Cytokine Release Syndrome and Neurotoxicity After CAR T-Cell Therapy

While the use of chimeric antigen receptor (CAR) T-cell therapy has increased rapidly, the clinical benefit seen with these products comes at a cost for patients who experience toxicities related to the induction of a powerful immune response.

The most frequent of these immune-mediated toxicities are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

“The spectrum of symptoms [for CRS] runs from mild to severe,” said Bilal Siddiqui, MD, of the University of Texas MD Anderson Cancer Center in Houston. “The mild cases manifest as fever and flu-like symptoms, but they can become more severe. They can involve the lungs, they can cause a drop in blood pressure, and in the most severe cases, blood pressure can get so low that patients actually have to go into the intensive care unit to get really aggressive treatment.”

“CRS is usually reversible and we use medicines to switch off the immune system, the most common being corticosteroids and targeted medications like tocilizumab (Actemra) — these are really the workhorses of how we reverse CRS,” he added.

Tocilizumab — an interleukin (IL)-6 receptor inhibitor — was approved by the FDA in 2017 for the treatment of severe or life‐threatening CAR T cell‐induced CRS in patients ages 2 years and older, and is now widely used to manage CRS associated with CAR T-cell therapy.

Like CRS, ICANS symptoms can range from mild to severe, with mild cases manifesting as confusion or tremor, Siddiqui said. “But, it can become severe and lead to seizures, nonresponsiveness, swelling in the brain, [and] coma, and so this is something that we take very, very seriously and treat seriously and aggressively.”

According to guidelines from the American Society of Clinical Oncology, the mainstay of ICANS treatment is supportive care and corticosteroids. Tocilizumab will not resolve it and may, in fact, worsen it. Thus, the management of ICANS may take priority over low-grade CRS in cases where these toxicities occur simultaneously.

“The two toxicities tend to happen very quickly with immunotherapy — often within hours of the initial infusion, so that for the most part, patients do need to be monitored in the hospital so that we can catch these side effects early and jump on them,” Siddiqui said.

The incidence of CRS has been reported to range from 57% to 93% and ICANS from 20% to 70%. The frequency and severity of these toxicities can vary depending on which CAR T-cell therapy is being used, which disease is being treated, and even among patients who have the same disease and same CAR T-cell product, said Michael Jain, MD, PhD, of the Moffitt Cancer Center in Tampa, Florida.

As to which patients are more susceptible to CRS or ICANS, “one of the biggest determinants of the likelihood of getting these toxicities is often related to the tumor burden that the patient has,” he added.

In a retrospective study of 142 patients, the number of lymphoblasts in bone marrow before lymphodepletion, peak concentration of IL-6, and C-reactive protein levels were independent risk factors for CRS in patients with acute lymphocytic leukemia treated with CAR T-cell therapy. Clinical stage of lymphoma and high tumor burden in marrow for patients with multiple myeloma were also independent risk factors for CRS.

Jain said that co-stimulation is also a key factor in activating T cells, and products that use CD28 for co-stimulation are likely to produce more CRS and neurotoxicity than products that use 4-1BB.

“There are things we do as physicians that can also influence the likelihood of getting these toxicities, such as giving steroids or anti-cytokine drugs as prophylaxis, or intervening earlier for lower-grade toxicities,” he said. “While we’ve gotten better at preventing these toxicities — I would say for most products the likelihood of getting grade 3 or higher CRS is generally less than 10% and can get a lot lower for some products — sometimes, despite our best efforts, patients will get severe versions of these toxicities.”

Emerging Treatments

Jain pointed out that the IL-1 receptor antagonist anakinra (Kineret) has emerged as a common agent used after tocilizumab and/or with corticosteroids, and is being evaluated in a number of prospective trials for the prevention and treatment of CRS and/or ICANS.

In a retrospective study of 43 patients with B-cell or plasma cell malignancies, researchers found that treatment with anakinra appeared to be feasible and safe for refractory CRS or ICANS after CAR T-cell therapy, and that a higher dose may lead to faster resolution and was independently associated with lower treatment-related mortality. Moreover, they observed an overall response rate of 77% after CAR T-cell therapy in these patients, suggesting anakinra had a limited effect on its efficacy.

Another agent being tested in this area is the novel Janus kinase (JAK)1 inhibitor itacitinib. In a phase II study of 47 patients treated with axicabtagene ciloleucel (axi-cel; Yescarta) for relapsed/refractory large B-cell lymphoma, itacitinib was well tolerated and resulted in a lower rate and grade of CRS and ICANS compared with placebo.

Lenzilumab, a granulocyte-macrophage colony-stimulating factor neutralizing monoclonal antibody, is also being evaluated for the management of CRS and ICANS. In a phase Ib trial of lenzilumab given in combination with axi-cel, the overall response rate was 83% in six patients with advanced diffuse large B-cell lymphoma, with no incidence of severe CRS or neurotoxicity at the recommended phase II dose.

“What is changing is that now we have a greater armamentarium of these anti-cytokine drugs that we can use to try and shut down these toxicities when they occur,” Jain said.