Cytokine Release Syndrome (CRS) From Immunotherapy

What Is Cytokine Release Syndrome?

Cytokine release syndrome is a systemic inflammatory condition that occurs when the body’s immune system responds aggressively to an infection or therapeutic interventions, such as CAR-T cell-mediated immunotherapy. By virtue of their immune-related functionalities, activated T cells release small chemical messengers, known as cytokines, which in turn stimulate and recruit other immune constituents and blood cells, such as monocytes, to mount an immune response.

However, in certain conditions, such as immunotherapy-related CAR-T cell infusion, the immune system may react too aggressively and release large amounts of these cytokine molecules in the bloodstream, causing cytokine release syndrome (CRS). CRS can result in various symptoms and manifestations in affected individuals, such as the onset of high fever, dip in blood pressure, respiratory insufficiencies, and inflammation throughout the body. CRS may lead to organ damage and sometimes death.

Who Does CRS Affect?

Individuals who are receiving T cell therapy or immunotherapy for cancer and other genetic ailments or immune dysfunctions may be affected by cytokine release syndrome. Individuals with large tumor burdens, autoimmune disease, the most extensive cancers and comorbidities, and those who develop the onset of CRS within three days of CAR-T cell infusion are at higher risk of developing a severe CRS from CAR-T cell therapy.

CRS can also develop as a response to a bacterial or viral infection, such as COVID-19. When the human body encounters an infectious agent, the immune system mounts a response to fight off the infection. However, sometimes the immune system triggers an overreaction to the infection, which may lead to the progression of CRS.

Causes of Cytokine Release Syndrome

CAR-T cell immunotherapy may result in the advent of cytokine release syndrome. Cytokines are small protein molecules that serve as immune system messengers for the stimulation, proliferation, and recruitment of blood and immune cells in response to an infection or adoptive CAR-T cell-mediated immunotherapy.

In general, the release of cytokines is a byproduct of effective T cell functioning, and CRS is considered an ‘on-target’ effect of CAR-T cell immunotherapy. Upon the infusion of CAR-T cells, the CAR engages with the specific antigen present on the cancer cells, which in turn, leads to the T cell activation and release of a variety of cytokines, such as IL-6, IL-2, and IFN-γ, for further immune activation.

However, the release of cytokines in an excess amount in response to T cell activation from CAR-T cell therapy may lead to CRS and cytokine-related immune and neurotoxicity, along with several other complications.

Symptoms of Cytokine Release Syndrome

Symptoms of CRS can range from fever and flu-like indications to widespread immune response and severe inflammation. Mild symptoms of CRS are characterized by a fever that tends to fluctuate, rapid heartbeat, low blood pressure, fatigue, headache, rashes, arthralgia, myalgia, etc. Severe CRS cases present hypotension and high fever and can progress to uncontrolled systemic inflammation and multi-organ system failure.

Furthermore, specific symptoms of CRS may vary depending on the most affected organ systems. For instance, when the respiratory systems are most affected, the symptoms may display as cough and shortness of breath and can progress to acute respiratory distress syndrome (ARDS).

Some patients with severe CRS can also develop renal failure, cardiac dysfunction, or neurologic complications spanning from headache, confusion, and dizziness to seizures, hallucinations, and decreased coordination and ability to control body movements.

Treatment of Cytokine Release Syndrome

CRS treatment can vary depending on the underlying condition of the patient, clinical signs, symptoms, and the severity of the CRS. For less severe cases of CRS, supportive and symptomatic treatment approaches are considered by managing fever, muscle pain, or fatigue.

Moderate to severe CRS may prompt the need for oxygen therapy, mechanical ventilation, IV fluids, and blood pressure and electrolyte-managing drugs. Immunosuppressive agents like corticosteroids and drugs that reduce inflammation by directly acting upon specific cytokines may be necessary to manage severe CRS conditions. IL-6 inhibitor Tocilizumab, Siltuximab, and Clazakizumab are some drugs used for managing severe CRS alongside other supplemental therapies.

Other approaches for CRS management include preventative measures that can potentially reduce CRS incidences after CAR-T cell therapy. One such approach is the reduction or adaptation of CAR-T cell dosage in accordance with the tumor burden and the type of malignancy to mitigate the severe CRS effectively.

Cytokine Release Syndrome vs. Cytokine Storm

Cytokine storm and cytokine-associated toxicity are other terms that are interchangeably used to denote cytokine release syndrome. However, the term cytokine storm more precisely represents a severe episode of CRS that is characterized by uncontrolled and excessive release of cytokines.

The clinical signs and symptoms of both CRS and cytokine storm appear similar but they vary in their characteristics. Upon the infusion of CAR-T cells, CRS symptoms may be delayed for days or weeks, while the cytokine storm is characterized by a severe and immediate onset of CRS symptoms.

Nanotein’s T_SCM Cells for CAR-T Cell Immunotherapy

In next-generation T cell therapy, stem cell memory T cells (T_SCM)—one of the less mature yet effective T cell states—are used because they are capable of self-renewal and expansion, unlike more mature states of T cells.

T_SCM is considered a clinically safe, highly effective, and endurable T cell type for immunotherapy purposes. In addition to their superior expansion potential, the higher content of T_SCM cells in CAR-T immunotherapy is shown to be intrinsically capable of curtailing cytokine production by regulating and diminishing monocyte activation.

Upon encountering an antigen on a cancer cell, T_SCM is activated to a lesser extent relative to other T cell types, thereby reducing CRS-related detrimental side effects without compromising the effective antitumor activity. Moreover, several pre-clinical and clinical studies revealed that the higher T_SCM content in T cell therapy persists for many years without relapse—unlike the first generation of CAR-T therapy—and shows better tumor neutralization with a higher survival rate.

CAR-T cell infusion products manufactured with Nanotein‘s activator consists of higher T_SCM cell content that not only provides superior performance of the CAR-T cell therapeutics end product but also alleviates the safety concerns over the occurrence of cytokine release syndrome, subsequently leading to better clinical outcomes for patients. To achieve better T cell activation and superior expansion efficiency, Nanotein Technologies also provides a T_SCM -enriching activation and expansion reagent to help improve CAR-T cell immunotherapy’s potential.

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