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State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
Health Policy and Hospital Management Research Center, Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
1.Health Policy and Hospital Management Research Center, Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
2.State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
Published: 2019-01 ,
Received: 07 August 2018 ,
Accepted: 26 December 2018
Cite this article
Sang-sang Ren, Jing-wen Deng, Meng Hong, et al. Ethical considerations of cellular immunotherapy for cancer. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 20(1):23-31(2019)
Sang-sang Ren, Jing-wen Deng, Meng Hong, et al. Ethical considerations of cellular immunotherapy for cancer. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 20(1):23-31(2019) DOI: 10.1631/jzus.B1800421.
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
Health Policy and Hospital Management Research Center, Department of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
With the rapid development of immunology, molecular biology, and associated technologies such as next-generation sequencing, cellular immunotherapy has recently become the fourth major cancer treatment. Immunotherapies based on T cells, natural killer cells, and dendritic cells play key roles in cancer immunotherapy. However, their application in clinical practice raises several ethical issues. Thus, studies should focus on proper adherence to basic ethical principles that can effectively guide and solve related clinical problems in the course of treatment, improve treatment effects, and protect the rights and interests of patients. In this review, we discuss cellular immunotherapy-related ethical issues and highlight the ethical practices and current status of cellular immunotherapy in China. These considerations may supplement existing ethical standards in cancer immunotherapy.
本文旨在对细胞免疫治疗相关的伦理学问题进行探讨,并通过分析我国细胞免疫治疗相关伦理学实践及现状,为规范我国肿瘤细胞免疫治疗的伦理标准提供参考.随着免疫学、分子生物学等学科的飞速发展和高通量测序等技术的普及,肿瘤免疫治疗已成为第四大肿瘤治疗方法.肿瘤细胞免疫治疗,如各种基于T细胞、自然杀伤(NK)细胞和树突状细胞(DC)的免疫治疗在其中发挥了重要作用.随着临床实践的开展,一些相关的伦理学问题逐渐暴露出来.如何在治疗过程中坚持基本伦理原则,有效指导并解决相关临床问题,提高治疗效果,保护受试者权益,是目前亟需研究的重要课题.本文对与之相关的伦理学问题进行探讨,并通过分析我国细胞免疫治疗相关伦理学实践及现状,以期为规范我国肿瘤细胞免疫治疗的伦理标准提供参考.
Cancer immunotherapy was evaluated as one of the top ten scientific and technological breakthroughs in Science in 2013 (Couzin-Frankel,
T cells, natural killer (NK) cells, and dendritic cells (DCs) play important roles in the anti-tumor immune response. At present, chimeric antigen receptor T (CAR-T) cell technology has achieved efficacy in the treatment of blood tumors and melanoma. NK cells, combined with immunological checkpoint inhibitors, cytokines, and CAR-NK, have shown good prospects for application to cancer immunotherapy. In 2010, the DC vaccine, as the first tumor therapeutic vaccine approved by the United States Food and Drug Administration (FDA), gradually caught the attention of researchers (Sims,
At present, two main methods of T cell immunotherapy are available. One method amplifies tumor-infiltrating lymphocytes (TILs) in vitro and then transfers them back to the patient for cancer therapy. The other, through gene modification, enables T cells to express receptors, mainly the T cell receptor T (TCR-T) and CAR-T that recognize tumor antigens.
Muul et al. (
TCRs can recognize the antigen peptide/major histocompatibility complex (MHC) on antigen-presenting cells (APCs), mediating T cell activation and proliferation. Therefore, recognition of tumor antigens with TCRs has become an effective method for adoptive immunotherapy of T cells. Morgan et al. (
To solve MHC restriction in TCR-T, a new structure named CAR was constructed by fusing an antigen–antibody recognition region with a TCR signal molecule containing an extracellular domain, a transmembrane domain, and an intracellular domain (Gross et al.,
The anti-tumor effect of NK cells was first observed by Ruggeri et al. (
The major limitations of NK cell therapy include the low proportion of NK cells in peripheral blood cells and technical problems of culture and amplification of NK cells in vitro. In NK cells, immune checkpoint inhibitors, such as KIRs, NKG2A (Ruggeri et al.,
Recently, CAR-NK cell therapy has been proven to be effective in tumor immunotherapy (Hermanson and Kaufman,
DCs are considered the most potent APCs, helping the activation and proliferation of T cells and enhancing their anti-tumor activity. The first clinical trial of ex vivo DCs on B cell lymphoma (Hsu et al.,
Distinguished by the use of tumor antigen-presenting DCs, DC-based vaccines can be divided into ex vivo generated DCs and in vivo DC targets. DCs differentiate mostly from CD14+ monocytes and CD34+ progenitor cells. Using granulocyte-macrophage colony-stimulating factor/IL-4 at proper intervals to induce differentiation, DCs can be induced to maturity by Toll-like receptor (TLR) agonists, TLR4, TLR7, TLR9, or a cocktail of pro-inflammatory cytokines including tumor necrosis factor-α, IL-1β, IL-6, and prostaglandin E2 (Hansen et al.,
Based on adaptive and acquired immune mechanisms, a variety of immunotherapies and the combined use of cancer-related research and clinical trials have shown continuous development. Cancer immunotherapy adds to the improvement of the treatment of cancer patients. However, in the development of tumor immunotherapy, especially cellular immunotherapy, a number of significant ethical issues must be settled to protect the rights of patients.
With the rapid development of cancer cellular immunotherapy technology, an increasing number of medical institutions and researchers have joined in the development of new therapies. If immunotherapy research units have weak admission criteria and their immunotherapy equipment does not meet prescribed cellular immunotherapy technical requirements, patients who suffer from diseases and who lack professional judgement may blindly join clinical trials. This will delay the most appropriate treatment opportunity, which will violate the principle of non-harm in medical ethical principles, such as in the case of the “Wei Zexi incident” in China (Su and Han,
To strengthen the management of medical institution access, the first step is to ensure technical entry requirements, for example, to guarantee a suitable immunotherapy environment and equipment, including software and hardware support. At the same time, medical teams with appropriate operational qualifications should also be recruited. Medical teams will also benefit from professional training or relevant treatment experience. Moreover, admission by the administration office of hospitals is required. Institutions intending to conduct immunotherapy should feature an accurate evaluation and supervision system, and the department should supervise and manage the technical path and clinical application standards. At the ethical level, admitted medical institutions should carry out long-term supervision and evaluation of new technologies. Immunotherapy techniques are updated frequently. Thus, medical institutions should also constantly monitor the safety and effectiveness of existing technologies and update the standards of treatment methods in a timely manner.
Researchers and medical staff engaged in cancer immunotherapy should possess considerable research aptitude and relevant professional qualifications issued by a certification authority. This should enable timely and accurate countermeasures to be taken for emergencies in the course of treatment. Also, strict standards of approval and admittance should be formulated for the ethics of researchers and medical staff to reduce improper benefit correlation in the treatment process and maximize the right to life and health of patients.
Cellular immunotherapy, as a promising tumor therapy, has brought great survival hope to many tumor patients. However, because of the different indications for different treatment options, choosing the right subject is an important factor in the safety and effectiveness of the treatment. Based on basic ethical requirements, researchers and research institutions should reasonably and comprehensively evaluate the risks and benefits to the participants and maximize the protection of patients’ rights. The main risk to patients in clinical trials is the risk of pain and complications caused by treatment. The benefits refer mainly to avoiding injury and obtaining a certain curative effect, or understanding whether the advantages outweigh the disadvantages. Therefore, when selecting subjects, researchers should inform them in such a way that they can understand the risks they may face, the possible benefits they may gain, and the reasons why the benefits outweigh the risks.
In clinical trials, the failure of patients to distinguish between the two concepts of clinical treatment and medical research may easily lead to therapeutic misunderstanding. If the patients believe that they can still obtain the clinical treatment services and treatment effects from clinical trials, they fail to fully understand the nature of scientific research, which will violate the principle of informed consent in scientific research. In recent years, many problems in drug clinical trials reported in China have been caused by therapeutic misunderstanding. Therefore, the strengthening of informed consent, the standardization and interpretation of the use of technical terms, and the strengthening of ethical review are needed to ensure that the ethical principles of medical research are not violated.
When enrolling subjects, first, an overall estimate should be obtained for the disease progression of each patient, and if necessary, relevant examinations should be carried out to determine whether the corresponding immunotherapy can be performed. Second, subject enrollment should be based on the principles of informed consent and respect, and be voluntary. Informed consent includes the investigator providing adequate information to the subject, ensuring that the subject understands the information correctly, and the subject voluntarily agreeing with and choosing the therapy. Given the possible side effects of cellular immunotherapy, such as a cytokine storm, patients undergoing immunotherapy face certain risks and should know the specific risks involved. Before the investigator determines the treatment plan, patients should be informed about the likely progress and prognosis of sickness, optional treatment plans, and the anticipated effects and possible adverse reactions of these treatments. The final plan must be implemented only when the patient decides and signs the informed consent form after learning all the pros and cons and optional treatment plans. The informed consent form should be patient-centered, and the language used must be easy to understand to avoid guiding the choice of the patients.
The cells used for immune therapy can be divided into autologous or allogeneic cells according to their origin. These include mainly peripheral blood-derived cells, umbilical cord blood-derived cells, hematopoietic stem cell-derived cells, and cell line-derived cells. Because immune cells need to be treated in vitro and have adoptive reinfusion processes, ensuring the accuracy of cell source, treatment and quality control can effectively comply with the non-harm principle in medical ethics. Therefore, the specific experimental scheme should be regulated according to common guiding principles. For example, the specific source of non-cell lines must be identified, and the specific tissue origin and cell type, cell morphology, and the exact information related to the markers should also be provided. Detailed immunological detection methods and results are needed for immunotherapy of allogeneic cells. In addition, the history, the number of descendants from the parent library, and the number of permitted generations are needed for cells such as NK-92, and their cell phenotype and functional stability must be maintained. If cells are to be cultured in vitro, strict monitoring of cell cultures and detection is required. Ensuring the high quality of the cells used in cancer cellular immunotherapy can avoid violation of the ethical principle of non-harm.
Given the complexity and diversity of cancer cellular immunotherapy, difficulty arises from establishing a unified clinical trial design standard, safety evaluation criteria, and a fully appropriate effectiveness evaluation system. According to the requirements of Good Clinical Practice (GCP), clinical trials should be randomized double-blind trials that require a blank control. On the other hand, in cancer cellular immunotherapy, setting a blank control is contrary to the ethical principles proposed in the Helsinki Declaration (World Medical Association,
Establishing a safety evaluation system for cellular immunotherapy is an essential requirement for ensuring the interests of patients. Safety evaluation criteria should be applied throughout the whole treatment process (Ying et al.,
The effectiveness of most cellular immunotherapy protocols should be demonstrated in animal models before starting clinical trials. Because of the differences in the immune system among species, the specific evaluation indicators and systems for a certain treatment should be derived from preclinical studies and clinical trials. The use of strict effectiveness evaluation criteria can guarantee the precise treatment of tumors.
The Declaration of Helsinki mentions that “Medical researchers should obey moral standards and protect patients’ right to health. In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society” (World Medical Association,
Cancer cellular immunotherapy has been studied in China for a long time, but the relevant ethical norms are not well constructed. In recent years, the level of medical institutions engaged in cellular immunotherapy in China was uneven, examination of researchers’ qualifications was not strict enough, and there were serious therapeutic misunderstandings when patients were treated with cellular immunotherapy. In 2016, Ze-xi WEI, a student of Xidian University, Xi’an, Shaanxi, China, died in the late stage of synovial sarcoma after receiving cell immunotherapy provided by a tertiary hospital, thereby exposing cancer cellular immunotherapy to public scrutiny. Although the Health Planning Commission has stopped biological immunotherapy and defined it and prevented clinical application, a vague understanding persists in China of the clinical research and irregularities in cancer cellular immunotherapy. China has issued several policies and regulations for the scientific development of cancer cellular immunotherapy technology.
In 1999, the China FDA issued “Guidelines for the Clinical Trial of Human Gene Therapy,” which regulates the relevant content of somatic cell therapy. In 2003, China promoted the “Guidelines for Human Cell Therapy Research and Preparation Quality Control Technology” to establish standard operating procedures for application materials, somatic cell collection, culture and in vitro operation, quality inspection and pre-clinical trial safety, and efficacy evaluation of adoptive cell transfer treatments, such as lymphokine-activated killer and TIL cells, and to provide a reference standard for somatic treatment in China. In 2013, based on the current development of ethics in China and documents, such as “Human Somatic Cell and Gene Therapy Conditions,” formulated by the US FDA Center in 1991 for biological products evaluation and research, the FDA of China issued the “Quality Control Points for Clinical Research of Human Somatic Cell Therapy and Gene Therapy,” which defined the basis of the research, identification of therapeutic cell populations, and safety and effectiveness of the evaluation of preclinical trials. It served as a foundation for examining the ethical issues related to cancer cellular immunotherapy in China. In December 2017, the “Guidelines for the Research and Evaluation of Cellular Therapeutic Products (Trial)” issued by the FDA of China provided guidelines for the development of clinical application rules for cancer cellular immunotherapy. At present, a number of clinical trials related to cellular immunotherapy, including those for lung cancer, stomach cancer, colorectal cancer, and liver cancer, have been reviewed and approved by the Chinese Ethics Committee (Table
Agent | Mechanism/combining agent | Disease | Phase | Patient | NCT number |
---|---|---|---|---|---|
CAR-T | PSCA, MUC1, PD-L1, or CD80/86 targeting CAR-T cells | Lung cancer | 1 | 30 | 03198052 |
EGFRvIII, IL13Rα2, Her-2, CD133, EphA2, GD2 targeting CAR-T cells | Recurrent malignant gliomas | 1 | 50 | 03423992 | |
Anti-MUC1 CAR-T cells | MUC1-positive solid tumor | 1, 2 | 20 | 02617134 | |
Anti-CD19 CAR-T cells | Refractory/relapsed B cell malignancies | 1, 2 | 100 20 | 03191773 02652910 | |
Anti-CD19, CD22 CAR-T cells | Relapsed and refractory lymphoma | 1, 2 | 10 12 | 03468153 03593109 | |
GPC3-T2-CAR-T cells | GPC3 expression HCC | 1 | 30 | 03198546 | |
EpCAM CAR-T cells | Nasopharyngeal carcinoma and breast cancer | 1 | 30 | 02915445 | |
CAR-NK | Anti-MUC1 CAR-pNK cells | MUC1+ relapsed or refractory solid tumor | 1, 2 | 10 | 02839954 |
Anti-CD33 CAR-NK cells | Relapsed/refractory CD33+ AML | 1, 2 | 10 | 02944162 | |
Anti-CD7 CAR-NK cells | CD7+ leukemia and lymphoma | 1, 2 | 10 | 02742727 | |
γδ T cells | Cryosurgery, IRE surgery, and surgery | Breast cancer | 1, 2 | 30 | 03183206 |
Cryosurgery or IRE surgery | Liver cancer | 1, 2 | 30 | 03183219 | |
Cryosurgery or IRE surgery | Lung cancer | 1, 2 | 30 | 03183232 | |
Cryosurgery or IRE surgery | Pancreatic cancer | 1, 2 | 30 | 03180437 | |
NK cells | NK and NKT cells | Non-small cell lung cancer | 1 | 30 | 03198923 |
NK cells | Small cell lung cancer | 2 | 120 | 03410368 | |
High-activity NK cells | Non-small cell lung cancer metastatic | 1, 2 | 20 | 03007875 | |
DCs | TACE | Advanced liver cancer | 1, 2 | 40 40 | 02873442 02862613 |
Chemotherapy | Advanced lung cancer | 1, 2 | 40 | 02873416 | |
Radical surgery | Gastric cancer | 2 | 120 | 03410732 |
PSCA, prostate stem cell antigen; MUC1, mucin 1; PD-L1, programmed cell death ligand 1; EGFRvIII, epidermal growth factor receptor vIII; IL13Rα2, interleukin 13 receptor α2; EphA2, EPH receptor A2; GD2, ganglioside D2; GPC3, glypican-3; EpCAM, epithelial cell adhesion molecule; IRE, irreversible electroporation; TACE, transcatheter arterial chemoembolization; HCC, hepatic cell carcinoma
China has made continuous progress in the construction of cellular immunotherapy systems, but compared with developed countries, it still needs to form a normative system, especially in relation to the ethical issues in treatment. In future, the main work in the construction of ethics related to cancer cellular immunotherapy in China will be to further systematize the standards for targeted clinical trials of tumor cellular immunotherapy, the preparation and quality control of immune cells, the evaluation of the efficacy of immunotherapy, and the admission of patients and researchers, and the formulation of national standard operating procedures.
With the continuous development of cancer cellular immunotherapy technologies and the introduction of relevant national normative policies, cancer immunotherapy will help more patients. Thorough implementation of relevant ethical guidelines during the entire clinical research process to achieve respect, fairness, and “lack of harm” can effectively protect patients’ rights.
Compliance with ethics guidelines
Sang-sang REN, Jing-wen DENG, Meng HONG, Yan-li REN, Hai-jing FU, Yan-ning LIU, and Zhi CHEN declare that they have no conflict of interest.
This article does not contain any studies with human or animal subjects performed by any of the authors.
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