardial effusion, arrhythmia, acute coronary syndrome, and systemic vasculitis, along with valvular disease, hypertension, conduction disturbances, and even sudden cardiac death can occur. Initially, the incidence of ICI-related cardiotoxicity was estimated to be less than 1%, but then it was suggested that the actual prevalence of ICI-associated cardiotoxicity is most likely underestimated due to unspecified symptomatology, potential overlap with cardiovascular diseases and other diseases, and general lack of awareness of this condition.
Thyroid Toxicities
Immune checkpoints play a crucial role in maintaining immunological self-tolerance and preventing autoimmune disorders. Because Immune Checkpoint Inhibitors (ICIs) interfere with this balance they can cause immune-related adverse events (irAEs) which present themselves as autoimmune disorders affecting various organs within the body. One of the most common irAEs is endocrinopathies. The thyroid gland is the endocrine gland most commonly affected by ICI-related irAEs, although recent studies suggest that the occurrence of thyroid disorders relies heavily on the class of ICI used. Various thyroid disorders were noticed in approximately 7% of patients receiving ipilimumab, 19% of those receiving PD-1 and PD-L1 inhibitors, and 28% of those receiving ipilimumab and nivolumab combination therapy (De Filette et al. 2019, Wei 2018). It was also reported of even higher rates of thyroid disorders, involving up to half of the patients receiving combination therapy (Morganstein et al. 2017). The most common thyroid dysfunction is hypothyroidism followed by thyrotoxicosis (or hyperthyroidism). Hypothyroidism, often referred to as an underactive thyroid, is a condition in which your thyroid gland produces insufficient amounts of certain important hormones. In the early stages of hypothyroidism, there may be no noticeable symptoms but if left untreated hypothyroidism can lead to a variety of health issues, including obesity, joint pain, infertility, and heart disease. Thyrotoxicosis, on the other hand, is a condition in which you have too much thyroid hormone in your body. Untreated thyrotoxicosis can cause a heart rhythm disorder called atrial fibrillation, which increases your risk of stroke and congestive heart failure. Incidences of hypothyroidism were lower with the anti-CTLA-4 antibody when compared to anti-PD-1/anti-PD-L1 ranging from 3.9-8.5%, while combination therapy was associated with the highest estimated occurrence at 10.2-16.4% of patients. In thyrotoxicosis, ipilimumab had low frequencies of 0.2–1.7%, and similarly, anti-PD-1/anti-PD-L1 drugs had higher frequencies from 0.6–3.7% (Barroso-Sousa et al. 2018, De Filette et al. 2019, Baxi et al. 2018). Thyroid events occur in approximately 10% of patients treated with anti-PD-1/PD-L1 monotherapy, and up to 15-20% of those treated with combination PD-1/CTLA-4 blockade (Larkin et al. 2019).
Hematological Adverse Effects
Immune-related hematological adverse events are uncommon but potentially fatal side effects of immune checkpoint inhibitors. As the number of patients exposed to these agents grows, so does the spectrum of their toxicity. Nonetheless, they stay largely undisclosed to many clinicians, presumably because of the lack of specific diagnostic criteria, which makes identification and proper reporting difficult, and possibly due to their likelihood, which is often too low to be mentioned in most clinical trial publications. However, the most common hematological irAE is Thrombocytopenia (TCP). Clinicians are less familiar with ir-TCP, which often leads to misdiagnosis which causes a delay in adequate care and could lead to a worse prognosis. TCP is a condition characterized by a low platelet count in the blood. Platelets are colorless blood cells that clump together and form clots in blood vessel injuries to stop bleeding. Thrombocytopenia can occur as a result of a bone marrow disorder such as leukemia or an immune system problem and could also be a side effect of taking certain medications. Autoimmune hematologic toxicities caused by ICIs, such as thrombocytopenia, are considered rare irAEs, and the increased use of ICIs in advanced cancers makes a significant contribution to the increase in reports of immune thrombocytopenia. The risk of bleeding, arterial thromboembolism, or venous thrombosis is increased in ir-TCP patients. However, the true mechanism and pathogenesis of immunotherapy-related thrombocytopenia are unknown and require further investigation.
Neurological Complications
Patients with advanced cancer who are treated with ICIs are at a higher risk of having immune-related neurological problems. The most prevalent autoimmune neurological disorders, usually develop within 2-12 weeks of ICI treatment. IRAE caused by increased T-cell activation affects almost every organ. These effects vary in severity, including colitis, hepatitis, pneumonitis, hypothyroidism, autoimmune retinopathy, uveitis, or iritis, and rheumatic or musculoskeletal disorders. They are most usually responsible for a series of autoimmune neurological events affecting muscle, neuromuscular junctions, nerves, pathways, the spinal cord, and the brain. The number of new cases with neurological problems ranges between 2% and 4% in patients. Mild events affect up to 6-12% of patients and are characterized by unspecified neurological symptoms such as headaches, dizziness, paresthesias, or small-fiber sensory neuropathies that have no overall influence on ICI treatment administration. More significant events occur in less than 1% of patients, ranging from 0.4-0.2% with nivolumab and pembrolizumab, 0.3-0.8% with ipilimumab, and 2.4-14% with the combination of PD-1 and CTLA-4 inhibitors (i.e. ipilimumab with nivolumab) (Feng et al. 2017, Postow et al. 2018, Khoja et al. 2017). Although there are more neurological effects of ICIs, I have chosen the three which had the most information available to them when researching.
Neuropathies:
Neuropathy is caused by the injury or malfunction of one or more nerves, resulting in numbness, tingling, muscle weakness, and pain in the affected area. Neuropathies commonly begin in the hands and feet, but other areas of the body might be affected as well.
Neuropathies occur in less than 1% of patients and range in severity from small-fiber sensory (common with chemotherapies, not compromising ICI continuation) to more usual immune-mediated therapy seen in 0.1-0.2% of patients.
Hypophysitis:
Hypophysitis, immune-related toxicity, can occur in up to 5-10% of patients, usually 6-12 weeks following ICI commencement. A brain MRI may demonstrate amplification and edema of the pituitary gland as well as headache, weariness, disorientation, and various anterior pituitary hormone deficits.
Autoimmune Encephalitis:
Autoimmune encephalitis occurs in 0.1-0.2% of individuals within days or weeks of starting ICI treatment, specifically when patients are given ipilimumab and nivolumab in combination. Autoimmune encephalitis is a group of disorders in which the body’s immune system attacks the brain, causing inflammation. The immune system creates antibodies, which mistakenly target brain cells.
Immune Checkpoint Inhibitors-Associated Neurotoxicity
Immune Checkpoint Inhibitors can, although rarely, be associated with neurological adverse effects. Hyperactivity of immune cells from ICIs downregulating T-cells may cause immune cells to attack other parts of the body apart from cancer, such as the nervous system, which may explain why many of these adverse effects occur. However, there remains a lack of sufficient research into this topic, and the true, full relationship between ICIs and these neurological disorders is very poorly understood. The most commonly reported adverse effects on the brain from ICIs are headaches, dizziness, encephalopathy, and meningitis. Similarly to CAR T-Cell Therapy, there is no clear pattern of neurological adverse effects that patients exhibit after ICI treatment.
Other common disorders or diseases in the brain from ICIs are Guillain-Barré syndrome and peripheral neuropathy. Meningitis and encephalitis are the most common effects on the central nervous system. Meningitis (inflammation of the meninges) and encephalitis (inflammation of the brain) can also cause headaches. Guilllain-Barré syndrome, another effect, describes a condition in which the immune system attacks nerves in the body like several cranial nerves because of inflammation in the cerebrospinal fluid. Similar to this syndrome is immune encephalitis, aseptic meningitis, and enteric neuropathy, all involving the immune system attacking and killing neurons in the brain and spinal cord.
Demyelination of neurons in the central nervous system has also been reported, which can lead to other neurodegenerative disorders like Multiple Sclerosis. Immune demyelinating polyradiculoneuropathy is another adverse effect that involves demyelination of neurons in the cerebrospinal fluid of the brain. Transverse myelitis is also a disorder from ICIs that damages the myelin of neurons in the spinal cord, thus interfering with communication between the spinal cord and the rest of the body. It is not known why these neurons lose their myelin sheath as a result of ICI treatment.
ICIs have several neuromuscular effects as well. Myositis, for example, causes changes in skeletal muscles as a result of inflammation. Another example is myasthenia gravis, a disorder involving neuromuscular transmission issues. In addition, it has been observed that creatine kinase levels in the bloodstream increase following ICI treatment, which has been marked as an indicator of muscle injury. Lastly, oculomotor nerves in the eye have also been shown to be weakened following ICI treatment.
Discussion
Immune Checkpoint Inhibitors
As previously stated in this review ICI therapy has also been linked to the occurrence of various immune-related adverse effects, which vary between individuals depending on the drug, malignancy, and individual susceptibility. The skin and colon are the most mutually beneficial organs, while ICIs have a deleterious impact on the liver, lungs, kidneys, and heart. According to recent data, the prevalence of severe immune-related adverse events (irAEs) with CTLA-4 blockage is as high as 27 percent compared to 16 percent with PD-1 blocking. It may improve to 55% if both medications are used jointly (Larkin et al. 2015(. Melanoma patients appear to have a greater frequency of rash and colitis. CTLA-4 inhibition may cause more colitis, hypophysitis, and inflammation, whereas PD-1 inhibition is linked to pneumonitis, thyroiditis/hypothyroidism, arthralgias, and vitiligo (Khoja et al. 2017, Friedman et al. 2016).
Although short- to medium-term toxicity in most organ systems appears to be controllable and transient, some irAEs may have long-term repercussions. However, there has been nothing reported on the outcomes of people suffering from severe neurological toxicity, and the extent to which such rare but serious issues may be treatable.
Despite the fact that there have been numerous ICI drugs approved by the FDA there remains little information on its adverse effects. One reason could be the transparent disclosure of possible toxicities with patients which dissuades them from continuing or commencing ICI treatment in clinical/research trials. Because there are not many patients that voluntarily participate in studies there is limited literature on this subject. In addition, the high mortality rate of these trials causes clinicians to not recommend ICI treatment to their patients unless they are faced with a fastly progressing disease.
CARTCT
There is no standard as to how the side effects should be recorded. Many studies only reported toxicity if their patients were noticeably affected by it, or if the toxicity was severe enough to be life-threatening. If a clinical trial recorded any adverse effects, even if the number would be zero, finding patterns and trends among the data and making connections would be much easier. However, this can only be helpful if the severity of the toxicity is recorded as well.
For example, more patients with hematologic malignancies experienced CRS than patients with solid tumors, but was the CRS more severe in patients with solid tumors? If so then CARTCT is safer for patients with hematologic malignancies as although CRS is experienced at a higher rate, patients are able to recover and have a positive response to the therapy. Furthermore, if a patient does experience an unusually severe toxicity, possible causes should be recorded. For example, if a patient experienced particularly severe GVHD, information such as from whom the T-cells were harvested, any comorbidities, and any previous cancer treatments should be recorded. Furthermore, currently, there are multiple grading systems for CAR T-cell toxicity. This makes it difficult to compare CAR T-cell products across studies (Brodno et al. 2019); a universal grading system is essential to be able to spot trends and possible correlations in data from multiple different studies. Overall, safety is not equally reported in regard to CARTCT clinical trials, solid tumor studies having reported much less on reported safety outcomes of interest. Moreover, follow-up periods are short, which makes it difficult to analyze the long-term effects, safety, and durability of CARTCT (Grigor et al. 2019). It is understandable that studies need to be published so that others have access to the new data, but follow-up reports could be published, which could help inform patients and their physicians if CARTCT is right for them. Studies need to have a universal standard as to what information to include and on what kind of scale because it will make analyzing the data easier and quicker. Finding trends and patterns, and possible causes and effects, are essential not only to people in the field of oncology, but also to cancer patients themselves so they can analyze the possible risks and benefits of CARTCT and make a decision based on data.
Summary and Conclusion
Overall, both immunotherapies need improvement in terms of efficacy and safety. The adverse effects of both CARTCT and ICI are not fully understood, which can cause problems with treating patients who do react negatively. In order for these goals to be achieved, further research must be done to understand all the details of how these therapies work, as it is better to treat the cause of the illness rather than just the symptoms. If the underlying mechanism of the adverse effects are fully understood, then either treatment will become well-known and ready if need be or the technology could be modified to avoid severe side effects. Although both have their issues, ICI and CARTCT have potential in the field of oncology as both have different uses. CARTCT has promising potential in treating cancers such as lymphoma, but is most likely not going to be a top treatment when it comes to solid tumors. However, although treatment is important, the field of oncology should be researching the cause of cancer. If the genesis of most cancers are known, then prevention can be the key. As the saying goes, an ounce of prevention is better than a pound of cure; if cancer is prevented in the first place, then thousands of lives could be saved. However, immunotherapies and overall treatment of cancer help us understand the disease more, and so could help us understand what causes it and how to prevent it. For example, CRISPR, the technology used to edit the CAR T-cells, could be used to edit out genes that have been linked to cancer. Overall, although our research has shown promise for treatment, we have realized that there is no such thing as a medical treatment, whether it be a drug or therapy, without any side effects. In the end, the best way to save patients is by making sure that they do not get sick in the first place.
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