Open Access

Clinical trials of CAR-T cells in China

Journal of Hematology & Oncology201710:166

https://doi.org/10.1186/s13045-017-0535-7

Received: 10 September 2017

Accepted: 13 October 2017

Published: 23 October 2017

Abstract

Novel immunotherapeutic agents targeting tumor-site microenvironment are revolutionizing cancer therapy. Chimeric antigen receptor (CAR)-engineered T cells are widely studied for cancer immunotherapy. CD19-specific CAR-T cells, tisagenlecleucel, have been recently approved for clinical application. Ongoing clinical trials are testing CAR designs directed at novel targets involved in hematological and solid malignancies. In addition to trials of single-target CAR-T cells, simultaneous and sequential CAR-T cells are being studied for clinical applications. Multi-target CAR-engineered T cells are also entering clinical trials. T cell receptor-engineered CAR-T and universal CAR-T cells represent new frontiers in CAR-T cell development. In this study, we analyzed the characteristics of CAR constructs and registered clinical trials of CAR-T cells in China and provided a quick glimpse of the landscape of CAR-T studies in China.

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].

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

Declarations

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.

Authors’ contributions

DL designed the study. All authors drafted the manuscript. All authors read and approved final manuscript.

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.

Authors’ Affiliations

(1)
School of Basic Medical Sciences and The Affiliated Cancer Hospital of Zhengzhou University
(2)
Henan Cancer Hospital and The Affiliated Cancer Hospital of Zhengzhou University

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