Chimeric antigen receptors (CARs) are recombinant receptors for antigens which redirect the specificity and function of T lymphocytes and/or other immune cells in a single molecule. The concept of using CARs in cancer immunotherapy is that CARs, which are programmed targeting tumor-associated antigens, can be replicated rapidly and homogeneously. Direct infusion of these armed tumor targeting T-cells bypass the barriers and kinetics of active immunization. Unlike general passive immunization using a direct antibody, CAR-modified T-cell with supraphysiologic activities work as an active medication, interacting with tumor-associated antigens which resulting in both immediate and long-term effects of anti-neoplasm.
Chimeric antigen receptors usually consist of an extracellular domain that binds to a specific antigen on tumor cells, a transmembrane domain and intracellular domains that provide signals for T-cell activation to attack tumor cells. Tisagenlecleucel is a cluster of differentiation (CD) 19-directed genetically modified autologous T-cell immunotherapy which involves reprogramming a patient’s own T-cells with a transgene encoding a CAR to identify and eliminate CD19-expressing cells, both malignant and normal. The CAR is made up of a murine single-chain antibody fragment; this recognizes CD19 and fuses to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta. The CD3 zeta component is critical for initiating T-cell activation and anti-tumor activity, while 4-1BB enhances the expansion and persistence of tisagenlecleucel. Upon binding to CD19-expressing cells, the CAR transmits a signal to promote T-cell expansion, activation, target cell elimination, and persistence of the tisagenlecleucel cells. Axicabtagene ciloleucel is another CD19-directed genetically modified autologous T-cell immunotherapy which binds to CD19-expressing cancer cells and normal B cells. Following anti-CD19 CAR T-cell engagement with CD19-expressing target cells, the CD28 and CD3-zeta co-stimulatory domains activate downstream signaling cascades that lead to T-cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines. This sequence of events leads to the killing of CD19-expressing cells.
Besides the two approved medications targeting CD19 on B lymphocytic cells treating B-cell malignancies, multiple tumor-associated antigens have been under investigation in targeting various types of cancer, especially in solid tumors. The following is a summary of reported tumor-associated antigens from a recent review, listing first the target and then the associated tumor(s) :
Both medications have no contraindication per packing insert but caution is advised in patients with autoimmune disorders and solid organ transplants.
For administration of both CAR-T cell treatments, it is of great importance to confirm the patient’s identity with the patient identifiers on the infusion bag as they are all only for autologous use. Leuodepleting filter cannot be used, and central venous access is the recommended method for infusion. Interleukin-6 antagonists (i.e., tocilizumab or siltuximab), corticosteroids and emergent equipment are needed before infusion and during the recovery period in case of side effects.
Both medications require administration at a certified health-care facility. It is essential to monitor the patient daily for at least 7 days following infusion for signs and symptoms of CRS and CRES. The patient should also be instructed to remain within proximity of the certified health-care facility for at least 4 weeks following infusion.
Multiple side effects are associated with CAR T-cell therapy. The most common two are cytokine-release syndrome(CRS) and neurologic toxicities, also known as CAR-related encephalopathy syndrome (CRES).
Cytokine-release syndrome is the most common adverse effect of CAR T-cell therapy. It presents with high fever, low blood pressure, hypoxia, with or without multi-organ toxicities including cardiovascular, gastrointestinal, respiratory, renal, hematological, and nervous system. The trigger for this condition is the activation of T-cells on the engagement of their T-cell receptors or CARs with cognate antigens expressed by the tumor cell. It typically occurs within the first week after CAR T-cell therapy and generally peaks within one to two weeks of cell administration. The management of cytokine-release syndrome has as its basis the grade which includes components of temperature, systolic blood pressure, oxygen saturation, and possible toxicity to other organs. The primary points for management include supportive care (ie, acetaminophen and hypothermia blanket for fever; intravenous fluid for dehydration or hypotension; supplemental oxygen for hypoxia), corticosteroids and Interleukin-6 antagonists.
CAR-related encephalopathy syndrome is characterized by typical manifestations similar to toxic encephalopathy with early signs of diminished attention, language disturbance and impaired handwriting. Other symptoms and signs include confusion, disorientation, agitation, aphasia, somnolence and tremors. The pathogenesis of CRES is unclear for now. It typically happens within the first five days after administration. The management of CRES is also based on the grade with components of neurological assessment score by CARTOX-10 (CAR-T-cell-therapy-associated toxicity 10-point neurological assessment), intracranial pressure and presence of seizure or motor weakness. The managements of CRES are similar to CRS which are primarily supportive care, corticosteroids and Interleukin-6 antagonists. To minimize the risk of aspiration and increase cerebral venous flow, the head of the patient’s bed is recommended to be elevated. Neurology consultation and evaluation are also warranted.
Other reported adverse effects are summarized as below based on system.
Constitutional: Fever, rigor, malaise, fatigue, anorexia, arthralgia.
Neurological: Headache, change in the level of consciousness, delirium, aphasia, apraxia, ataxia, hallucination, tremor, dysmetria, myoclonus, facial nerve palsy, seizure.
Hepatic: Transaminitis, hyperbilirubinemia.
Hematologic: Anemia, thrombocytopenia, neutropenia, febrile neutropenia, lymphocytopenia, B-cell aplasia, prolonged prothrombin time, prolonged activated partial thromboplastin time, elevated d-dimer, hypofibrinogenemia, disseminated intravascular coagulation, hemophagocytic lymphohistiocytosis.
Cardiovascular: Tachycardia, widened pulse pressure, hypotension, arrhythmia, decreased left ventricular ejection fraction, troponinemia, QT prolongation.
Pulmonary: Tachypnea, hypoxia.
Renal: Acute kidney injury, hyponatremia, hypokalemia, hypophosphatemia, tumor lysis syndrome.
Gastrointestinal: Nausea, emesis, diarrhea.
Musculoskeletal: Myalgia, elevated creatine kinase, weakness.
The first United States Food and Drug Administration(FDA) approved CAR-T cell treatment, in August 2017, is tisagenlecleucel. It is indicated in patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in the second or later relapse. It also has indications in adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma. The second U.S. FDA approved CAR-T cell treatment, in October 2017, is axicabtagene ciloleucel which is indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Of note, neither treatment has an indication for patients with primary central nervous system(CNS) lymphoma. According to U.S. National Institute of Health clinical trial registration, multiple clinical trials are currently going on with CAR-T cell treatment for different malignancies including multiple myeloma, CNS tumor, hepatocellular carcinoma, lung cancer, etc.
Providing CAR T-cell treatment to the patient requires an interprofessional team of healthcare professionals that includes physicians in different specialties, nurses, pharmacists, and laboratory technologists. CAR T-cell therapy preparation is from the patient's peripheral blood cells obtained via leukapheresis and infused back to the patient for tumor-attacking. Nurses are required to perform both leukapheresis and infusion. Different specialty nurses may also be required, for example, in some facilities the dialysis nurse performs leukapheresis, and an oncology nurse delivers immunotherapy. It is a significant role of the nurse in taking care of the patient especially during and after the transfusion. Close attention is required for monitoring any adverse effect including early symptoms and signs of cytokine-releasing syndrome and CAR-T-cell-related encephalopathy. A variety of physicians in different specialties are required especially when adverse effects occur. Pharmacists are important prior to treatment because Interleukin-6 antagonists (ie, tocilizumab or siltuximab), corticosteroids, and emergent equipment are needed prior to infusion and during the recovery period in case of side effects. Critical care may also warranted if side effects are severe and need to stand by during and after the medication infusion. Neurology consultation and evaluation and required if neurotoxicity occurs. The adverse effect can happen in most organs or systems, interprofessional communication and opinion exchange are essential when taking care of a patient undergoing CAR-T cell therapy especially in the situation of any adverse effect.[Level V]