četvrtak, 10 Septembar 2015 19:49

CHIMERIC ANTIGEN RECEPTOR – T Cell Therapy

By Nermina Lamadema, Postdoctoral Research Associate at King's College London


Current Cancer Therapy Approaches

Currently several different approaches are applied to treat the cancer depending on its type and the stage of advancement. The treatment typically involves surgery to remove cancerous tissue. This is then be followed by either External Beam or Internal radiotherapy to kill or slow down the growth of cancerous cells. Alternative line of treatment called chemotherapy or chemo involves use of chemical drugs tailored for a specific cancer type to either destroy cancerous cells or slow down its growth.  More recently new generation of targeted therapy drugs have been developed such as Imatinib Gleevec® to recognize specific molecular targets on cancer cells of several leukaemia types. Another is trastuzumab Herceptin® used to treat HER2+ breast cancer and stomach adenocarcinoma.

Immunotherapy approach uses patients own immune system to fight the cancer. For example monoclonal antibodies can be designed to bind to specific targets in the body leading to an immune response to destroy the cancer cells. Alternatively monoclonal antibodies can be used to mark the cancer cells allowing the host immune system to find and destroy them.

Improvement to the cancer therapy depends on continuous development of novel approaches to identify, and target the malignant cell. One example of most recent developments is a biological therapy based on the principle of adoptive cellular immunotherapy called Chimeric Antigen Receptor (CAR) therapy.

Chimeric Antigen Receptor therapy

CAR T cell immunotherapy is a novel platform technology based on using patients own T cells isolated in laboratory. The cell is modified using a specific artificial surface receptor and once re introduced into the patient instructed to recognize, attack and kill a particular cancer cell harbouring an antigen on its surface.

Human T lymphocytes

T cells are a specialised type of white blood cells essential for our immunity. They continuously circulate in our blood scanning for the signs of infections. T cells can be divided into two subsets CD4+ helper and CD8+ killer T cells. Killer T cells “read” the surface of the body cells they encounter in order to “see” what is happening inside that cell i.e. is it infected or cancerous and then respond accordingly by either doing nothing if the cell is normal or by mounting an attack on the rogue cell. Helper T cells help orchestrate an immune response.   Figure below shows a diagram of human T cell (purple) circulating and surveying other cells for signs of infection.

 

Hybrid Medical Animation

 T cells carry out their function using the receptors on their surface via which they establish communication between the cells external environmental stimuli and internal response to that stimuli. Furthermore they help the T cell to engage with the antigen and mount an attack against it if it sees it as a non- self-entity. Figure below shows T cell receptor Y shaped structure engaging a viral antigen in yellow.

Scientific animations.com

How does the CAR therapy work?

CAR Therapy is often referred to as the ‘Living Drug’ because the process involves isolation of patients own T cells. These cells are then genetically engineered using specialized retroviral vectors to be able to produce on their surface specific receptors called Chimeric Antigen receptors to target tumour associated antigens.

Once engineered CAR T cells are expanded in the laboratory until their reach very high confluence (billions of cells are usually required). The cells are then re-introduced into the patient and allowed to further multiply and be guided by their CAR receptors to find and destroy cancer cells harbouring specific antigens.

CAR Therapy promises

These receptors show remarkable promise in the fight against cancer and so far the efficacy has been evaluated in the small clinical trials. At the moment the studies are aimed at the last stage disease where all other options have failed. Early phase trials using engineered T cells which target CD19 antigen a marker expressed on B cell related blood cancers in adults and children with leukaemia and lymphoma show very promising results. A Seattle based  biotech company Juno Therapeutics  is currently running clinical trials for Acute Lymphoblastic Leukaemia (ALL), non-Hodgkin’s lymphoma and Chronic Lymphocytic Leukaemia (CLL) and is about to enter into the trials for three more CAR T cell immunotherapies that are going to be used for treatment of solid cancers.

Studies so far indicate that the engineered T cells are able to multiply thousand fold once infused into the patients and can be detected in the patient’s nervous system. This is quite important because cancer cells are known to hide and evade destruction by chemo and radiotherapy by seeking sanctuary in the nervous system of the patient.

Development of the next generation of CAR T cell therapy in order to improve antigen recognition specificity is already in progress. The refined CAR T cells possess in addition to the antigen recognition domain another domain with a molecular switch that can only be activated in a response to a specific small molecule drug. This will allow the cells to only become activated once they encounter a cancer cell and become stimulated with the anti-cancer drug simultaneously.

CAR therapy side effects

CAR T cell therapy is not without safety concerns. Several serious side effects related to so called ‘cytokine storm’ have been recorded at the clinical trials so far. At the several clinical trials so far treatment related deaths occurred as a result of cytokine release syndrome in response to the CAR T cell therapy.

Cytokines are a chemical messengers released by the T cells that enable the cell to perform its function. Pro inflammatory cytokines released in response to the activation of T cells are responsible for a number of symptoms including high fever, hypotension, pulmonary oedema and delirium. It appears that the severity of the cytokine release closely relates to the tumour burden of the patient. The greater the mass of the cancerous tissue and therefore malignant cells the patients has the stronger the immune reaction in response to CAR T cell therapy will be. It appears so far that the adults are much more susceptible to these kinds of responses than the children and that the severity of the response can be dampened by using corticosteroids and or anti IL6 antibody. IL6 is one of the pro inflammatory cytokines that the T cells release.

CAR Therapy Future directions

Promising results coming through from various clinical trials have sparked a great deal of interest and investment in this type of therapy. Many of the treatment therapies are being fast tracked by the US Food and Drug Administration (FDA) and the European Medicines Agency. CAR T cell therapy has been hailed as a revolutionary new approach for the treatment of many types of cancers with a potential to usher chemotherapy out and replace it as a first line of cancer therapy. However despite all the hype surrounding the therapy as well as its huge market potential a cautionary approach is required which should take into the account all the possible risks associated with CAR engineered T cells.

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