For many years, chemotherapy, surgery and radiotherapy have been the cornerstones of cancer treatment. Due to the severe side effects of traditional chemotherapy and radiotherapy, new classes of targeted drugs including monoclonal antibodies (for example, rituximab, cetuximab) and small molecule drugs (for example, tyrosine kinase inhibitors such as imatinib, dasatinib) have been introduced. They target cancer cells by homing in on specific molecular changes seen primarily in those cells and allowing the distinction between potentially harmful cells and healthy cells. These agents are ideally only toxic to the cells identified as harmful. Compared with conventional chemotherapy, they are usually less toxic and more comfortable for the patient.1,2
Many targeted therapies, including monoclonal antibodies (mAbs), non-specific immunotherapies, T-cell therapy, oncolytic virus therapy, and cancer vaccines use the patient’s immune system to fight the disease. Although immunotherapy has provided many new therapeutic approaches, cancer treatment still remains a challenge, especially in cases of failure or resistance to therapies. Patients with haematologic malignancies, for example, often have a poor prognosis in cases of disease progression after primary and secondary therapies. Novel treatment options are needed for patients who have failed multiple lines of chemotherapy.1,2 Whereas conventional cytotoxic drugs cause adverse events and toxicities by compromising defence mechanisms, immunotherapy may induce serious overwhelming inflammatory responses and auto-immunity, thereby complicating their use.1,2 Several types of immunotherapy are under study in clinical trials to determine their effectiveness in treating various types of cancer, or have recently been licensed: one such type is chimeric antigen receptor (CAR) T-cell therapy.
Basis of CAR-T therapy
T-cells can be genetically modified to express CARs. These are fusion proteins containing both an antigen recognition moiety and T-cell activation domains.3–5
CAR T-cell therapy starts with the collection of T-cells from the patient. This is performed by apheresis and the cells are re-engineered in a laboratory where they are genetically engineered to produce CARs on their surface. These modified cells, known as CAR T-cells, allow the T-cells to recognise an antigen on targeted tumour cells. These re-engineered CAR T-cells are then multiplied and the number of genetically modified T-cells expanded by laboratory cell culture. The CAR T-cells are consequently frozen and, when there are sufficient quantities, are infused into the patient. The engineered immune cells recognise targets with high precision and have the potential to decrease the non-selective toxicity that is observed with conventional chemotherapeutics.2,4
So far, CAR T-cells targeting the CD19 antigen on B-cells have been used successfully in relapsed or chemotherapy-refractory acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, and non-Hodgkin lymphoma. CAR T-cells can produce durable remissions in haematological malignancies that are not responsive to standard therapies.6
CAR T-cell therapies have shown promising results in other indications and have also been studied in early stages for solid tumours.2,3,5 Currently, the main pharmaceutical players leading this field are Kite Pharma (KTE-C19), Novartis (CTL019) and Pfizer (UCART19). Tisagenlecleucel (Kymriah, Novartis Pharmaceuticals Corp) and axicabtagene ciloleucel (Yescarta, Kite Pharma) have been FDA approved.
However, following CAR T-cell infusion, potentially severe and unique side effects including immune-mediated adverse events have been observed. These can be acute, delayed, mild, severe, and/or persist for the duration of the genetically modified T-cell lifespan.
CAR T-cell-related toxicities
CAR T-cell therapy is associated with serious toxicities. The most acute, feared, troublesome and common toxicity in patients treated with CD19-specific CAR T-cells is cytokine release syndrome (CRS).3,4,7
Other toxicities include macrophage activation syndrome/haemophagocytic lymphohistiocytosis, neurotoxicity, febrile neutropenia, tumour lysis syndrome, fever and hypogammaglobulinaemia.3,4,7
CRS, a potentially life-threatening condition, is a systematic inflammatory response caused by cytokines released by the infused CAR T-cells or other immune cells, such as macrophages, that might produce cytokines in response to cytokines produced by the infused CAR T-cells.3,6,7 The expected time of onset varies depending on the type of CAR T-cells used.3,6
When CRS occurs, there is a rapid and huge release of cytokines into the patient’s bloodstream, leading to high fevers and drops in blood pressure.3,6 Symptoms in general can range from mild to life-threatening. CRS caused by CAR T-cells often manifests as high fever, myalgia, fatigue, anorexia, hypotension, pulmonary oedema, and coagulopathy.8,9 Progressively worsening CRS can lead to multi-organ dysfunction including (but not limited to) cardiovascular, pulmonary and renal failure. Fortunately, with timely and appropriate management, CRS is reversible in the vast majority of patients despite severe abnormalities.
A modification of the Common Terminology Criteria for Adverse Events10 has resulted in a grading mechanism suitable for grading CRS due to T-cell therapies.6,10,11
- Grade 1 symptoms: require symptomatic management
- Grade 2 symptoms: respond to moderate intervention, including oxygen requirement < 40%, grade 2 organ toxicity, or hypotension responding to intravenous fluids or low doses of one vasopressor
- Grade 3 CRS: includes oxygen requirement ≥ 40%, hypotension requiring high-dose or multiple vasopressors, grade 4 transaminitis, and grade 3 organ toxicity at other sites.
- Grade 4 CRS: life-threatening symptoms requiring ventilator support or grade 4 organ toxicity other than transaminitis
mAbs against IL-6 receptors, such as tocilizumab (approved for treatment of severe, active and progressive rheumatoid arthritis), have been used off-label for toxicity following CAR T-cell therapy. Tocilizumab has recently been FDA approved for the treatment of CAR T-cell-induced CRS. Such mAbs could represent a therapeutic option for the management of CRS.3,6 Tocilizumab, a humanised mAb, blocks the IL-6 receptor and subsequent signalling. This results in decreased production of anti-inflammatory mediators. Its use as a rescue medication for severe CRS due to CAR T-cell therapy, has been associated with near-immediate reversal of CRS symptomatology (for example, fever, hypotension, respiratory distress).3
Dosages for tocilizumab can range from 4mg/kg to 8mg/kg (maximum of 800mg per dose) for patients ≥30kg. Tocilizumab is infused intravenously over 60 minutes.3 A subsequent dose can be considered for patients with persistent symptoms after 12–24 hours. The acquisition of tocilizumab should be considered for all patients undergoing CAR T-cell therapy.3 Pharmacists and clinicians must ensure that tocilizumab (or other anti-cytokine therapy) is available on site and available for administration prior to CAR T-cell infusion so that patients can receive the drug as quickly as possible when needed.
Because of the high cost and the potential of severe adverse events (for example, infections, reactivation of viruses, tuberculosis, and hepatotoxicity), the use of tocilizumab should be limited strictly to critically ill patients.1 The use of corticosteroids remains controversial. Administration of high-dose corticosteroids in the treatment of CRS results in decline in detectable CAR T-cells via apoptosis.3 Dosing of steroids (intravenous methylprednisolone and dexamethasone) should be performed on protocol-specific recommendations and characteristics of the individual patient. Dexamethasone is the preferred agent, due to superior central nervous system penetration.4,7 The corticosteroids should be tapered quickly based on symptom resolution to diminish the CAR T-cell effect.
Other agents that have been considered or used in the management of CRS are siltuximab, etanercept, infliximab and anakinra; however, there are limited data so far.4,6,7
Macrophage activation syndrome/haemophagocytic lymphohistiocytosis
Some patients might experience CRS with symptoms similar to macrophage activation syndrome (MAS) or haemophagocytic lymphohistiocytosis (HLH).3,7 Studies have shown that tocilizumab does not prevent the development of MAS/HLH and its complications.3
Central nervous system toxicities
Patients may also experience severe neurological toxicities such as altered mental status, confusion, aphasia, delirium and even seizures and coma.7 It remains important to monitor the degree of confusion, somnolence and encephalopathy to determine appropriate management of symptoms (CAR T-cells detectable in the cerebrospinal fluid).6 Some case-reports of lethal cerebral oedema in patients treated with CAR T-cells have been described.12 The pathophysiology of these neurotoxic effects is still unclear but inflammatory cytokines seemto be involved.1,7
Because dexamethasone has excellent CNS penetration, its use can considered in cases of severe and life-threatening neurologic symptoms requiring urgent medical intervention.3,6 Antiepileptic prophylaxis, such as levetiracetam, can be given to patients at risk of seizures.
Tumour lysis syndrome
Tumour lysis syndrome (TLS) has been reported in patients treated with CD19-targeted cells, especially in patients with chronic lymphocytic leukaemia.7,13 TLS complications are usually managed as per standard of care, that is, prophylactic allopurinol, fluids and rasburicase as needed.7,13
Following administration of chemotherapy followed by CAR T-cells, patients frequently become neutropenic and lymphopenic. This can predispose patients to opportunistic infections. The degree and rates of neutropenia vary depending on the conditioning regimen received. Prophylaxis with granulocyte colony-stimulating factors may be initiated 24 hours after completion of the conditioning regimen and continued until neutrophil recovery. Prophylactic antimicrobials may also be considered for patients with neutropenia.
Nearly all patients develop fever after CAR T-cell infusion with 80–100% having grade 3 or greater fever. Supportive treatments include use of acetaminophen for all patients who develop fever. Non-steroidal anti-inflammatory drugs should be avoided.6
This is a common condition observed with the profound and prolonged B-cell aplasia that occurs following anti-CD19 CAR T-cell infusions. Replacement therapy with intravenous immunoglobulins has been used.6,7
CAR T-cell therapy is a powerful new tool in the oncologist’s arsenal and can induce remissions (CD19 CAR T-cell) in otherwise refractory children and young adults with acute lymphoblastic leukaemia. Recently, tisagenlecleucel (Kymriah® Novartis) and axicabtagene ciloleucel (Yescarta®, Kite Pharma) have been FDA approved. CAR T-cells bring spectacular opportunities, but also challenges, for pharmacists, especially in the management of side effects and toxicities. Supportive care and early anti-cytokine therapy is absolutely required to mitigate the life-threatening consequences of severe CRS. Education of pharmacists involved in CAR T-cell infusion and knowledge of potential side effects is important.
1 Kroschinsky F et al; Intensive Care in Hematological and Oncological Patients (iCHOP) Collaborative Group. New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management. Crit Care 2017;21(1):89.
2 Shoushtari AN et al. Principles of cancer immunotherapy. www.uptodate.com/contents/principles-of-cancer-immunotherapy (accessed December 2017).
3 Shank BR et al. Chimeric antigen receptor T cells in hematologic malignancies. Pharmacotherapy 2017;37(3):334–45.
4 Bonifant C et al. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics 2016;20;3:16011.
5 Clinical trials. http://www.Clinicaltrials.gov
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8 Maude SL et al. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 2014;20(2):119–22.
9 Minagawa K, Di Stasi A. Novel toxicology challenges in the era of chimeric antigen receptor T-cells therapies. Transl Cancer Res 2016;doi:10.21037/tcr.2016.09.06.
10 Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Published: May 28, 2009 (v4.03: June 14, 2010). https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_… (accessed December 2017).
11 Lee DW et al. Current concepts in the diagnosis and management of cytokine release syndrome [published correction appears in Blood. 2015;126(8):1048]. Blood 2014;124(2):188–95.
12 Garde D, Keshavan M. Two patients deaths halt trial of Juno’s new approach to treating cancer. www.statnews.com/2016/11/23/juno-cancer-immunotherapy-deaths-2/ (accessed June 2017).
13 Porter DL et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011;365(8):725–33.