Chimeric Antigen Receptor (CAR) T-Cell Therapy


Article Author:
Chen Zhang


Article Editor:
Anup Kasi


Editors In Chief:
Rodrigo Kuljis
Oleg Chernyshev
Aninda Acharya


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
2/6/2019 10:39:11 AM

Introduction

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.[1][2]

Indications

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.[3][4][5][6][7]

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) [8]:

  • 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

Contraindications

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

Equipment

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.

Personnel

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.

Complications

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.[9]

Other reported adverse effects are summarized as below based on 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 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.[3][4][5][6]

Enhancing Healthcare Team Outcomes

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]


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Chimeric Antigen Receptor (CAR) T-Cell Therapy - Questions

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Based on early clinical trial data, chimeric antigen receptor therapy (CAR-T) has been most successful in which population?



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What is the most common adverse effect of chimeric antigen receptor therapy (CAR-T)?



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From the early clinical trials involving chimeric antigen receptor T cell therapy (CAR-T), cytokine release syndrome has been a major problem. To block the high levels of interleukin 6, what has been approved to use?



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On which malignancies is Chimeric Antigen Receptor T-cell therapy (CAR-T) being tested?



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In the recent clinical trials involving Chimeric Antigen Receptor T cell therapy (CAR-T), which complication led to a halt in the studies?



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To date in clinical trials, chimeric antigen receptor T (CAR-T) cell therapy has been used to treat which type of cancer?



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So far in the early clinical trials, chimeric antigen receptor-engineered T cells (CAR-T cells) have targeted which receptor in the treatment of acute lymphoblastic leukemia?



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Which condition has not been shown to respond to chimeric antigen receptor-engineered T cells (CAR-T cells) therapy?



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What are the present hurdles faced with chimeric antigen receptor-engineered T cells (CAR-T cells) therapy?



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What specific tumor-associated antigen was targeted by current approved CAR-T-cell therapy in treatment of relapsing or refractory lymphoma?



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What of the following is not an indication for tisagenlecleucel?



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Which of the following are early signs or symptoms of CAR-T-cell-related encephalopathy syndrome?



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Which of the following about cytokine-releasing syndrome is incorrect?



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A 22-year-old female with no significant past medical history presented with one month of intermittent fever, night sweats, and 15-pound weight loss without intention. She was worked up for possible underlying malignancy and was referred to the hematology clinic by her primary care provider due to "lymphoblastic cells in the peripheral blood smear." An extensive workup was done including flow cytometry of peripheral blood smear and a bone marrow biopsy. She was diagnosed with B-cell acute lymphoblastic leukemia (ALL) with positive Philadelphia chromosome. She was started on imatinib and went into partial remission but relapsed in the following months. Treatment was then switched to dasatinib, another tyrosine kinase inhibitor, with which no remission was achieved. She was recommended to start chimeric antigen receptor T-cells (CAR T-cells) therapy and started on tisagenlecleucel. Two days after the infusion of medication, she became short of breath and progressively worse. She was sent to the emergency department of her cancer center and intubated due to acute hypoxemic respiratory failure. She became hypotensive and was admitted to the intensive care unit. Hematology/oncology was consulted. Besides the ventilation and blood pressure support, which of the following medication is the best next step in this situation?



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Chimeric Antigen Receptor (CAR) T-Cell Therapy - References

References

Davila ML,Brentjens R,Wang X,Rivière I,Sadelain M, How do CARs work?: Early insights from recent clinical studies targeting CD19. Oncoimmunology. 2012 Dec 1     [PubMed]
Sadelain M,Brentjens R,Rivière I, The basic principles of chimeric antigen receptor design. Cancer discovery. 2013 Apr     [PubMed]
Vairy S,Garcia JL,Teira P,Bittencourt H, CTL019 (tisagenlecleucel): CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia. Drug design, development and therapy. 2018     [PubMed]
Schuster SJ,Bishop MR,Tam CS,Waller EK,Borchmann P,McGuirk JP,Jäger U,Jaglowski S,Andreadis C,Westin JR,Fleury I,Bachanova V,Foley SR,Ho PJ,Mielke S,Magenau JM,Holte H,Pantano S,Pacaud LB,Awasthi R,Chu J,Anak Ö,Salles G,Maziarz RT, Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. The New England journal of medicine. 2018 Dec 1     [PubMed]
Geyer MB, First CAR to Pass the Road Test: Tisagenlecleucel's Drive to FDA Approval. Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Nov 21     [PubMed]
Axicabtagene ciloleucel (Yescarta) for B-cell lymphoma. The Medical letter on drugs and therapeutics. 2018 Jul 16     [PubMed]
Ghobadi A, Chimeric antigen receptor T cell therapy for non-Hodgkin lymphoma. Current research in translational medicine. 2018 May     [PubMed]
Neelapu SS,Tummala S,Kebriaei P,Wierda W,Gutierrez C,Locke FL,Komanduri KV,Lin Y,Jain N,Daver N,Westin J,Gulbis AM,Loghin ME,de Groot JF,Adkins S,Davis SE,Rezvani K,Hwu P,Shpall EJ, Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nature reviews. Clinical oncology. 2018 Jan     [PubMed]
Brudno JN,Kochenderfer JN, Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016 Jun 30     [PubMed]
Yu S,Li A,Liu Q,Li T,Yuan X,Han X,Wu K, Chimeric antigen receptor T cells: a novel therapy for solid tumors. Journal of hematology     [PubMed]

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