Immunotherapy with activation of NK cells

Shaghayegh Pezeshki,Payam Hashemi

1Department of Immunology,School of Medicine,Iran University of Medical Science,Tehran,Iran.2MD (Doctor of Medicine),Faculty of medicine,Tehran University of Medical Science,Tehran,Iran

Abstract

Keywords:Danggui Buxue decoction,Pulmonary fibrosis,Network pharmacology,Myofibroblast,Chinese medicine formula,Mechanism of action

Introduction

Chimeric antigen receptor T cells (also known as CAR T cells) are T cells that have been genetically engineered to produce an artificial T-cell receptor for use in immunotherapy [1,2].Chimeric antigen receptors (CARs,also known as chimeric immunoreceptors,chimeric T cell receptors or artificial T cell receptors) are receptor proteins that have been engineered to give T cells the new ability to target a specific protein.The receptors are chimeric because they combine both antigen-binding and T-cell activating functions into a single receptor [3].

CAR-T cell therapy uses T cells engineered with CARs for cancer therapy.The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to more effectively target and destroy them.Scientists harvest T cells from people,genetically alter them,then infuse the resulting CAR-T cells into patients to attack their tumors [4].CAR-T cells can be either derived from T cells in a patient's own blood (autologous) or derived from the T cells of another healthy donor (allogeneic).Once isolated from a person,these T cells are genetically engineered to express a specific CAR,which programs them to target an antigen that is present on the surface of tumors [5].For safety,CAR-T cells are engineered to be specific to an antigen expressed on a tumor that is not expressed on healthy cells [6,7].

After CAR-T cells are infused into a patient,they act as a "living drug" against cancer cells.When they come in contact with their targeted antigen on a cell,CAR-T cells bind to it and become activated,then proceed to proliferate and become cytotoxic CAR-T cells destroy cells through several mechanisms,including extensive stimulated cell proliferation,increasing the degree to which they are toxic to other living cells (cytotoxicity) and by causing the increased secretion of factors that can affect other cells such as cytokines,interleukins and growth factors [8,9].

Cancer immunotherapy has been firmly established as a new milestone for cancer therapy,with the development of multiple immune cells as therapeutic tools.Natural killer (NK) cells are innate immune cells endowed with potent cytolytic activity against tumors,and meanwhile act as regulatory cells for the immune system.The efficacy of NK cell-mediated immunotherapy can be enhanced by immune stimulants such as cytokines and antibodies,and activated NK cells in vivo [10,11].

Based on the above,we have decided in our hypothesis to design a CAR-T cell,incorporating within its gene panel a CD16 activating protein or antibody gene by genetic engineering and cloning techniques.Until CAR T cell is activated by its surface antibody (receptor) bound to tumor antigen,this gene can be activated and capable of producing NK cell activating antibody or protein in addition to its role in CAR-T cells.Fight against cancer,Nk cells also play an important role in the fight against cancer.

1 Hypothesis

Insert the CD16 antibody-producing gene or activator protein,which is one of the most important markers of NK cell activation for ADCC into the CAR-T cell panel,in addition to the role of CAR-T cells to fight cancer,the role of NK cells.In the fight against cancer.

2 Discussion

Early CAR-T cell research has focused on blood cancers.The first approved treatments use CARs that target the antigen CD19,present in B-cell-derived cancers such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL).There are also efforts underway to engineer CARs targeting many other blood cancer antigens,including CD30 in refractory Hodgkin's lymphoma; CD33,CD123,and FLT3 in acute myeloid leukemia (AML); and BCMA in multiple myeloma [12].

Solid tumors have presented a more difficult target [13] Identification of good antigens has been challenging:such antigens must be highly expressed on the majority of cancer cells,but largely absent on normal tissues.CAR-T cells are also not trafficked efficiently into the center of solid tumor masses,and the hostile tumor microenvironment suppresses T cell activity [14].

Clinical studies and FDA approvals

The first two FDA-approved CAR-T therapies both target the CD19 antigen,which is found on many types of B-cell cancers [15].Tisagenlecleucel (Kymriah) is approved to treat relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL),while axicabtagene ciloleucel (Yescarta) is approved to treat relapsed/refractory diffuse large B-cell lymphoma (DLBCL) [16].

As of March 2019,there were around 364 ongoing clinical trials happening globally involving CAR-T cells,Most of those trials target blood cancers:CAR-T therapies account for more than half of all trials for hematological malignancies.CD19 continues to be the most popular antigen target,followed by BCMA (commonly expressed in multiple myeloma),In 2016,studies began to explore the viability of other antigens,such as CD20 [17].Trials for solid tumors are less dominated by CAR-T,with about half of cell therapybased trials involving other platforms such as NK cells [18].

Although the initial clinical remission rates after CAR-T cell therapy in all patients are as high as 90% [19] long term survival rates are much lower.The cause is typically the emergence of leukemia cells that do not express CD19 and so evade recognition by the CD19-CAR T cells,a phenomenon known as antigen escape [20],Preclinical studies developing CAR-T cells with dual targeting of CD19 plus CD22 or CD19 plus CD20 have demonstrated promise,and trials studying bispecific targeting to circumvent CD19 downregulation are ongoing [19].The generated NK cells show a strong IFNγ expression upon cultivation with K562 tumor cells and demonstrate a high cytotoxicity toward leukemic as well as solid tumor cell lines in vitro.Altogether,these characteristics promise a high clinical potency of thus produced NK cells awaiting further evaluation.

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