|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 2019 Jan 17];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.
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[Table 1], [Table 2]