Chimeric Antigen Receptor T-Cell Therapy

Indications

Chimeric antigen receptors usually contain an extracellular domain that binds to a specific antigen on tumor cells, a transmembrane domain, and intracellular domains that signal T-cell activation to attack tumor cells. Tisagenlecleucel is a cluster of differentiation (CD) 19-directed genetically modified autologous T-cell immunotherapy that involves reprogramming a patient’s T-cells with a transgene encoding a CAR to identify and eliminate CD19-expressing cells, both malignant and normal. The CAR comprises 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 that 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.[3][4][5][6][7]

Besides the 2 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):

• Epidermal growth factor receptor(EGFR) - non-small cell lung cancer, epithelial carcinoma, and glioma
• Variant III of the epidermal growth factor receptor (EGFRvIII) - glioblastoma
• Human epidermal growth factor receptor 2(HER2) - ovarian cancer, breast cancer, glioblastoma, colon cancer, osteosarcoma, and medulloblastoma
• Mesothelin - mesothelioma, ovarian cancer, and pancreatic adenocarcinoma
• Prostate-specific membrane antigen(PSMA) - prostate cancer;
• Carcinoembryonic antigen(CEA) - pancreatic adenocarcinoma, breast cancer, and colorectal carcinoma
• Disialoganglioside 2(GD2) - neuroblastoma and melanoma;
• Interleukin-13Ra2 - glioma
• Glypican-3 - hepatocellular carcinoma
• Carbonic anhydrase IX(CAIX) - renal cell carcinoma
• L1 cell adhesion molecule(L1-CAM) - neuroblastoma, melanoma, and ovarian adenocarcinoma
• Cancer antigen 125 (CA 125) - epithelial ovarian cancer;
• Cluster of differentiation 133 (CD 133) - glioblastoma and cholangiocarcinoma
• Fibroblast activation protein(FAP) - malignant pleural mesothelioma
• Cancer/testis antigen 1B(CTAG1B) - melanoma and ovarian cancer
• Mucin 1 - seminal vesicle cancer
• Folate receptor-a(FR-a) - ovarian cancer [8]

Contraindications

Both medications have no contraindications per packing insert, but caution is advised in patients with autoimmune disorders and solid organ transplants.

Equipment

For administering both CAR-T cell treatments, it is important to confirm the patient’s identity with the patient identifiers on the infusion bag, as they are all for autologous use. A leuodepleting filter cannot be used, and central venous access is the recommended method for infusion. Interleukin-6 antagonists (ie, tocilizumab or siltuximab), corticosteroids, and emergent equipment are needed before infusion and during the recovery period in case of side effects.

Personnel

Both medications require administration at a certified healthcare 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 near the certified healthcare facility for at least 4 weeks following infusion.

Complications

Multiple side effects are associated with CAR T-cell therapy. The most common 2 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, and 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 1 to 2 weeks of cell administration. The management of cytokine-release syndrome is based on the grade, including 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 5 days after administration. The management of CRES is also based on the grade of the components of the neurological assessment score by CARTOX-10 (CAR-T-cell-therapy-associated toxicity 10-point neurological assessment), intracranial pressure, and the presence of seizure or motor weakness. The management of CRES is similar to CRS, which primarily involves 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 should be elevated. Neurology consultation and evaluation are also warranted.[9] Other reported adverse effects are summarized below based on the system.[10]

• 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.

Clinical Significance

The first CAR-T cell treatment approved by the United States Food and Drug Administration(FDA) in August 2017 was 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 2 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 US 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 2 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. Neither treatment indicates patients with primary central nervous system(CNS) lymphoma. According to the US National Institute of Health clinical trial registration, multiple clinical trials are underway with CAR-T cell treatment for different malignancies, including multiple myeloma, CNS tumors, hepatocellular carcinoma, lung cancer, etc.[3][4][5][6]

Enhancing Healthcare Team Outcomes

Providing CAR T-cell treatment to the patient requires an interprofessional team of healthcare professionals, including 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 into the patient for tumor attack. Clinicians are required to perform both leukapheresis and infusion. Different specialty clinicians may also be required; for example, in some facilities, the dialysis clinician performs leukapheresis, and an oncology clinician delivers immunotherapy. The clinician's significant role is to care for the patient, especially during and after the transfusion. Close attention is required to monitor adverse effects, including early symptoms and signs of cytokine-releasing syndrome and CAR-T-cell-related encephalopathy. Various physicians in different specialties are required, especially when adverse effects occur. Pharmacists are important before treatment because Interleukin-6 antagonists (ie, tocilizumab or siltuximab), corticosteroids, and emergent equipment are needed before 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 are 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.