6.6.4 Severe Side Effects and Toxicities
While CAR T cell therapy has shown impressive clinical benefit, it is sometimes associated with a variety of toxicities that can be life-threatening.Several death cases were reported, especially in the last year.These were due to neurotoxicity caused by cerebral edemas in the CD19-CAR trials sponsored by Juno Therapeutics.After the first reported deaths, the trial was interrupted and the conditioning regimen was changed from cyclophosphamide and fludarabine to cyclophosphamide alone.However, soon after re-initiation, two more fatal cases excluded the conditioning regimen as causative.These fatal outcomes are on the one hand surprising when considering that other ongoing CD19-CAR T cell trials did so far not report cumulating fatal cases of cerebral edemas.On the other hand, there had been at least one fatal outcome of neurotoxicity in another CD19-CAR T trial 122 days after CAR T cell infusion.Furthermore, reversible symptoms of neurotoxicity including confusion, delirium, expressive aphasia, encephalopathy, and seizures were reported in several other studies.In some patients, CD19-CAR T cells have been found in cerebrospinal fluid.Whether neurological toxicities are solely restricted to CD19-specific CAR T cells or generally associated with CAR T cell therapy remains to be elucidated.Indeed, the potential causes for the occurrence of neurotoxicity are under debate.The postulated pathophysiological mechanisms include cytokine diffusion and/or translocation of activated CAR T cell across the blood-brain barrier [165,167,169,170].
A direct connection to another frequent side effect, the cytokine-release syndrome (CRS), appears likely.CRS has so far been the most frequent observed adverse drug reaction.The hallmark of CRS is immune activation resulting in elevated inflammatory cytokines especially IL-6.Symptoms such as high fever, fatigue, nausea, tachycardia/hypotension, and cardiac dysfunction have most often been reported in trials with CD19-CARs but also occurred when other antigens of hematological malignancies, or mesothelin for the treatment of solid tumors, were targeted.Systemic corticosteroid administration rapidly reversed symptoms in most cases, but can result in ablation of the infused CAR T cells, thus limiting the anti-tumoral effect.A currently preferred alternative is treatment with tocilizumab, a therapeutic IL-6 receptor blocking antibody, which does not affect CAR T cell persistence.However, one death case has been reported due to severe CRS with multi-organ failure 3 days after the CAR T cell infusion, despite treatment with tocilizumab, the TNFα inhibitor etanercept, and corticosteroids [165,167,168,171].
Besides CRS and neurotoxicity, other severe complications have been observed.In contrast to the former, however, their pathogenesis is better understood and can thus be more easily prevented.Tumor lysis syndrome (TLS) results from rapid tumor cell death leading to metabolic disturbances like hyperuricemia and hyperkalemia, among others.TLS has been reported for at least four different studies treating hematological malignancies.Notably, one ALL patient died from acute TLS 12 h after receiving a second CD19-CAR T cell infusion.Reducing tumor size before treatment and/or controlling the extent of tumor lysis by adapting the amount of infused CAR T cells can be applied to control TLS [165].
Both cellular and humoral immune responses resulting in the rejection of CAR T cells have been observed.This did not only limit the anti-tumoral activity but resulted in acute anaphylaxis for some patients after the third infusion with CAR T cells harboring mouse scFv sequences.To circumvent this unwanted immune reaction, only humanized scFv should be used in the future.Seven ongoing clinical trials are using humanized CAR constructs [164].(https://www.daowen.com)
On-target, off-tumor recognition has become a relevant concern, since many targeted tumor antigens are also expressed on normal tissue.Among these, B-cell aplasia is a common adverse event in CAR T cell trials targeting B-cell malignancies.The CD19 as well as CD20 antigen is expressed by transformed malignant as well as healthy B cells, which are therefore killed by CD19-specific or CD20-specific CAR T cells.The severity of B-cell aplasia ranges from transient to long lasting.Notably, B-cell aplasia is a surrogate marker, rather than a causative factor of CAR T cell activity.Patients can have a durable response even without B-cell aplasia, although in most trials, B-cell aplasia correlates with clinical benefit.In addition, patients have been described with ongoing long-term remission with recovered B-cell counts.B-cell aplasia can be effectively managed by infusion with gamma globulin as replacement therapy, although this is certainly costly especially in case of long-term treatment.In addition, CD20-CAR T cells have been reported to damage normal tissue in sites around lesions due to a low-level expression of CD20 on normal,non-B-cell tissue leading to dyspnea and respiratory distress [165,172].
The most severe case of on-target toxicity was reported in a trial targeting ErbB2 in patients suffering from lung carcinoma.Due to the recognition of ErbB2 on normal lung cells, one patient died from rapid respiratory failure and multi-organ dysfunction.Lowering the T-cell dose and using second instead of third-generation CARs may prevent this type of toxicity [173].
To improve the safety and efficacy of CAR T cell therapy, 4th-generation CARs as well as smart CARs have entered clinical trials.These may overcome the obstacles encountered in the current trials, such as loss of targeted antigen, off-target toxicity, or low persistence.For example,NCT02465983 uses a pooled CAR T cell product consisting of mesothelin- and CD19-specific CAR T cells.In the clinical trial description available at ClinicalTrials.gov, the investigators hypothesize that this combination therapy may prolong the duration of mesothelin-specific CAR T cells in the body, due to the ablation of B cells and thus CAR-specific antibodies by the CD19-CAR T cell.In contrast, NCT02737085 applies sequential infusion of CD19- and CD20-targeted CAR T cells to reduce the risk of B-cell relapse through a CD19 escape mutation.In the same context, NCT02903810 uses a pooled CAR T cell product consisting of CD19- and CD22- specific CAR T cells.In addition,eight trials having a suicide gene or suicide switch integrated have been initiated [165].