What is the role of cytokines in CAR T cell therapy?

CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines released by infused CAR T cells can lead to widespread reversible organ dysfunction.

Can CAR T cells cross the blood brain barrier?

The study is first to show that a peripherally infused CAR T-cell therapy can cross the blood–brain barrier and infiltrate tumors.

What does Icans stand for?

Immune effector cell-associated neurotoxicity syndrome (ICANS) may manifest as delirium, encephalopathy, aphasia, lethargy, difficulty concentrating, agitation, tremor, seizures, and, rarely, cerebral edema.

What is the most common toxicity with car T cell therapy?

The most commonly observed CAR T-cell–associated toxicity is CRS. Fever is usually the first symptom of CRS. The time of onset of fever can be quite variable, ranging from a few hours to more than a week after CAR T-cell infusion.

How long do side effects of CAR T cell therapy last?

Signs of CAR T cell-related encephalopathy syndrome show up around one to four weeks after the transfusion and last two to four days. While these side effects can be upsetting, they’re reversible most of the time.

Does Pembrolizumab cross the blood-brain barrier?

These data are significant because pembrolizumab is a monoclonal antibody, which is a relatively large-molecule drug that does not readily cross the blood-brain barrier.

What is cytokine release syndrome?

(SY-toh-kine reh-LEES SIN-drome) A condition that may occur after treatment with some types of immunotherapy, such as monoclonal antibodies and CAR-T cells. Cytokine release syndrome is caused by a large, rapid release of cytokines into the blood from immune cells affected by the immunotherapy.

How is CRS treated?

Patients with severe CRS are treated with drugs that counteract the immune response. These medicines include targeted therapies to block specific cytokines, as well as more general immunosuppressive drugs. A common cytokine target is interleukin-6 (IL-6).

What is CAR T cell-related encephalopathy syndrome?

CAR-T cell-related encephalopathy syndrome Typically, patients develop an encephalopathy with dysphasia and disorientation. Seizures can occur, as can focal motor symptoms. 18. In some but not all patients experiencing these symptoms, CAR-T cells have been detected in the cerebrospinal fluid (CSF).

How long does it take to recover from CAR T-cell therapy?

This is a one-time infusion, although patients may remain in the hospital for several weeks to monitor response to treatment, overall condition, and side effects. Recovery: Patients who receive CAR T-cell therapy have a risk/recovery period of approximately 2-3 months.

Can immunotherapy cause brain damage?

Neurological adverse events following treatment with ICIs — which can involve headaches, encephalopathy, and meningitis — appear to be rare, according to a 2017 review of nearly 60 clinical studies that found that the overall incidence of neurological adverse events was, on average, 3.8\% with anti-CTLA4 antibodies, and …

What are the possible side effects of CAR T-cell therapy?

The two primary toxicities associated with CAR T-cell therapy include cytokine-release syndrome and neurotoxicity. Cytokine-release syndrome is generally self-limited but high-grade toxicities like hypotension and hypoxemia can be managed with agents that block the effects of IL-6, like tocilizumab, and/or corticosteroids.

What predictors of neurotoxicity are associated with CAR T-cell therapy?

Clinical predictors of neurotoxicity included younger age, preexisting neurologic comorbidities, fludarabine-containing conditioning, higher total CAR T-cell dose, higher peak CAR T-cell counts, early and/or severe CRS, cytopenias, and markers of diffuse intravascular coagulation.

What is the pathophysiology of neoneurotoxicity?

Neurotoxicity is associated with cytokine release syndrome, which occurs in the setting of in-vivo chimeric antigen receptor-T cell activation and proliferation.

When do neurologic symptoms occur after CAR T-cell leukemia treatment?

There have been three reported time periods in which neurologic symptoms occur: concurrent with CRS, shortly after CRS subsides, and a delayed form in the third or fourth weeks after CAR T-cell infusion ( 4, 25 ).