Immunotherapy and cell therapy for cancer

Jeremy COPP，XIE Wei-dong，Charles ZHANG，Jon BERGLIN（.Theragene Pharmaceuticals，Inc.555 Sorrento Valley Road，Suite A，San Diego，CA，USA 922；2.Lindan Biotech，Ltd.4-250 Waverly Street，Winnipeg，MB，Canada；3.Institute of Dongguan-Sun Yan-Sen University,Tower 9,Xinzhu Center，Songshan Lake, Dongguan 523000，China）

·FRONTIER VIEWS·

Immunotherapy and cell therapy for cancer

Jeremy COPP1，XIE Wei-dong2，3，Charles ZHANG1，Jon BERGLIN1
（1.Theragene Pharmaceuticals，Inc.11555 Sorrento Valley Road，Suite A，San Diego，CA，USA 92121；2.Lindan Biotech，Ltd.4-1250 Waverly Street，Winnipeg，MB，Canada；3.Institute of Dongguan-Sun Yan-Sen University,Tower 9,Xinzhu Center，Songshan Lake, Dongguan 523000，China）

Jeremy COPP，Ph.D..A native of Colorado.Dr.Copp received his B.S.in Biochemistry from Colorado State University(summa cum laude)and his M.S.and Ph.D.in Chemistry from the University of California,San Diego.He was an American Cancer Society postdoctoral fellow in the laboratory of Tony Hunter at the Salk Institute for Biological Studies.At the conclusion of his postdoctoral studies he joined Theragene Pharmaceuticals，Inc.，where he is currently the Director of Research and Development.

Cancer immunotherapies are recently gaining attention as viable therapeutic options. There are two types of immunotherapy：passive and active.The passive immunotherapies include several treatments such as monoclonal antibodies，either alone or as antibody-drug conjugates.The active immunotherapies include cancer vaccines which utilize the patient′s own cells as antigen presenting cells and target specific cancer antigens，and chimeric antigen receptor T-cell（CAR-T）therapy which engineers a patient′s T-cells to recognize cancer antigens through chimeric antigen receptors.Recent successes include the US FDA approval of a number of cancer immunotherapies such as treatments utilizing monoclonal antibodies against immune checkpoint inhibitors，the Provenge cancer vaccine that targets prostrate cancer，and a CAR-T against relapsed/refractory acute lymphoblastic leukemia that was designated with breakthrough drug status，all of which has had drug companies investigating cancer immunotherapies with intense enthusiasm.In this review we discuss where the field of immuneoncology stands today，highlight the latest findings and hypothesize future directions.

cancer；immunotherapy；passive immunotherapy；active immunotherapy；cancer vaccine；chimeric antigen receptor T-cell（CAR-T）

Fig.1 Passive versus active immunotherapy.In passive immunotherapy（Fig.1A），components of the immune system that target specific molecules，such as monoclonal antibodies against immune system inhibitors like cytotoxic T lymphocyte-associated antigen 4（CTLA-4）and programmed cell death protein 1（PD-1）and its ligand PD-L1，have proven particularly effective in activating an immune response against cancer.Antibodies targeting CTLA-4 are represented in green，while antibodies targeting PD-1 and PD-L1 are represented in blue and pink，respectively.In active immunotherapies（Fig.1B），a patient′s immune cells，often antigen presenting cells（APCs）or T cells，are isolated and manipulated before being put back into the patient.For APCs，they are engineered to present specific antigens on their cell surface via the major histocompatibility complex（MHC）I.When CD8+T lymphocytes encounter the proper antigen（shown in red）and bind to it through their T-cell receptors，they become activated，and are cytotoxic towards tumor cells with that same antigen/MHCⅠcomplex on their surface.For T cells，the cells are engineered with chimeric antigen receptors（CARs）that recognize specific cancer antigens.This is known as CAR-T therapy，and it has shown extremely promising results against cancers of the blood.

Cancer immunotherapies，or immune-oncology，activate a patient′s immune system to kill tumor cells［1］.Recently interest in immunotherapy has been intensified due to its established efficacy and less toxicity when compared to traditional chemotherapy.Therearetwotypesofcancer immunotherapies：passive and active.Passive immunotherapiesutlilizecomponentsofthe immune system，such as monoclonal antibodies，that are manufactured outside the body（Fig.1A）. Active immunotherapies，such as cancer vaccines and cell therapies，utilize components of the patient′s own immune system to stimulate an immune response against the tumor.Often，the patient′s own immune cells are engineered in some manner and then infused back into the patient to direct the immune system against malignant cells（Fig.1B）.It is an exciting time in the field of immune-oncology due to the emergence of checkpoint blockade inhibitors and engineered T-cell therapies.Passiveandactive immunotherapies can be further broken down into 3 categories：antibody-based，cell-based and cytokine-based.Antibody therapy is the most effective and successful treatment for cancer so far，with proven results in treating a variety of cancers，especially solid tumors［1］.Cell based therapies［2］，such as cancer vaccines and chimeric antigen receptor T-cells（CAR-T）therapy，on the other hand，are still in the early stage of development but starting to show striking results［3］. Thus far，the US FDA has only approved one cell-based therapeutic drug：Provenge©（Dendreon/ Valeant，approved in 2012），a drug based on dendritic cells to treat prostate cancer.Currently many types of cells，including T cells，natural killer （NK）cells，and B cells，are being researched and developed for cell-based therapeutics targeting cancer.Cytokines are an essential part of the immune system that，by modulating cytokines，can be activated totargetcancer.Currently，interferon-a and interlukin-2 are effective drugsfor the treatmenthairy-cell-leukemia，melanoma，and renal cell carcinoma［4］.

Antibody and cytokine therapies are passive immunotherapies，because they are generated outside of the patient′s body as drugs［5］.Cellbased therapies are considered active：cells are isolated from the patient′s blood and trained in vitro to recognize cancer cells，or to help activate specificly mphocytes to target cancer cells.The patient′s cells are then infused back into the patient to attack tumors.The process is also known as adoptive cell transfer［6］.

1　ANTIBODY THERAPY

Antibodies are proteins，which are generated by the immune system to fight pathogens such as virus，bacteria and other foreign invasion to the host body.The mechanism for the antibody to work is to recognize a specific foreign protein or antigen of the invading virus or bacteria，leading to an antibody-mediated host defence.Antigens are often located on the surface of the virus or bacteria.Cancer arises from abnormal regulation of the signaling pathways that regulate cell division. When this happens，many proteins are overexpressed or upregulated in malignant cells.As such，cancer cells are recognized as different from normal cells in the host body.Furthermore，the transformation of normal cells into tumor cells causes overexpression of key signaling molecules on the cell surface，leading to potential surface antigens that the host immune system can recognize via specific antibodies.For antibody therapy，the specific antibody（drug）binds to the antigen，resulting in antibody-dependent，cytotoxic T-cell mediated destruction of malignant cells［1］. 1.1 Specific cancer antigens and antibodies

The general principle of antibody therapy for cancer is to develop antibodies to target specific cancer antigens.Ideally，these antigens are not expressed in normal tissues，or at least overexpressed in malignant cells to minimize off-target effects.Many different types of antigens are being studied as potential targets for the treatment of cancer.Several US FDA approved antibodies have achieved clinical and commercial success，including alemtuzumab（aCD52），ipilimumab〔αcytotoxic T lymphocyte-associated antigen 4 （CTLA4）〕，of atumumab（aCD20），nivolumab 〔α-programmedcelldeathprotein（PD）-1〕，pembrolizumab（αPD-1），and rituximab（aCD20）. Other popular tumor antigens in various stages of research and development（from currently in clinical trials to FDA-approved drugs on the market are epidermal growth factor receptor（EGFR），ERBB2， vascularendothelialgrowthfactor （VEGF），CD30，CD52，and programmed-death ligands（PDL）-1 and PDL-2.

There is a great deal of interest and enthusiasm regarding monoclonal antibodies targeting the immune-response checkpoint inhibitors CTLA4 and PD-1.Several years of intense preclinical and clinical studies have led to the development ofthreecheckpointinhibitorimmunotherapy drugs：the anti-CTLA4 antibody ipilimumab and two antibodies directed against PD-1，nivolumab and pembrolizumab.Ipilimumab was approved for metastatic melanoma based on a phase 3 study where patients treated with ipilimumab had overall survival（OS）rates of 23.5%and patients treated with a glycoprotein vaccine had OS rates of 13.7%［7］.Between 2011 and 2014，the US FDA approved all the three immunotherapy drugs for use in metastatic melanoma，and there is a great deal of interest in studying their efficacy in other indications，such as non-small cell lung，kidney，brain，lymphoma，and prostate cancer［8］. Adverse effects associated with these drugs include rash，diarrhea，colitis，hyper and hypothyroidism and pneumonitis.While most of these side effects dissipate after treatment，hypothyroidism can be permanent but treatable.

1.2Antibody-drug conjugates（ADCs）

LIke antibody therapy，ADCs are another proven and effective method of treating cancer［9］. ADCs are a unique class of highly potent and specific biopharmaceutical drugs that utilize antibodies targeting specific cancer antigens.ADCs are complex molecules composed of an antibody，usually an antibody fragment such as a single-chain variable fragment（scFv）.This fragment is linked by chemical linker to labile bonds to a biological active，cytotoxic，payload of anticancer drug.The purpose of the complex is to utilize the specificity of the antibody to specifically recognize the cancer antigen and deliver a toxic drug in a localized manner to the tumor.Due tothe higher specificity and localization over standardchemotherapies，ADCstypicallyexhibit less side effects and toxicity［10］.

The history of ADCs is mixed.To date，the US FDA has approved three drugs，with two currently on the market.Gemtuzumab ozogemicin was first approved in 2001，but withdrawn from the market in 2010 at the request of the US FDA due to concerns about safety and effectiveness. Brentuximab vedotin was approved in 2011 for the use in Hodgkin lymphoma and systemic anaplastic large cell lymphoma，while trastuzumab emtansine was approved in 2013forHER2+breast cancer.The durable clinical response to these drugs has renewed interest in developing novel ADCs and it will be intriguing to witness where this field develops in the future［11］.

2　CELL BASED IMMUNOTHERAPY

Cell based therapy is considered active immunotherapy，which uses the patient′s own immune system to treat cancers.Cell based immunotherapy usually requires the removal of lymphocytes from the patient′s blood，training of specific immune cells to recognize cancer cells in vitro and subsequent infusion the trained cells back into the patient.The infused cells then either directly kill the patient′s malignant cells or activate other immune cells，such as cytotoxic T cells，to do the killing.The cells are isolated from the patient by a process during a procedure known as leukapharesis，while the process of infusing them back into the patient is called adoptive cell transfer（ACT）.The lymphocytes most commonly used for cancer immunotherapy are natural killer（NK）cells，lymphokine-activated killer cells，cytotoxic T lymphocytes（CTLs）and dendritic cells（DCs）.These cells may originate from the patient（autologous）or from allogeneic donors.Currently，autologous treatment is much more popular than allogeneic because autologous cells reduce the occurrence graft vs host disease［6］. 2.1 DC based immunotherapy

The first US FDA approved cell therapy， Provenge，isaDCbasedvaccineagainst metastatic castration-resistant prostate cancer （mCRPC）.Approved in 2010，it is currently the only vaccine approved for use as a cancer therapeutic.In this therapy，DCs act as APCs［12］. They are manipulated to present a specific cancer antigen to CTLs，which activates them and directs them to kill cancer cells which present that antigen on their cell surface.In the case of Provenge，the antigen is the prostate tumor antigen protein acid phosphatase（PAP）fused to granulocyte macrophage colony-stimulating factor （GM-CSF），which acts to fully activate the DCs into mature APCs.

Once DCs are isolated from the patient，the synthetic fusion protein combining PAP and GMCSF is introduced into DCs ex vivo in a laboratory. The DCs are allowed time to mature into APCs and are then infused back into the patient′s body.These activated DCs then present the PAP antigen to T cells to activate them.The activated T cells will destroy prostate cancer cells expressing the cancer cell surface antigen PAP［13］.

2.2NK cell based immunotherapy

NK cells are similar to CTLs，but they do not require the presence of major histocompatibility complex（MHC）or antibodies to be activated as like CTLs do.This unique character of NK cells allows them rapid responses to viral-infected cells，acting at around 3 days after infection.NK cells are extremely important for host defense against harmful pathogens that are missing MHC classⅠantigens.Because some malignant cells have mechanisms to down-regulate MHC type I molecules，NK cell manipulation is an effective method of cancer treatment［14］.

In normal circumstances，NK cells are not active or able to recognize and kill cancer cells. ControllingNKcellactivation/inactivationis achieved through NK cell activating and inhibitory receptors.Activating receptors include Ly49，Naturalcytotoxicreceptors（NCRs），CD49/ NKG2，and CD16（FcyIIIA）.Inhibitory receptors include killer-cell immunoglobulin-like receptors （KIRs），leukocyte inhibitory receptors（LIRs），and Ly49（has both activating and inhibitory isoforms）.NK cells are inactive while these receptors are in equilibrium.NK cells are activated upon antibody secretion（binding to CD16），cytokine secretion（IL-2，IL-12，IL-15，IL-18 and TNF-α and IFN-γ），and down-regulation of MHC typeⅠ. Under stressful conditions，cells can down-regulate MHC typeⅠ expression，causing NK cells to lose inhibitory signaling and be activated.This process is called″missing-self″recognition，during which NK cells seem to have the ability to compare what receptors the host has versus receptors that are missing in response to an″invading″pathogen，Therefore，when MHC typeⅠ is missing in infected cells，or in cancer cells，then NK cells are activated.Similarly，the activating receptors in NK cells can recognize new molecules or antigens that the host does not express，which is called″non-self″recognition，or selfexpressed antigens/proteins that are up-regulated by stressed conditions，called″stress-induced self″recognition.All these conditions can activate NK cells and allow them to recognize and kill infected cells or malignant cells［15-16］.

Current studies are focused on modifying these three signaling pathways（missing self，non-self and stress-induced self）with NK cells for cancer therapeutic development.For cytokine treatment，NK cells are activated after administration of large amounts of cytokines to patients. However，this can result in severe toxicity due to the cytokine itself.Since NK cells express FcyⅢA/CD16 receptor，NK cells can recognize antibody-labeled target cancer cells and they are activated upon binding to these antibodies.This resultsinantibody-dependent cell-mediated cytotoxicity（ADCC），which can kill antibodylabled malignant cells.Clinical data showed that NK cells play a critical role in cancer treatment by anti-cancer antibodies，such as anti-CD20 （rituxumab）and anti-HER2（Herceptin/trastuxumab）treatments.There are modified proteins or antibodies being developed for this purpose，such as AFM13，a genetic modified antibody developed by Affimed NV（Heidelberg，Germany）. AFM13 is specifically designed to bind CD16a and activate NK cells.Nantkwest（Culver City，CA USA）is developing genetically modified NK cells that do not express KIRs（inhibitory receptors）for cancer treatment.Although there is a great deal of interest in developing cancer treatments that target NK cells，much more data on tolerance and efficacy are needed.

2.3CAR-T technology

Possibly the most intense interest in developing an active cell therapy lies in the area of CAR-T therapy.This technology is a promising new approach to cancer.In July 2014，US FDA granted breakthrough therapy designation（BTD）toNovartisPharmaceuticals′ investigational CAR-T therapy CTL019 for treatment of adult and pediatric relapsed/refractory acute lymphoblastic leukemia（r/r ALL）.This is the first CART technology to receive the FDA′s BTD.The CAR-T technology for CTL019 employs a viral vector carrying a small gene encoding the CD19 cancer antigen binding protein fused to specific T-cell activation domains.T cells from the patient are obtained via leukapharesis and engineered in vitro with the vector so that the patient′s T cells will destroy cancer cells expressing the CD19 antigen once infused back into the patient′s body. Many biopharmaceutical companies，such as Juno Therapeutics，Kite Pharmaceuticals and Celgene，are developing CAR-T technology for cancer therapy.

The CAR-T approach，like other adoptive cell therapy methods，relies on the removal of cells from the patient′s body.The T cells are manipulated via transfection by a viral vector that expresses a chimeric receptor specific to a cellsurface antigen.The cells are cultured so that the modified T cells mature and multiply，and then they are infused back into the patient.The infused T cells can recognize and kill malignant cells located in the patient［17］.Theapproach usually employs autologous cells to reduce host defense.Allogeneic cells from other donors are also under investigation，but not very practical at the moment.

The structure of chimeric antigen receptors are composed of an extracellular domain with an antigen recognition region to binds to a specific cancer antigen fused to an intracellular T cell activationdomain.Theantigenrecognition region is usually derived from single chain variable fragment（scFv）from an antibody，which can recognize and bind to a specific cancer antigen （such as CD19）.Upon binding of the antigen，the intracellular T cell activation domain transduces a signal to activate the T cells.The most common activationdomainisCD3-zeta，containing 3 immunoreceptor tyrosine-based activation motifs （ITAMs）for better signal transduction.In addition，more signal enhancers can be incorporated for more potent T cell activation.The second generation of CAR-Ts is incorporated with CD28，41BB or iCOS receptor at the cytoplasmic tail of the CAR to enhance activation of T cells，while the third generation has combined several of the receptors such as CD3z-CD28-41BB or CD3z-CD28-OX40 to further increase the efficacy of treatment［18-19］.Several biopharmaceutical companies，including Juno Therapeutics，are conducting research on the next generation of CARs，which includes the addition of a second antigen recognition/binding domain for enhanced specificity of cancer cell identification and recognition.

CAR-T technology is a promising form of cancerimmunotherapysupportedbydata obtained in several preclinical and clinical trials. Research and studies are focusing on engineering improved chimeric receptors to achieve higher efficacy and low toxicity for patients.The current clinical results show that CAR-T is only effective in treating blood related cancers，such as many types of leukemia.Treating solid tumors is still early in research and development，and many morestudiesareneededtoexplorethis area.Although CAR-T has achieved great success in clinical trials to treat leukemia，there is a high level of toxicity associated with this treatment. The most severe events include tumor lysis syndrome，cytokine release syndrome and organ specific toxicity.These toxicities can be life threatening［20］.

Tumor lysis syndrome is a group of metabolic abnormalities after treatment of lymphomas and leukemia.It is most likely caused by the release of cellular contents into the blood upon cancercell lysis.This leads to higher blood potassium，phosphate，uric acid and BUN，but low blood calcium，changing blood electrolyte and metabolite levels，and can be fatal［21］.Cytokine release syndrome is due to T cell activation and release of inflammatory cytokines into the blood stream，including IL-6，IFN-γ and TNF-α.This can causeseverehypotension， hypoxia， fever，multi-organ failure and coagulation disorder，and can also lead to fatality［22］.Organ specific toxicity is due to antigen specific toxicity，CNS depression，liver function change and pulmonary problems that are specific to anti-CD19 products［23］.

3　PROSPECTIVE

Cancer therapy is a complicated and longterm approach.In today′s standard care，one is treated by surgery，chemotherapy，or radiation therapy alone，or by combination of the three. After these treatments，the patient is considered cancer free，but in many cases relapse often occurs within a short period of time.Upon recurrence，the prognosis is very poor mainly due to metastasis of the disease to other tissues or organs.At this point，the cancer is much more difficult to treat，and the survival rate is very low. Immunotherapy is particularly designed to treat cancers after they escape from standard-of-care treatments，and both passive and active immunotherapies have shown great efficacy for this purpose.However，more and more immunotherapies are proving to be effective as first line treatments，while others are promising as second line，adjuvant or combination therapies with other anticancer drugs.The future of the field may lie in the utilization of therapies targeting checkpoint inhibitors in combination with some type of active immunotherapeutic（vaccine or CAR-T）to lower the toxicity of the former while increasingthe efficacy of the latter.With whole genome sequencing，it is conceivable that these therapies willbecomepartofpersonalizedmedicine，attempting to target the exact cancer antigens that are involved in the pathology of a particular patient′s disease.In general，cancer immunotherapy defines a new class of treatments designed to be more specific to a patient′s particular cancer，thus making them a highly effective，less toxic，treatment option.

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癌症的免疫治疗和细胞治疗

Jeremy COPP1，谢伟东2，3，张朝杰1，Jon BERGLIN1
（1.Theragene Pharmaceuticals，Inc.11555 Sorrento Valley Road，Suite A，San Diego，CA，USA
92121；2.Lindan Biotech，Ltd.4-1250 Waverly Street，Winnipeg，MB，Canada；3.东莞中山大学研究院，广东东莞 523000）

最近，癌症免疫治疗作为可行性的新治疗法而得到广泛青睐。免疫治疗主要分为2种类型，即被动免疫治疗和主动免疫治疗。被动免疫治疗包括单克隆抗体和（或）抗体-药物偶联物治疗；主动免疫治疗包括癌症疫苗和嵌合抗原受体T细胞（CAR-T）治疗。癌症疫苗是利用患者自身的细胞作为抗原递呈细胞，识别特异性的肿瘤抗原。CAR-T治疗是利用遗传工程改造的患者的T细胞，通过嵌合抗原受体识别肿瘤抗原。最近一些成功的案例，包括美国FDA批准的癌症免疫疗法，让各大制药公司对癌症免疫治疗研究报以强烈兴趣，如使用抗免疫检查点抑制剂单克隆抗体治疗肿瘤和针对前列腺癌的Provenge癌症疫苗，以及治疗复发或难治性急性淋巴细胞白血病的具有突破性的CAR-T免疫治疗。本综述讨论了目前肿瘤免疫学领域的最新进展以及未来的发展方向。

癌症；免疫治疗；被动免疫治疗；主动免疫治疗；癌症疫苗；嵌合抗原受体T细胞（CAR-T）

Jeremy COPP，Tel：（858）2043104，E-mail：eremycopp@theragenepharma.com

2016-01-12接受日期：2016-02-14）

R730.51Document code：AArticle ID：1000-3002（2016）02-0087-08

10.3867/j.issn.1000-3002.2016.02.001

（本文编辑：齐春会）

Jeremy COPP，Tel：（858）2043104，E-mail：jeremycopp@theragenepharma.com