Immunotherapy, including CAR T-cell therapy, has become a fourth arm of cancer therapy and a mainstay in the armamentarium of treatment options for patients with cancer. CAR T-cell therapy is potent but comes with some unique toxicities, including cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS).

“About half of patients require ICU management and fatalities have occurred,” said Elizabeth J. Shpall, MD, UT MD Anderson Cancer Center, who moderated Management of Toxicity of Immune Cell Therapy.

“Clearly multi-departmental infrastructure is required for the safe and careful management of this patient population,” she said.

During the session, Shpall and other experts updated attendees of the management of toxicity of immune cell therapy. Their talks were discussed in further detail during a live panel discussion later in the meeting.

CRS grading, management

Shpall opened the session with a discussion of CRS, a systemic inflammatory response caused by cytokines released by the CAR T-cells and other immune cells that results in reversible organ dysfunction.

All-grades of CRS are common in both acute lymphoblastic leukemia (ALL) and in adults with non-Hodgkin lymphoma treated with CAR T-cell therapy, with grade 3 or higher CRS occurring in a smaller percentage of patients.

Patients with grade 4 or higher CRS experience the most dramatic side effects and biomarkers of CRS compared to those with lesser grade CRS. With grade 4 or higher, fever happens almost within the first day of infusion and max temperature is higher than with lower grades of CRS, Shpall said. Patients with severe CRS also have lower systolic and diastolic blood pressure, higher heart rates and respiratory rates, as well as lower serum albumin/protein and higher weight changes.

Multivariable analysis has shown independent predictors of CRS include high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, and thrombocytopenia before lymphodepletion.

According to Shpall, for consensus grading of CRS the CRS has to be attributable to no other causes. That means one must rule out infection or other reasons for the side effects, and fever must be greater than 38°C. After treatment, fever is no longer required for CRS grading, and CRS grading is driven by hypotension and hypoxia. CRS grade is determined by the more severe event.

Shpall also discussed mainstays of management of CRS, tocilizumab and steroids.

ICANS

Bianca D. Santomasso, MD, PhD, of Memorial Sloan Kettering Cancer Center, discussed ICANS related to CAR T-cell therapy.

Severe ICANS can occur a few days after CRS, she said. In almost all cases, neurotoxicity events are reversible.

Studies have shown some association between CRS and ICANS. For example, patients who developed more severe CRS developed severe ICANS. However, some patients developed severe ICANS after fever alone.

Neurotoxicity is best described as global encephalopathy or delirium with aphasia, seizure or seizure-like activity, obtundation, tremor or myoclonus, hallucinations, and in rare cases, rapid onset cerebral edema. Although CRS resolves rapidly with IL-6R blockade, this does not appear to be the case with ICANS, Santomasso said.

Trials have looked at risk factors for ICANS and found both patient- and product-related risk factors. Patients with ALL or diffuse large B-cell lymphoma appear to be at higher risk for severe ICANS, particularly those patients with higher tumor burden. Patients with pre-existing inflammatory or endothelial activation, those with performance status greater than ECOG 0, and those with thrombocytopenia before lymphodepletion may also be at increased risk.

Santomasso noted that CAR T-cell products also appear to play a role in ICANS. Some factors can include lymphocyte composition, the CAR T-cell target, dose, and infusion type.

Ongoing studies are also looking into correlates of severe ICANS, including higher peak CAR T-cell expansion in the blood, earlier onset of fever, higher C-reactive protein and higher ferritin, and elevated serum cytokines, as well as multiple other factors.

Santomasso also discussed ASTCT consensus grading for CRS and ICANS, the use of immune effector-cell associated encephalopathy (ICE) score, and the management of ICANS including prophylactic and early interventions.

“ICANS is a unique acute toxicity that requires vigilant monitoring, aggressive supportive care, and specialized management,” Santomasso said.

Mitigating IEC toxicities

Sattva S. Neelapu, MD, UT MD Anderson Cancer Center, discussed mitigation strategies for immune effector cell (IEC) toxicities.

Corticosteroids are frequently used for the management of CRS and ICANS, Neelapu said. But a critical question is whether corticosteroids affect CAR T-cell efficacy.

A retrospective study of 100 patients with relapsed or refractory large B-cell lymphoma who had received steroids within 30 days of CAR T-cell therapy showed that use of corticosteroids was associated with shorter progression-free survival and a trend toward lower progression-free survival in patients with longer duration of corticosteroids. The researchers also observed that corticosteroid use was associated with shorter overall survival. Neelapu noted that these data are not definite but do raise the question of the optimal way to use corticosteroids and whether something different could be done to mitigate toxicities.

Current strategies to mitigate toxicities are mostly reactive, he said. Research is being done now to find strategies to prevent these toxicities altogether.

A possibility is altering CD3ƺ. One study tested this theory by altering immunoreceptor tyrosine-based activation motif  (ITAM) domains present on CD3ƺ on the CAR and found that the 1XX variant appeared to be optimal and produced strong effector functions without shutting off memory programs. 1XX also favored persistence of highly functional CARs and decreased inflammation.

Another study has suggested that altering the non-signaling domain on a CAR molecule could alter or mitigate toxicity. In this study, researchers altered the length of the CD8α hinge and transmembrane region. This decreased cytokine production but retained cytolytic activity in preclinical studies. This was tested in a phase 1 trial of 25 patients with relapsed or refractory B-cell lymphoma. At the highest dose tested the complete response rate was 55 percent and they only found grade 1 CRS with no evidence of ICANS.

Another possible strategy to mitigate CAR T-cell toxicity is using allogeneic CAR-NK cell therapy, Neelapu said. A study of this approach was tested in 11 patients with relapsed or refractory B-cell malignancies. In this study, the researchers observed a 73 percent complete response rate with no CRS or neurotoxicity.

Neelapu closed his presentation by discussing alternative methods to mitigate toxicities associated with existing CAR T-cell products such as targeting GM-CSF or IL-1.

Community adoption

Panelists took questions from attendees during the live Panel Discussion including one question on how the emerging strategies to manage toxicities will impact community adoption of CAR T-cell therapy and T-cell receptor engineering in the future.

In response, Shpall encouraged community practice to have rigorous guidelines and training for multidisciplinary teams in order to have all the pieces in place to do these procedures safely. She also encouraged practices to participate in Foundation for the Accreditation of Cellular Therapy training.

“By going through their training session and getting accredited, you have the adoption of the best practices for managing toxicities,” Shpall said. “Many community centers are becoming accredited, and it is enhancing patient safety as these new products come along and are offered in community settings.”