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01.12.2017 | Rapid communication | Ausgabe 1/2017 Open Access

Journal of Hematology & Oncology 1/2017

Clinical trials of CAR-T cells in China

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2017
Autoren:
Bingshan Liu, Yongping Song, Delong Liu
Abbreviations
ALL
Acute lymphoblastic leukemia
AML
Acute myeloid leukemia
BCMA
B cell maturation antigen
CTX
Cyclophosphamide
DLBCL
Diffuse large B cell lymphoma
FLU
Fludarabine
HL
Hodgkin’s lymphoma
LV
Lentiviral
MCL
Mantle cell lymphoma
NHL
Non-Hodgkin lymphoma

Background

Novel immunotherapeutic agents targeting CTLA-4, programmed cell death-1 protein receptor (PD-1), and the ligand PD-L1 are revolutionizing cancer therapy [17]. Cancer immunotherapy by re-igniting T cells through blocking PD-1 and PD-L1 is highly potent in a variety of malignancies [812]. Allogeneic hematopoietic stem cell transplantation has been proven to be a curative immunotherapy for leukemia though with significant toxicities [1318]. Autologous T cells with re-engineered chimeric antigen receptors (CAR-T) have been successfully used for leukemia and lymphoma without graft-vs-host diseases [1925]. The first such product, tisagenlecleucel, has recently been approved for clinical therapy of refractory B cell acute lymphoblastic lymphoma (ALL). More and more clinical trials of CAR-T cells are being done throughout the world [2638].
In recent years, more and more clinical trials from China are being done and registered in ClinicalTrials.​gov. CAR-T cells have become a major source of cellular immunotherapy in China. This study summarized the CAR-T clinical trials being conducted in China and provided a quick glimpse of the landscape of CAR-T studies in China.

Methods

We searched ClinicalTrials.​gov using keywords “CAR T,” “CAR-T,” “chimeric antigen receptor,” “adoptive therapy,” “third generation chimeric,” and “fourth generation chimeric”; country: China. All relevant trials registered at the ClinicalTrials.​gov prior to July 18, 2017, were included in the analysis. One trial was excluded (NCT03121625) because the target antigen was not disclosed. A search of the PubMed database was also done to include those trials and cases that have been published.

Results

Distribution of CAR-T trials in China

Currently, there are 121 trials reported and/or registered at ClinicalTrials.​gov from China (Table 1). The trials are mainly carried out in leading hospitals from Beijing, Shanghai, Guangzhou, and Chongqing. CAR-T trials are started in hospitals throughout China. In this study, to avoid duplication of trials that can lead to miscalculation, those trials in Chinese registries were not included. It is possible that the number of institutions carrying out CAR-T trials will increase at a slower pace once regulatory policies are in place. We believe these CAR-T cells should be regulated as drugs [39].
Table 1
Distribution of clinical trials with CAR-T cells in China
Beijing
30
Shanghai
22
Guangdong
20
Chongqing
15
Jiangsu
13
Others
21

Chimeric antigen receptors, vectors, and co-stimulatory molecules used in the CAR constructs

T cell receptors (TCRs) are engineered by incorporating a specific antigen-targeting element and CD3 element to form a completely novel TCR structure, the chimeric antigen receptor (CAR) [35, 40]. In addition, several co-stimulating sequences have been used to facilitate the expansion of the CAR-T cells [41]. CAR-engineered T lymphocytes have been in active clinical development to treat patients with advanced leukemia, lymphoma, and solid tumors [4245].
One of the major hurdles in CAR-targeted cellular therapy has been the limited cell dose due to the lack of adequate in vivo cell expansion. Co-stimulatory signals can enhance immune responses of effector T cells [46]. Inducible co-stimulatory signal (ICOS), 4-1BB (CD137), CD28, OX40 (CD134), CD27, and DAP10, along with CD3ζ, have been investigated [31, 4750]. Among these, 4-1BB (CD137), CD28, and CD3ζ are the most commonly used COS elements in the CARs (Tables 2, 3, and 4) [51, 52].
Table 2
Clinical trials of CD19-directed CAR-T cells in China
Target antigen
Diseases
CAR
Vector
NCT no.
CD19
Leukemia, lymphoma
4-1BB- CD3ζ
RV
NCT01864889
CD19
B cell malignancies
CD28, CD137, CD27
LV
NCT03050190
CD19
MCL
4-1BB-CD3ζ
RV
NCT02081937
CD19
Leukemia
NA
NA
NCT03142646
CD19
B cell lymphomas
CD27-CD3ζ
LV
NCT02247609
CD19
Leukemia, lymphoma
NA
NA
NCT02349698
CD19
Elderly relapsed/refractory B cell ALL
NA
NA
NCT02799550
CD19
Leukemia, lymphoma
NA
NA
NCT02537977
CD19
B cell leukemia
NA
NA
NCT02644655
CD19
B cell leukemia and lymphoma
NA
NA
NCT02813837
CD19
B cell lymphoma
NA
NA
NCT02547948
CD19
B cell lymphoma
CD28-CD3ζ
RV
NCT02652910
CD19
Leukemia, lymphoma
CD28, CD3ζ
LV or RV
NCT02456350
CD19
Recurrent or refractory acute non-T-lymphocyte leukemia
NA
NA
NCT02735291
CD19
Lymphoma
NA
NA
NCT02728882
CD19
Leukemia, lymphoma
NA
NA
NCT02546739
CD19
B cell lymphomas
NA
NA
NCT02842138
CD19
ALL
NA
NA
NCT02810223
CD19
ALL
CD28-CD137-CD3ζ
LV
NCT02186860
CD19
B cell leukemia, B cell lymphoma
CD3ζ, CD28, and 4-1BB
LV
NCT02963038
CD19
NHL
TCRζ, 4-1BB
LV
NCT03029338
CD19
B cell ALL
TCRζ, 4-1BB
LV
NCT02975687
CD19
B cell leukemia and lymphoma
NA
LV
NCT02933775
CD19
B cell leukemia
4-1BB
LV
NCT02672501
CD19
Central nervous system B cell acute lymphocytic leukemia
NA
NA
NCT03064269
CD19
ALL
4-1BB
LV
NCT02965092
CD19
Acute leukemia
NA
NA
NCT02822326
CD19
Leukemia, lymphoma
CD28 or 4-1BB and a CD3ζ
LV or RV
NCT03076437
CD19
Leukemia and lymphoma
NA
NA
NCT02851589
CD19
Leukemia and lymphoma
NA
NA
NCT02819583
CD19
DLBCL
NA
LV
NCT02976857
CD19
Recurrent or refractory B cell malignancy
NA
NA
NCT02782351
CD19
Leukemia and lymphoma
TCRz-CD28, TCRz-CD137
NA
NCT02685670
CD19
B cell lymphoma
4-1BB, CD3ζ
NA
NCT03101709
CD19
ALL
NA
NA
NCT02924753
CD19
ALL
NA
NA
NCT03027739
CD19
B cell leukemia
NA
LV
NCT02968472
CD19
B cell lymphoma
CD28ζ
NA
NCT02992834
CD19
AML
NA
NA
NCT03018093
CD19
Systemic lupus erythematosus
4-1BB
LV
NCT03030976
CD19
NHL
NA
LV
NCT03154775
CD19
Lymphoma
NA
NA
NCT03086954
CD19
ALL, CLL, lymphoma
CD28 or 4-1BB and CD3ζ
NA
NCT03191773
CD19
B cell lymphoma
4-1BB-CD28-CD3
NA
NCT03146533
CD19
Leukemia
NA
NA
NCT03173417
CD19
Relapsed or refractory B cell lymphoma
4-1BB
LV
NCT03208556
CD19
B cell leukemia and lymphoma
  
NCT03166878
CD19
B cell lymphoma
NA
NA
NCT03118180
CD19 or CD20
Relapse/refractory B cell malignancies
NA
LV
NCT02846584
CD19 and CD20
DLBCL
NA
NA
NCT02737085
CD19 and CD22
Hematopoietic/lymphoid cancer
TCRζ, 4-1BB
NA
NCT02903810
CD19/CD20
B cell leukemia and lymphoma
CD3ζ, 4-1BB-CD3ζ
RV
NCT03097770
CD19/CD22
B cell malignancy
NA
RV
NCT03185494
CD19/CD22
B cell leukemia, B cell lymphoma
NA
LV
NCT03098355
CD19/CD20/CD22/CD30
B-NHL
NA
NA
NCT03196830
CD19/CD20
B cell malignancy
NA
NA
NCT03207178
CD19 and CD20/CD22/CD38/CD123
B cell malignancy
NA
LV
NCT03125577
AMMS Academy Military Medical Sciences, ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, BCMA B cell maturation antigen, CTX cyclophosphamide, DLBCL diffuse large B cell lymphoma, FLU fludarabine, HL Hodgkin’s lymphoma, LV lentiviral, MCL mantle cell lymphoma, NA not available, NHL non-Hodgkin lymphoma, RV retroviral, TCM traditional Chinese medicine
Table 3
Clinical trials of CAR-T cells targeting non-CD19 antigens in China
Target Antigen
Disease
CAR
Vector
NCT no.
CD20
Lymphoma
4-1BB-CD3ζ
LV
NCT01735604
CD20
B cell lymphoma
CD3ζ and CD28
RV
NCT02965157
CD20
B cell malignancies
NA
NA
NCT02710149
CD22
CD19-refractory or resistant lymphoma
TCRζ, 4-1BB
RV
NCT02721407
CD22
Recurrent or refractory B cell malignancy
NA
NA
NCT02794961
CD22
B cell malignancies
NA
NA
NCT02935153
CD30
Lymphoma
NA
LV
NCT02274584
CD30
HL, NHL
NA
NA
NCT02259556
CD30
Lymphocyte malignancies
NA
NA
NCT02958410
CD33
AML
4-1BB-CD3ζ
RV
NCT01864902
CD33
AML
NA
NA
NCT02799680
CD33
Myeloid malignancies
NA
NA
NCT02958397
BCMA
B cell malignancies
NA
NA
NCT02954445
BCMA
Multiple myeloma
TCRζ, 4-1-BB
RV
NCT03093168
CD123
Leukemia
NA
NA
NCT02937103
CD123
AML recurred after allo-HSCT
41BB-CD3ζ
NA
NCT03114670
CD138
Multiple myeloma
4-1BB-CD3ζ
RV
NCT01886976
CD138/BCMA
Multiple myeloma
NA
NA
NCT03196414
Lewis-Y
Myeloid malignancies
NA
NA
NCT02958384
AMMS Academy of Military Medical Sciences, ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, BCMA B cell maturation antigen, CTX cyclophosphamide, FLU fludarabine, HL Hodgkin’s lymphoma, LV lentiviral, MCL mantle cell lymphoma, NA not available, NHL non-Hodgkin lymphoma, RV retroviral, TCM traditional Chinese medicine
Table 4
Clinical trials of CAR-T cells for solid tumors in China
Target antigens
Diseases
CAR
Vector
NCT no.
GPC3
Hepatocellular carcinoma
NA
NA
NCT02723942
GPC3
Hepatocellular carcinoma
CD3ζ, CD28, and 4-1BB
NA
NCT02395250
GPC3
Lung squamous cell carcinoma
NA
LV
NCT02876978
GPC3
Hepatocellular carcinoma and liver metastases
4-1BB
NA
NCT02715362
GPC3
Hepatocellular carcinoma
4-1BB
NA
NCT03130712
GPC3
Advanced hepatocellular carcinoma
4-1BB-CD3ζ
RV
NCT03084380
GPC3
Hepatocellular carcinoma, squamous cell lung cancer
NA
NA
NCT03198546
GPC3
Hepatocellular carcinoma
NA
LV
NCT03146234
GPC3, mesothelin, CEA
Hepatocellular, pancreatic cancer, colorectal cancer
NA
LV
NCT02959151
Mesothelin
Malignant mesothelioma, pancreatic Cancer, ovarian tumor, triple-negative breast cancer, endometrial cancer, other mesothelin-positive tumors
4-1BB-CD3ζ
RV
NCT02580747
Mesothelin
Recurrent or metastatic malignant tumors
NA
NA
NCT02930993
Mesothelin
Pancreatic cancer and pancreatic ductal a denocarcinoma
4-1BB
NA
NCT02706782
Mesothelin
Solid tumor, adult advanced cancer
NA
NA
NCT03030001
Mesothelin
Advanced solid tumor
NA
NA
NCT03182803
EpCAM
Liver neoplasms
NA
NA
NCT02729493
EpCAM
Stomach neoplasms
NA
NA
NCT02725125
EpCAM
Nasopharyngeal carcinoma and breast cancer
NA
LV
NCT02915445
EpCAM
Colon cancer, esophageal carcinoma, pancreatic cancer, prostate cancer, gastric cancer, hepatic carcinoma
CD3ζ, CD28
LV
NCT03013712
GD2
Neuroblastoma
NA
LV
NCT02765243
GD2
Relapsed or refractory neuroblastoma
NA
NA
NCT02919046
GD2
Solid tumor
NA
LV
NCT02992210
HER-2
Advanced HER-2-positive solid tumors
CD3ζ, 4-1BB-CD3ζ
NA
NCT01935843
HER-2
Breast cancer
CD28-CD3ζ
RV
NCT02547961
HER-2
Breast cancer, ovarian cancer, lung cancer, gastric cancer, glioma, pancreatic cancer
NA
NA
NCT02713984
EGFR
Advanced EGFR-positive solid tumors
4-1BB-CD3ζ
LV
NCT01869166
EGFR
Advanced solid tumor
NA
NA
NCT03182816
EGFR
Colorectal cancer
4-1BB-CD28-CD3
NA
NCT03152435
EGFRvIII
Recurrent glioblastoma multiform
NA
LV
NCT02844062
EGFRvIII
Glioblastoma multiform
NA
NA
NCT03170141
MUC1
Malignant glioma of brain, colorectal carcinoma, gastric carcinoma
NA
NA
NCT02617134
MUC1
Advanced refractory solid tumor (hepatocellular carcinoma, NSCLC, pancreatic carcinoma, triple-negative invasive breast carcinoma)
CD28-4-1BB- CD3ζ
LV
NCT02587689
MUC1
Advanced solid tumor
NA
NA
NCT03179007
CEA
Lung cancer, colorectal cancer, gastric cancer, breast cancer, pancreatic cancer
NA
NA
NCT02349724
EphA2
EphA2-positive malignant glioma
NA
NA
NCT02575261
LMP1
Nasopharyngeal neoplasms
NA
NA
NCT02980315
MG7
Liver metastases
4-1BB
NA
NCT02862704
CD133
Liver cancer, pancreatic cancer, brain tumor, breast cancer, ovarian tumor, colorectal cancer, ALL, AML
CD3ζ, 4-1BB-CD3ζ
RV
NCT02541370
HerinCAR-PD1
Advanced malignancies
NA
NA
NCT02873390
HerinCAR-PD1
Advanced solid tumor (lung, liver, and stomach)
NA
NA
NCT02862028
PD-L1 CSR
Glioblastoma multiform
NA
NA
NCT02937844
NY-ESO-1
Advanced NSCLC
NA
LV
NCT03029273
Zeushield
NSCLC
NA
NA
NCT03060343
PSCA/MUC1/PD-L1/CD80/86
Advanced lung or other cancers
NA
NA
NCT03198052
PSMA, FRa
Bladder cancer, urothelial carcinoma bladder
NA
NA
NCT03185468
Claudin18.2
Advanced gastric adenocarcinoma, pancreatic adenocarcinoma
NA
LV
NCT03159819
CTX cyclophosphamide, FLU fludarabine, LV lentiviral, NA not available, NSCLC non-small cell lung cancer, RV retroviral
Most CARs in the CAR-T trials in China are second-generation CAR constructs, which have one co-stimulatory signal [41]. A trial of CAR-T cells containing a third-generation CAR construct with both CD28 and CD137 co-stimulatory signals is still recruiting patients with relapsed/refractory ALL (NCT02186860). Fourth-generation CARs have incorporated additional elements in the CAR constructs, such as an inducible caspase-9 gene element that can lead to self-destruction by apoptosis of the CAR-T cells [53]. A total of 10 trials of CAR-T cells contain a fourth-generation CAR (Table 5). Among these, five trials are evaluating CARs with an inducible caspase-9 suicide switch.
Table 5
Clinical trials of CAR-T cells with fourth-generation CARs in China
Target antigen
Disease
Vector
NCT no.
CD19
B cell malignancies
LV
NCT03050190
CD19
B cell lymphomas
LV
NCT02247609
CD19
B cell leukemia
LV
NCT02968472
CD19/CD22
B cell leukemia, B cell lymphoma
LV
NCT03098355
CD19 and CD20/CD22/CD38/CD123
B cell malignancy
LV
NCT03125577
CD30
Lymphoma
LV
NCT02274584
PSMA, FRa
Bladder cancer, urothelial carcinoma bladder
NA
NCT03185468
EGFRvIII
Glioblastoma multiform
NA
NCT03170141
GD2
Neuroblastoma
LV
NCT02765243
GD2
Solid tumor
LV
NCT02992210
LV lentiviral vector, NA not available
The recombinant CAR cassette is typically packaged into a pseudo-lentivirus vector which can efficiently incorporate into the genome of T cells. To date, the lentiviral vector is the most commonly used vector in CAR-T cells. The other vector commonly used is the retroviral vector (Tables 2, 3, and 4).

Antigen targets

By altering a specific antigen-targeting element, the specificity of the CAR-T cells can be easily re-directed to a specific type of malignancy. This makes the CAR-T cell therapy highly versatile. A number of antigens have been targeted in this way. More and more antigens are being engineered into CAR-T cells, leading to a large repertoire of CAR-T cells that are being explored for the therapy of both solid and hematological malignancies (Tables 3 and 4).
CD19 is the most commonly targeted antigen to date (Table 2). Out of the 121 trials, 57 trials have CD19 as a target. Currently, there are 19 clinical trials in China targeting non-CD19 antigens, including CD20, CD22, CD30, CD33, CD38, CD123, CD138, BCMA, and Lewis Y antigen for hematological malignancies (Table 3). Dual- and multi-specificity CAR-T cells have also been in clinical trials in China.

Current trials on hematological malignancies

The most common type of diseases in CAR-T trials are B cell malignancies, including leukemia, lymphoma, and myeloma.
The CD19-targeted autologous CAR-T product, tisagenlecleucel, was recently approved by FDA for therapy of refractory/relapsed (r/r) B cell ALL. In 30 patients including children and adults who received this product, 90% of them achieved complete remission (CR) [54]. Severe cytokine-release syndrome (CRS) was reported in 27% of the patients. This product has been in clinical trials for CD19+ B cell malignancies, including CLL, ALL, and lymphoma [2124, 54, 55]. In a Chinese study (NCT 02813837), 30 patients (5 children and 25 adults) with r/r ALL were treated with autologous CD-19 CAR-T cells [56]. In this 2017 report of preliminary results of a seven-center clinical trial, CR was 86% and severe CRS was seen in 26% of the patients [56]. Successful outcome has been reported with other CAR-T cells against CD19 antigen in r/r ALL [29, 32, 5759].
The CD19-specific CAR-T cells, axicabtagene ciloleucel (axi-cel, KTE-C19), have been reported to be safe for treatment of aggressive lymphomas including r/r diffuse large cell lymphoma (DLBCL) [25]. In the phase II part of the ZUMA-1 trial, overall response rate (ORR) was 76% (47% CR and 29% PR) at the time of report in the cohort 1 of 51 patients [60]. This product is currently under evaluation by FDA.
CD33 and CD123 are targets on myeloid leukemias. Currently, there are three trials on CAR-T cells targeting CD33 and two trials targeting CD123 antigen in China (Table 3). In the USA, three CAR-T trials targeting CD123 were either terminated (NCT02623582) or suspended (UCART123, NCT02159495, and NCT03190278) at this time.
B cell maturation antigen (BCMA) is an antigen target on myeloma cells. Currently, three trials on BCMA-targeted CAR-T cells are being done in r/r myeloma in China (Table 3). In one of the trials of CAR-T cells targeting BCMA in China, 19 patients with r/r multiple myeloma were evaluable and 7 of the patients were followed for more than 6 months at the time of the report [61]. CRS was observed in 14 (74%) patients. The ORRs were close to 100% in the evaluable r/r myeloma patients. The outcome from the preliminary report was highly encouraging. Complete response was also reported in a case of r/r myeloma patient who received autologous CTL019 cells, even though 99.95% of the myeloma cells were negative for CD19 [38, 62]. It appears therefore that multiple myeloma is highly sensitive to immunotherapy.
There are also a few registered clinical trials that are testing two or more CARs either simultaneously or sequentially. In the trial NCT02846584, patients receive intravenously infused autologous anti-CD19 or anti-CD20 CAR-T cells to treat B cell malignancies. Another trial, NCT02737085, is to explore the sequential therapeutic effect of anti-CD19 and anti-CD20 CAR-T cells in the treatment of DLBCL.
The trial NCT02903810 was planned with a treatment scheme of infusion of equal numbers of anti-CD19 and anti-CD22 CAR-T cells in the treatment of refractory hematologic malignancies. Two trials (NCT03097770 and NCT03098355) target two antigens simultaneously with one CAR construct (Table 2). These trials are ongoing at this time.

Current trials on solid tumors

Multiple solid tumors are being studied in CAR-T clinical trials. At the time of this report, 20 different antigens are being targeted in solid tumor trials (Table 4). GPC3, mesothelin, epidermal growth factor receptor (EGFR), and EpCAM were the most targeted antigens (Table 4). This is consistent with reports from international trials [6368]. Liver cancer remains the most commonly studied solid tumor in China [69]. In a preliminary report of a trial of CAR-T cells against CD133+ epithelial tumors (NCT02541370), 24 patients were enrolled, including 14 patients with sorafenib-refractory hepatocellular carcinoma (HCC), 7 with pancreatic carcinomas, 2 with colorectal carcinomas, and 1 with cholangiocarcinoma [69]. The number of CAR-T cells was found to be inversely related to the CD133+ epithelial cells in peripheral blood. There was a separate report treating refractory cholangiocarcinoma with sequential infusion of two different types of CAR-T cells targeting EGFR and CD133 [70].
Two trials in China are evaluating GD2 antigen-targeted CAR-T cells in neuroblastoma (Table 4). Another two trials are evaluating CAR-T cells against EGFRvIII+ glioblastoma. There was one case report in the literature on rapidly progressing refractory glioblastoma that showed dramatic CR to IL13Rα2-targeted CAR-T cells after repeated infusion [71]. In a separate report, nine patients with refractory EGFRvIII+ glioblastoma received autologous CART-EGFRvIII cells in a pilot study [66]. Interestingly, there was no CRS observed. CAR-T cell infiltration was shown in the resected tumor specimen. This study suggested that the CAR-T cells are safe and immunologically active with tracking capability to the cancer cells in the brain.
Multiple antigens are being explored as targets in solid tumors for CAR-T cells (Table 4). Preliminary reports have been presented and published throughout the world [64, 65, 67, 72]. Outcomes from larger sample size and longer follow-up are clearly needed from these trials.

CAR-T trials for non-malignant diseases

There is currently one clinical trial of autologous CAR-T19 cells for patients with systemic lupus erythematosus (NCT03030976, Table 2). This trial is designed to infuse 1 × 106 cells/kg. More trials are expected to come for non-malignant diseases.

Discussion

This study analyzed CAR-T trials in China. Most CAR-T trials are employing autologous T cells. CD19 is the most commonly targeted antigen. Therefore, B cell leukemia and lymphoma are the most common malignancies in CAR-T trials. Solid tumors remain a significant challenge for CAR-T therapy [45, 70, 73, 74]. Challenges include selection of target antigens, management of toxicities, and modulation of tumor microenvironment [75, 76]. Loss of CD19 expression is a known mechanism for relapse from CD19-directed CAR-T therapy [77]. The first CAR-T product, tisagenlecleucel, was recently approved. KTE-C19 for large cell lymphoma is under evaluation by FDA [25, 60]. It is unclear which product among many ongoing clinical CAR-T trials in China has independent patent that may lead to final approval for clinical application in China.
It has been well documented that CAR-T cells can cross the blood-brain barrier [23, 78, 79]. CAR-T cells may become an effective therapy for refractory CNS diseases [66, 71, 7881]. In addition to trials of single-target CAR-T cells, simultaneous and sequential CAR-T cells are being studied for clinical applications [70]. Multi-target CAR-engineered T cells are also entering clinical trials (Tables 2, 3, and 4).
The currently approved tisagenlecleucel CAR-T therapy relies on transduction of autologous T cells from patients. It is important therefore to be able to reliably obtain and propagate adequate amount of T cells. This may become a major limitation for wide application of this new therapy. Therefore, newer CARs are being actively investigated [41, 8284]. Universal CAR-Ts have been generated by inactivating HLA class I molecules and used successfully in patients [82, 85, 86]. Allogeneic CAR-T cells are entering clinical trials [42, 87]. T cell receptor-engineered CAR-T cells represent another frontier in CAR-T cell development [8890]. It is foreseeable that CAR-T immunotherapy will become a major modality of cancer therapy (Table 5) [91].

Acknowledgements

This study was partly supported by Henan Cancer Hospital and The Affiliated Cancer Hospital of Zhengzhou University.

Funding

This project was partly supported by the Zhengzhou University training fellowship (BL) and by the National Natural Science Foundation of China (NSFC grant no. 81470287, YPS). BL is a recipient of the 2017 CAHON Young Investigator Award (www.​cahon.​org).

Availability of data and materials

The material supporting the conclusion of this study has been included within the article.

Ethics approval and consent to participate

This is not applicable for this study.

Consent for publication

This is not applicable for this study.

Competing interests

The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.

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