|Year : 2015 | Volume
| Issue : 2 | Page : 43-49
Review of Cancer Immunotherapy: Application of Chimeric Antigen Receptor T Cells and Programmed Death 1/Programmed Death-ligand 1 Antibodies
Tengfei Zhang1, Ling Cao2, Zhen Zhang2, Dongli Yue2, Yu Ping2, Hong Li2, Lan Huang2, Yi Zhang3
1 Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Department of Hematology and Oncology, Harvard Medical School, Boston, MA, USA
2 Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
3 Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan; Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan; Engineering Key Laboratory for Cell Therapy of Henan Province, Zhengzhou, Henan; School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
|Date of Submission||01-Feb-2015|
|Date of Acceptance||06-Apr-2015|
|Date of Web Publication||28-Apr-2015|
Prof. Yi Zhang
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe Road, Zhengzhou 450052, Henan
Source of Support: This work was supported by grants
from National Natural Science Foundation of China (Grant
No. 31400752 and 81271815) and the Basic and Advanced
Technology Research Foundation from Science and Technology
Department of Henan Province (Grant No. 201403067, Conflict of Interest: None
Cancer immunotherapy strategies based on chimeric antigen receptor (CAR) transduced T cells or antibodies against immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), achieved significant successes from bench to clinic in the past 2 years. CARs are artificial engineered receptors that can specifically target tumor cell surface antigen, activate T cell and further enhance T cell function, independent of major histocompatibility complex. CAR T cells have shown promising outcomes in cancers, especially in hematologic malignancies. CTLA-4 and PD-1 are two important immune checkpoints negatively regulating T cell activation. Clinical benefits of CTLA-4/PD-1 antibodies are significant in melanoma and other solid tumors. PD-1 is predicted to have fewer side effects and greater antitumor activity than CTLA-4. In this review, we will summarize current immunotherapies based on CAR T cells and PD-1.
Keywords: Cancer immunotherapy, chimeric antigen receptor T cells, programmed death 1
|How to cite this article:|
Zhang T, Cao L, Zhang Z, Yue D, Ping Y, Li H, Huang L, Zhang Y. Review of Cancer Immunotherapy: Application of Chimeric Antigen Receptor T Cells and Programmed Death 1/Programmed Death-ligand 1 Antibodies. Cancer Transl Med 2015;1:43-9
|How to cite this URL:|
Zhang T, Cao L, Zhang Z, Yue D, Ping Y, Li H, Huang L, Zhang Y. Review of Cancer Immunotherapy: Application of Chimeric Antigen Receptor T Cells and Programmed Death 1/Programmed Death-ligand 1 Antibodies. Cancer Transl Med [serial online] 2015 [cited 2020 Jan 27];1:43-9. Available from: http://www.cancertm.com/text.asp?2015/1/2/43/155923
| Introduction|| |
Cancer remains the leading cause of death worldwide.  Surgery, radiation and chemotherapy are regular treatments deployed for cancer but each with risks and adverse side effects. Cancer immunotherapy, a new weapon for cancer, aimed to harness the patient's own immune system to fight cancer, was named as "breakthrough of the year" by science in 2013.  Immunotherapies showed the possibility of long-term durable remissions for cancers. With the rapid development of basic and translational research, eventually, millions of cancer patients will benefit from immunotherapies.
T cells play an important role in anti-tumor immune responses. In order to activate T cell, first the tumor specific antigens should be taken up and processed by antigen presenting cells (APCs). After these antigens are displayed on the surface of APCs in the context of major histocompatibility complex class I and II molecules, tumor cells can be recognized by CD4 + and CD8 + T cells. Then, T cells clonally expand and kill tumor cells with imuno-stimulatory signals. Finally, to avoid prolonged antigen exposure, co-inhibitory signals are recruited to stop T cell activation after immune reactions. The recognition of tumor specific antigens and the balance of co-stimulatory and co-inhibitory receptors are critical for T cell function.  The co-inhibitory receptors are also referred as immune checkpoints.
Tumor cells develop a series of immune escape mechanisms to avoid eradication by the immune system. , Harnessing the immune system to recognize and kill tumor cells is one of the basic principles for immunotherapy. Immunotherapy is based on chimeric antigen receptor (CAR) T cells and two immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) that have achieved significant successes from bench to clinic.  CAR activates T cells to recognize specific tumor cell antigens, while immune checkpoint blocking maintains T cell activation against tumor cells. CTLA-4 is the first immune checkpoint receptor immunotherapy target that can significantly improve the overall survival for cancer patients. CTLA-4 regulates T cells at the stage of initial T cell activation, whereas PD-1 predominantly regulates the effector phase of T-cell responses.  Immunotherapy based on PD-1 is predicted to have fewer side effects and greater antitumor activity than CTLA-4.  Therefore, in this review, we focus on immunotherapies based on CAR T cell and PD-1.
| Immunotherapy Based on Chimeric Antigen Receptor T Cell|| |
Basic chimeric antigen receptor design
Chimeric antigen receptors consist of a single-chain variable fragment (scFV) derived from the targeted surface antigen, a hinge domain, a transmembrane domain, an intracellular signal domain and co-stimulatory components. , The scFV is engaged to recognize the targeted antigen (protein, carbohydrate and glycolipid structures) on tumor cell surface. The scFV can be derived from murine, humanized antibodies, or phage libraries. , The hinge domain contributes to the interaction with antigen, assembly of the immunologic synapse and association of the CAR with other proteins to transduce a robust activation signal. The intracellular signaling domains define CAR generations. The first-generation CARs only have CD3 zeta signaling domain; the second-generation CARs include one CD28 or 4-1BB co-stimulatory components combined with CD3 zeta signaling domain; the third-generation CARs include two co-stimulatory domains such as CD28, 4-1BB and others. The co-stimulatory components attribute greater strength of signaling, and longer persistence of T cells in vivo. The first and second-generations CARs have been used in clinical trials. ,,,
Clinical outcomes of chimeric antigen receptors in hematologic malignancies
Due to the well-known antigens expressed on hematologic cells and fewer barriers for T cell homing to hematologic organs, CAR T cells were first targeted to hematologic malignancies. The target on B cell malignant cells used for CAR T design include CD19, CD20, Lewis-Y, CD30, CD33 and CD138. , Reported clinical trials have mainly focused on CD19. Clinical trials using CAR T targeted on CD30, CD33 and CD138 are ongoing.  There are 14 clinical trials published on CD19-CAR T cells, 3 clinical trials on CD20 CAR T cells and 1 clinical trial on Lewis-Y CAR T cell in B cell malignancies. CD19 is an antigen expressed restrictively on normal and malignant B cells but not on other normal cells.  Objective tumor responses were reported in patients with chronic lymphocytic leukemia, acute lymphoblastic leukemia and other indolent lymphomas after infusion with autologous or allogeneic T cells genetically modified with CD19 CARs. ,,, The clinical outcomes of each study are listed in [Table 1]. Some of the CD19 CAR T cell clinical trials showed a 100% positive response in B cell malignancies patients. Clinical trials using CD20 and Lewis-Y CAR T cells showed lower response than CD19 CAR T cell clinical trials. ,, Relapse after the first-line standard chemotherapy regiments were very common in B cell malignancies patients. Response rates of refractory B cell malignancies patients to chemo-immunotherapeutic combinations were no better than 40%. ,,, Although there was some variation among CD19-CAR T cells clinical trials, the high remission rate and better survival of patients with refractory B cell malignancies in these CD19-CAR T cell clinical trials are encouraging.
Chimeric antigen receptor T cells in solid tumor
Compared with hematologic malignancies, the clinical efficacy of CAR T cells in solid tumors was limited. , The reasons for the limitation include a lack of a powerful specific antigen like CD19 to recognize solid tumor cells from normal cells, the insufficient T cell infiltration of tumor tissues and high immunosuppressive microenvironment in solid tumors.  The targets of CAR T cells designed for solid tumors in research include human epidermal growth factor receptor 2 (erb-b2 receptor tyrosine kinase 2) for breast cancer, osteosarcoma, , GD2 (Ganglioside 2) for neuroblastomas and osteosarcoma, , epidermal growth factor receptor variant III (EGFRvIII), (the most common extracellular mutation domain in EGFR genes for glioblastoma), , and mesothelin for metastatic pancreatic (ductal) adenocarcinoma, epithelial ovarian cancer, and malignant epithelial pleural mesothelioma. , Compared with hematologic malignancies, clinical trials on CAR in solid tumors are not as well developed. To date, there are no sizable published Phase I trials on CAR T in solid tumors as most Phase I clinical trials are ongoing. CAR vectors developed for solid tumor are more complex than the CAR vectors in published clinical trials. To enhance tumor specificity and to prolong the CAR T cell persistence time, a second antigen and virus structures will be combined. New technology and the next generation of CARs will help to advance the clinical trials and achieve better outcomes in solid tumors.
Toxicity of chimeric antigen receptor T cells immunotherapy
Fever, obtundation, seizures, aphasia and mental status changes were common adverse effects of patients after infusion with CD19-CAR T cells. But the major safety concerns for CAR T cell products are the risk of on-target but off-tumor effects and cytokine released syndrome (CRS). The on-target but off-tumor effects result from the immune reaction activated in normal cells with the CAR targeted antigens. B-cell aplasia was the on-target but off-tumor effects of CD19-CAR directed therapies. , B-cell aplasia can be managed with g-globulin infusion, but the replacement treatment can be expensive and difficult, and more seriously, could put patients at risk of infection. The on-target but off-tumor effects could be much severe and dangerous in solid tumors. In Morgan's case report, the patient sustained severe adverse toxicities and died 5 days later.  Another study showed that T cells expressing CARs can cause anaphylaxis in humans.  Highly restricted tumor specific antigens are needed. CRS could be the consequence of cytokine secretion in response to the activation of CAR-T cells. CRS often accompanied by macrophage activation syndrome (MAS) characterized by hyper inflammation with prolonged fever, hepatosplenomegaly and cytopenias.  MAS could be driven by high levels of interleukin 6 (IL-6), but which cell type is responsible for the high expression of cytokines, particularly IL-6, is still unclear. IL-6 blocker tocilizumab may be used to relieve symptoms induced by CRS and MAS in the clinical setting.
Methods used to introduce CAR constructions were also correlated with the toxicity of CAR T cells. Gamma retrovirus, retroviruses, lent virus and other nonviral-based DNA transfection have been used in current clinical trials. These methods have different demands on cell culture time, antibiotic selection, but the preferred method still needs more investigation. Recently, T cells engineered with a new method, Sleeping Beauty, with stable gene transfer, sustained transgene expression and less toxicity, are now entering clinical trials.  The in vitro T cell culture and the lymph deletion regimen before CAR T cell infusion may also induce the toxicities. ,,, The new generation CAR T cells also have been shown to reduce the toxicities of CAR T cells. ,,
Structural design improvement of chimeric antigen receptor T cells
To improve efficiency and to reduce the toxicities, several new strategies have been recruited for CAR T cell constructs. Suicide gene inducible caspase 9 (iCasp9) can be incorporated to CAR as a safety switch. iCasp9 can be activated by a small molecule dimerizer drug AP1903 to induce apoptosis in inappropriately activated CAR T cells when needed. ,, Another strategy is to introduce both CAR and a chimeric co-stimulatory receptor that recognizes a second antigen. The study combined CAR T with prostate-specific membrane antigen and prostate stem cell antigen, showing that T cells only destroy tumors that express both antigens but do not affect cells expressing either antigen alone.  In addition, CAR can be designed based on immune checkpoints to reduce the off-target toxicities.  This will be promising to avoid some of the side effects of CAR T cell therapies.
| Immunotherapy Based on Antibodies Targeting Programmed Death 1/Programmed Death Ligand 1|| |
Programmed death 1/programmed death ligand 1/2 pathway
Programmed death 1 is a 288 amino acid cell surface protein molecule. PD-1 can inhibit T cells activities in peripheral tissues at the time of inflammatory response to infection, limit autoimmunity and cancer.  This inhibitory activity can also be exerted during the effector phase of T cell activation. , PD-1 expression can be increased by cytokines IL-2, IL-7, IL-15 and IL-21.  PD-1 is highly expressed on tumor infiltrating lymphocytes such as CD4 + T cells, CD8 + T cells, natural killer cells, Treg cells, B cells and other monocytes. ,, PD-1 has two ligands PD-ligand 1 (L1) and PD-L2.  PD-1/PD-L1 interaction can inhibit proliferation, survival, effector function and induce apoptosis of CD8 + CTL.  The high expression of PD-1 in Treg cells can increase Treg cell proliferation to enhance immune suppression in tumor microenvironment.  PD-1 mediated the immune suppression in tumor microenvironment through both effector T cell activation and Treg inhibition. At the same time, PD-1 ligands are upregulated in multiple cancer cell surfaces to inhibit antitumor T-cell responses by binding to PD-1. , Induced expression of PD-L1 on tumor cells in vitro can inhibit local antitumor T cell-mediated responses.  PD-L1 expressionwas correlated with poor clinical outcomes in human cancers including melanoma, lung, breast, bladder, ovarian, pancreatic cancers, esophageal adenocarcinoma, kidney tumors and even hematopoietic malignancies.  The poor clinical outcomes may due to the inhibition of immune responses against cancer, permitting cancer progression and metastasis by induced PD-l pathways. , These findings suggest a therapeutic potential of targeting PD-1/PD-L1 pathway for cancer immunotherapies.
Clinical outcomes of programmed death 1/programmed death-ligand 1 antibody
Antibodies blocking PD-1/PD-L1 showed promising outcomes in several clinical trials. Nivolumab (a fully human PD-1 IgG4 monoclonal antibody, Opdivo; Bristol-Myers Squibb/Ono Pharmaceuticals), ,,,, pembrolizumab (a humanized IgG4 antibody, Keytruda; Merck and Co.), , pidilizumab (a humanized IgG1 antibody, CureTech), ,, BMS936559 (a fully human PD-L1 specific IgG4 antibody, Bristol-Myers Squibb)  are main PD-1/PD-L1 specific antibodies used in current clinical trials. The clinical outcomes of these antibodies are listed in [Table 2]. PD-1 antibodies showed high response rate for metastatic melanoma and clinical efficacy in nonmelanoma cancers including renal cell carcinoma, nonsmall cell lung cancer and hematological cancers. ,,, More importantly, PD-1 antibodies showed rare severe toxicities compared with CTLA-4 antibodies. , Nivolumab and pembrolizumab have been approved by the US Food and Drug Administration for treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and for BRAF V600 mutation-positive patients, a BRAF inhibitor.  Nivolumb was also approved for melanoma in Japan. 
Safety with programmed death 1 immunotherapy
The most common adverse events reported for PD-1/PD1-L1 antibodies include mild fatigue, rash, pruritus and diarrhea, but these symptoms can be usually managed by discontinuation. Pneumonitis was observed in some patients as a class-related toxic effect related to PD-1 antibodies. In all, there appear to be fewer adverse events for PD-1/PD1-L1 antibodies than for other immunotherapies.
| Future Prospectives|| |
Immunotherapies based on both CAR T cells and PD-1/PD-L1 antibodies achieved significantsuccesses in the past few years. However, their use is still limited because of the "on-target, off-tumor" toxicities in CAR T cells, the dependency of PD-L1 positive for objective response in PD-1/PD-L1 antibodies and some adverse effects. Combination of therapeutic strategies may help to narrow these limitations. For example, there are ongoing studies on these immune-modulatory antibodies, CAR T cells combined with other small molecular inhibitors. Moreover, the combination therapeutic strategy of CTLA-4 and PD-1 showed promising results without a significant increase in toxicity. PD-1and CTLA-4 based inhibitory CAR T cells provide a dynamic, self-regulating safety switch to prevent, rather than treat the consequences of inadequate T cell specificity. The combination strategies may help immunotherapies to achieve more successes in the future.
| References|| |
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin
2014; 64 (1): 9-29.
Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science
2013; 342 (6165): 1432-3.
Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol
2013; 13 (4): 227-42.
Pardoll D. Immunotherapy: it takes a village. Science
2014; 344 (6180): 149.
Momtaz P, Postow MA. Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway. Pharmgenomics Pers Med
2014; 7: 357-65.
Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol
2007; 19 (7): 813-24.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer
2012; 12 (4): 252-64.
Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov
2013; 3 (4): 388-98.
Davila ML, Brentjens R, Wang X, Rivière I, Sadelain M. How do CARs work?: early insights from recent clinical studies targeting CD19. Oncoimmunology
2012; 1 (9): 1577-83.
Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood
2014; 123 (17): 2625-35.
Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, Kamble RT, Bollard CM, Gee AP, Mei Z, Liu H, Grilley B, Rooney CM, Heslop HE, Brenner MK, Dotti G. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest
2011; 121 (5): 1822-6.
Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med
2011; 365 (8): 725-33.
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng ZH, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med
2014; 371 (16): 1507-17.
Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet
2015; 385 (9967): 517-28.
Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, Forman SJ. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant
2010; 16 (9): 1245-56.
Ritchie DS, Neeson PJ, Khot A, Peinert S, Tai T, Tainton K, Chen K, Shin M, Wall DM, Hönemann D, Gambell P, Westerman DA, Haurat J, Westwood JA, Scott AM, Kravets L, Dickinson M, Trapani JA, Smyth MJ, Darcy PK, Kershaw MH, Prince HM. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther
2013; 21 (11): 2122-9.
Uckun FM, Jaszcz W, Ambrus JL, Fauci AS, Gajl-Peczalska K, Song CW, Wick MR, Myers DE, Waddick K, Ledbetter JA. Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins. Blood
1988; 71 (1): 13-29.
Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, Morgan RA, Rosenberg SA. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood
2010; 116 (20): 4099-102.
Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM, Raffeld M, Feldman S, Lu L, Li YF, Ngo LT, Goy A, Feldman T, Spaner DE, Wang ML, Chen CC, Kranick SM, Nath A, Nathan DA, Morton KE, Toomey MA, Rosenberg SA. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol
2015; 33 (6): 540-9.
Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, Laurencot C, Rosenberg SA. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood
2012; 119 (12): 2709-20.
Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, Hakim FT, Halverson DC, Fowler DH, Hardy NM, Mato AR, Hickstein DD, Gea-Banacloche JC, Pavletic SZ, Sportes C, Maric I, Feldman SA, Hansen BG, Wilder JS, Blacklock-Schuver B, Jena B, Bishop MR, Gress RE, Rosenberg SA. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood
2013; 122 (25): 4129-39.
Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE, Raubitschek A, Forman SJ, Greenberg PD, Riddell SR, Press OW. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood
2012; 119 (17): 3940-50.
Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ, Gopal AK, Pagel JM, Lindgren CG, Greenberg PD, Riddell SR, Press OW. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood
2008; 112 (6): 2261-71.
Zinzani PL, Pellegrini C, Derenzini E, Argnani L, Pileri S. Long-term efficacy of the combination of lenalidomide and rituximab in elderly relapsed/refractory diffuse large B-cell lymphoma patients. Hematol Oncol
2013; 31 (4): 223-4.
Ogura M, Ando K, Suzuki T, Ishizawa K, Oh SY, Itoh K, Yamamoto K, Au WY, Tien HF, Matsuno Y, Terauchi T, Mori M, Tanaka Y, Shimamoto T, Tobinai K, Kim WS. A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma. Br J Haematol
2014; 165 (6): 768-76.
Gleissner B, Gökbuget N, Bartram CR, Janssen B, Rieder H, Janssen JW, Fonatsch C, Heyll A, Voliotis D, Beck J, Lipp T, Munzert G, Maurer J, Hoelzer D, Thiel E. Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood
2002; 99 (5): 1536-43.
Forman SJ, Rowe JM. The myth of the second remission of acute leukemia in the adult. Blood
2013; 121 (7): 1077-82.
Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang WC, Ostberg JR, Jensen MC. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther
2007; 15 (4): 825-33.
Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, Vulto A, den Bakker M, Oosterwijk E, Debets R, Gratama JW. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther
2013; 21 (4): 904-12.
Nishio N, Diaconu I, Liu H, Cerullo V, Caruana I, Hoyos V, Bouchier-Hayes L, Savoldo B, Dotti G. Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. Cancer Res
2014; 74 (18): 5195-205.
Rainusso N, Brawley VS, Ghazi A, Hicks MJ, Gottschalk S, Rosen JM, Ahmed N. Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma. Cancer Gene Ther
2012; 19 (3): 212-7.
Gheybi E, Amani J, Salmanian AH, Mashayekhi F, Khodi S. Designing a recombinant chimeric construct contain MUC1 and HER2 extracellular domain for prediagnostic breast cancer. Tumour Biol
2014; 35 (11): 11489-97.
Singh N, Liu X, Hulitt J, Jiang S, June CH, Grupp SA, Grupp SA, Barrett DM, Zhao Y. Nature of tumor control by permanently and transiently modified GD2 chimeric antigen receptor T cells in xenograft models of neuroblastoma. Cancer Immunol Res
2014; 2 (11): 1059-70.
Gargett T, Brown MP. Different cytokine and stimulation conditions influence the expansion and immune phenotype of third-generation chimeric antigen receptor T cells specific for tumor antigen GD2. Cytotherapy
2015; 17 (4): 487-95.
Sampson JH, Choi BD, Sanchez-Perez L, Suryadevara CM, Snyder DJ, Flores CT, Schmittling RJ, Nair SK, Reap EA, Norberg PK, Herndon JE 2 nd
, Kuan CT, Morgan RA, Rosenberg SA, Johnson LA. EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res
2014; 20 (4): 972-84.
Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J
2013; 280 (21): 5350-70.
Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G, Chew A, Zhao Y, Levine BL, Albelda SM, Kalos M, June CH. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res
2014; 2 (2): 112-20.
Adusumilli PS, Cherkassky L, Villena-Vargas J, Colovos C, Servais E, Plotkin J, Jones DR, Sadelain M. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med
2014; 6 (261): 261ra151.
Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O, Olszewska M, Bernal Y, Pegram H, Przybylowski M, Hollyman D, Usachenko Y, Pirraglia D, Hosey J, Santos E, Halton E, Maslak P, Scheinberg D, Jurcic J, Heaney M, Heller G, Frattini M, Sadelain M. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood
2011; 118 (18): 4817-28.
Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther
2010; 18 (4): 843-51.
Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu X, Zhao Y, Kalos M, June CH. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res
2013; 1 (1): 26-31.
Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med
2013; 368 (16): 1509-18.
Maiti SN, Huls H, Singh H, Dawson M, Figliola M, Olivares S, Rao P, Zhao YJ, Multani A, Yang G, Zhang L, Crossland D, Ang S, Torikai H, Rabinovich B, Lee DA, Kebriaei P, Hackett P, Champlin RE, Cooper LJ. Sleeping beauty system to redirect T-cell specificity for human applications. J Immunother
2013; 36 (2): 112-23.
Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med
2011; 3 (95): 95ra73.
Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, Chung SS, Stefanski J, Borquez-Ojeda O, Olszewska M, Qu J, Wasielewska T, He Q, Fink M, Shinglot H, Youssif M, Satter M, Wang Y, Hosey J, Quintanilla H, Halton E, Bernal Y, Bouhassira DC, Arcila ME, Gonen M, Roboz GJ, Maslak P, Douer D, Frattini MG, Giralt S, Sadelain M, Brentjens R. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med
2014; 6 (224): 224ra25.
Cruz CR, Micklethwaite KP, Savoldo B, Ramos CA, Lam S, Ku S, Diouf O, Liu E, Barrett AJ, Ito S, Shpall EJ, Krance RA, Kamble RT, Carrum G, Hosing CM, Gee AP, Mei Z, Grilley BJ, Heslop HE, Rooney CM, Brenner MK, Bollard CM, Dotti G. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood
2013; 122 (17): 2965-73.
Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, Borquez-Ojeda O, Qu J, Wasielewska T, He Q, Bernal Y, Rijo IV, Hedvat C, Kobos R, Curran K, Steinherz P, Jurcic J, Rosenblat T, Maslak P, Frattini M, Sadelain M. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med
2013; 5 (117): 177ra38.
Hoyos V, Savoldo B, Quintarelli C, Mahendravada A, Zhang M, Vera J, Heslop HE, Rooney CM, Brenner MK, Dotti G. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia
2010; 24 (6): 1160-70.
Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol
2013; 31 (1): 71-5.
Fedorov VD, Themeli M, Sadelain M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med
2013; 5 (215): 215ra172.
Gargett T, Brown MP. The inducible caspase-9 suicide gene system as a "safety switch" to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front Pharmacol
2014; 5: 235.
Budde LE, Berger C, Lin Y, Wang J, Lin X, Frayo SE, Brouns SA, Spencer DM, Till BG, Jensen MC, Riddell SR, Press OW. Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. PLoS One
2013; 8 (12): e82742.
Massari F, Santoni M, Ciccarese C, Santini D, Alfieri S, Martignoni G, Brunelli M, Piva F, Berardi R, Montironi R, Porta C, Cascinu S, Tortora G. PD-1 blockade therapy in renal cell carcinoma: current studies and future promises. Cancer Treat Rev
2015; 41 (2): 114-21.
Keir ME, Francisco LM, Sharpe AH. PD-1 and its ligands in T-cell immunity. Curr Opin Immunol
2007; 19 (3): 309-14.
Sfanos KS, Bruno TC, Meeker AK, De Marzo AM, Isaacs WB, Drake CG. Human prostate-infiltrating CD8 T lymphocytes are oligoclonal and PD-1. Prostate
2009; 69 (15): 1694-703.
Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med
2009; 206 (13): 3015-29.
Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, Rosenberg SA. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood
2009; 114 (8): 1537-44.
Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med
2012; 366 (26): 2517-9.
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature
2006; 439 (7077): 682-7.
Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3 - potential mechanisms of action. Nat Rev Immunol
2015; 15 (1): 45-56.
Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol
2008; 8 (6): 467-77.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med
2002; 8 (8): 793-800.
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A
2002; 99 (19): 12293-7.
Drake CG, Jaffee E, Pardoll DM. Mechanisms of immune evasion by tumors. Adv Immunol
2006; 90: 51-81.
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol
2014; 32 (10): 1020-30.
Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet
2014; 384 (9948): 1109-17.
Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, Zhang T, Yang J, Seestaller-Wehr L, Zhang SY, Hopson C, Tsvetkov L, Jing J, Zhang S, Smothers J, Hoos A. The BRAF and MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD1, PD-L1 and CTLA-4. Clin Cancer Res
2015; 21 (7): 1639-51.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med
2012; 366 (26): 2455-65.
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, Koren-Michowitz M, Shimoni A, Nagler A. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res
2008; 14 (10): 3044-51.
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A
2010; 107 (9): 4275-80.
Armand P, Nagler A, Weller EA, Devine SM, Avigan DE, Chen YB, Kaminski MS, Holland HK, Winter JN, Mason JR, Fay JW, Rizzieri DA, Hosing CM, Ball ED, Uberti JP, Lazarus HM, Mapara MY, Gregory SA, Timmerman JM, Andorsky D, Or R, Waller EK, Rotem-Yehudar R, Gordon LI. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol
2013; 31 (33): 4199-206.
Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, Zhao X, Martinez AJ, Wang W, Gibney G, Kroeger J, Eysmans C, Sarnaik AA, Chen YA. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol
2013; 31 (34): 4311-8.
Hamid CR, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Schaap JE, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang P, Ribas A. Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma. N Engl J Med
2013; 369 (2): 134-44.
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol
2010; 28 (19): 3167-75.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med
2012; 366 (26): 2443-54.
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med
2013; 369 (2): 122-33.
Westin JR, Chu F, Zhang M, Fayad LE, Kwak LW, Fowler N, Romaguera J, Hagemeister F, Fanale M, Samaniego F, Feng L, Baladandayuthapani V, Wang Z, Ma W, Gao Y, Wallace M, Vence LM, Radvanyi L, Muzzafar T, Rotem-Yehudar R, Davis RE, Neelapu SS. Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. Lancet Oncol
2014; 15 (1): 69-77.
Poole RM. Pembrolizumab: first global approval. Drugs
2014; 74(16): 1973-81.
[Table 1], [Table 2]