Thérapie cellulaire CAR-T : le revers de la médaille

La thérapie cellulaire CAR-T est très controversée . Ses deux effets secondaires les plus importants - le syndrome de libération de cytokines et les neurotoxicités - ont été abordés lors d'un symposium (article en anglais).

A controversial therapy in cancer treatment

CAR-T cell therapy is highly controversial in research. The two most important side effects, cytokine release syndrome, and neurotoxicities were presented and discussed in a symposium.

CAR-T cell therapy is highly effective, very expensive and associated with significant side effects. The two most important side effects, cytokine release syndrome, and neurotoxicity were presented and discussed at a symposium chaired by Elizabeth J. Shpall, MD Anderson Cancer Center, Houston, Texas, USA, on May 31 at the 2019 Annual Meeting of the American Society of Clinical Oncology (ASCO).

CAR-T cell therapy involves the ex vivo production and multiplication of CAR-T cells from the patient's T cells by genetic modification. These manipulated cells are infused into the patient after conditioning, usually with cyclophosphamide and fludarabine. Using the chimeric antigen receptor (CAR), the CAR-T cells recognize their target cells, bind to them and kill them. In most cases, the patients remain in the clinic for about 7 days after the infusion, but according to Shpall, the therapy is increasingly carried out on an outpatient basis as well.

Effective, expensive and sometimes poorly tolerated

In August 2017, the FDA approved Tisagenlecleucel (Kymriah, Novartis), the first CAR-T cell therapy, initially for the treatment of relapsed refractory ALL in children and young adults up to 25 years of age, and in May 2018 for adults with r/r NHL (relapsed or refractory non-Hodgkin lymphoma). The costs for the first indication in the USA are about 475,000 US dollars, for the second about 373,000 US dollars.

In October 2017, the FDA approved Axicabtagene ciloleucel (Yescarta, Kite Pharma) for the treatment of adult patients with relapsed or refractory diffuse large cell B cell lymphoma (DLBCL) and primarily mediastinal large cell B cell lymphoma (PMBCL) following two or more systemic therapies. The cost in the USA is 373,000 US dollars. In both cases, the FDA requires a Risk Evaluation and Mitigation Strategies (REMS).

The response rates to the therapy are impressive, 40 to 60% of patients with refractory B-cell diseases show a persistent complete response. However, the treatment is associated with characteristic side effects such as cytokine release syndrome (CRS, cytokine storm) and immune cell-associated neurotoxicity syndrome (ICANS). Up to 50% of patients require intensive care and an experienced team is a prerequisite for successful treatment.

The Cytokine Storm

A CRS occurred in adults with NHL in studies with tisagenlecleucel in 58%, with axicabtagene ciloleucel (axi-cel) in 93% of the cases, with 23% and 12% respectively being assigned to severity level 3 or higher. In the median, it took 3 or 2 days for the CRS to begin and it lasted 7 or 8 days in the median.

A comparison of clinical and real-world data from Axi-cel showed a high agreement in frequency and severity of adverse effects, which, according to Shpall, means that the therapy can be therapy standard even under real-world conditions, provided that the treatment team has the appropriate expertise.

CRS is characterized by fever, a drop in blood pressure and respiratory insufficiency and is associated with an increase in cytokines in serum. At higher degrees of severity, the fever occurs very quickly and reaches higher values than in less severe forms, the blood pressure drops more strongly, the heart rate increases higher. Hematopoietic effects such as a greater decrease in hemoglobin, thrombocytes, and fibrinogen should also be considered. Hematologic toxicities can also occur late up to 60 days after the infusion. The more severe the course, the greater the increase in the cytokines interferon gamma, interleukin-6 (IL), IL-8, IL-10, and IL-16.

Risk factors for a severe CRS are a high tumor load, conditioning with cyclophosphamide and fludarabine, a high CAR-T cell dose and thrombocytopenia before depletion.

The IL-6 antagonist tocilizumab, which leads to a rapid decrease in IL-6 levels and a decrease in symptoms, is suitable for the therapy of CRS. Steroids are also suitable. According to recent studies, both therapies do not influence the efficacy of CAR-T cell therapy, so there is currently a tendency to use it earlier, although the optimal time of application is not yet known.

In animal models, the IL-1 receptor antagonist Anakinra also proved to be effective and additionally reduced neurotoxic effects.

Shpall presented the CARTOX program developed at the MD Anderson Cancer Center in Houston to diagnose and manage CAR-T cell toxicities. CARTOX provides intensive training for all professional groups involved in the treatment and discusses all protocols on a regular basis. An app for toxicity assessment and management will also be available from 7 June 2019.

Neurotoxic side effects

Neurotoxicities can occur when a CRS has completely disappeared, according to Bianca D. Santomasso, Neurological Department, Memorial Sloan Kettering Cancer Center, New York. ICANS shows global encephalopathy, aphasia, cramps, tremors, and hallucinations. Diffuse cerebral edema is rare. Although it is self-limiting, it can potentially be life-threatening and lead to death. Symptoms and prevalence were different in different studies. ICANS of severity 3 and above occurred in 12 to 30% of patients with lymphoma and in 13 to 42% with leukemia.

In severe ICANS, CAR-T cells usually expanded strongly, patients fevered early and had elevated serum cytokine levels. In addition, the cytokine levels in the cerebrospinal fluid are elevated.

New consensus papers on the severity classification of neurotoxic side effects facilitate safe administration of therapy because they provide the framework for the best therapeutic strategies, including prophylactic and early interventions.

Tocilizumab is not recommended for the treatment of isolated severe ICANS and glucocorticoids are used in most centers. In patients treated with glucocorticoids, the efficacy of CAR-T cell therapy is not limited; it is unclear whether they affect the duration of the response.

The other site of CAR T-cell therapy: cytokine release syndrome, neurologic toxicity, and financial burden. Educational Symposium, 2019 ASCO Annual Meeting, Chicago, May 31 to June 4, 2019.