CAR T‑cell therapy for gastric cancer: Potential and perspective (Review)

  • Authors:
    • Bo Long
    • Long Qin
    • Boya Zhang
    • Qiong Li
    • Long Wang
    • Xiangyan Jiang
    • Huili Ye
    • Genyuan Zhang
    • Zeyuan Yu
    • Zuoyi Jiao
  • View Affiliations

  • Published online on: February 12, 2020     https://doi.org/10.3892/ijo.2020.4982
  • Pages: 889-899
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Abstract

Gastric cancer (GC) is one of the most frequently diagnosed digestive malignancies and is the third leading cause of cancer‑associated death worldwide. Delayed diagnosis and poor prognosis indicate the urgent need for new therapeutic strategies. The success of chimeric antigen receptor (CAR) T‑cell therapy for chemotherapy‑refractory hematological malignancies has inspired the development of a similar strategy for GC treatment. Although using CAR T‑cells against GC is not without difficulty, results from preclinical studies remain encouraging. The current review summarizes relevant preclinical studies and ongoing clinical trials for the use of CAR T‑cells for GC treatment and investigates possible toxicities, as well as current clinical experiences and emerging approaches. With a deeper understanding of the tumor microenvironment, novel target epitopes and scientific‑technical progress, the potential of CAR T‑cell therapy for GC is anticipated in the near future.

1. Introduction

Immunotherapies utilize monoclonal antibodies (mAbs), immunological checkpoint blockade (ICB) agents, cytokine-induced killer cells, tumor-infiltrating lymphocytes (TILs) and T-cell receptors (TCRs). In recent years, the rapid development of immunotherapies has produced novel treatment options for many different types of cancer (1,2). The most attractive feature of tumor immunotherapy is the ability to control or eliminate tumors by restarting and maintaining the tumor-immune cycle in vivo, as well as stimulating and restoring the body's normal anti-tumor immune response (3). However, in contrast to other adoptive cell transfer therapies, chimeric antigen receptor (CAR) T-cells recognize tumor surface-associated antigens directly, independent of the major histocompatibility complex (MHC) restriction (4). The use of anti-CD19 CAR T-cells for the treatment of chemotherapy-refractory hematological malignant tumors has revealed encouraging results, including effective targeting, killing and persistence (5). Furthermore, its use has provided novel solutions for immune cell therapy, demonstrating the tremendous potential for the development and clinical application of CAR T-cell therapy (6,7). Significant improvements in the efficacy of CAR T-cell therapy for hematological malignancies have prompted its development for use in solid tumors (8).

Gastric cancer (GC) is one of the most frequently diagnosed digestive malignancies and is the third leading cause of cancer-associated death worldwide (9). According to the CONCORD-3 (10) statistical data of GC obtained from 62 countries in 2010 to 2014 revealed that 29 countries exhibited a 5-year survival rate <30%, occupying 46% of all countries studied. Furthermore, existing conventional treatments, including surgery, chemotherapy and radiotherapy, have limited efficacy in GC; thus, there is an urgent need for novel therapeutic strategies. In contrast to TCR and ICB immunotherapy, the study of CAR T-cells is still in its infancy and appears less efficacious for GC. However, producing an effective CAR T-cell treatment for GC (11,12) may be possible as the Food and Drug Administration have approved two second-generation CAR T-cell therapies, for the treatment of relapsed/refractory B-cell lymphoma: Kymriah (CD28/CD3ζ costimulatory domain) and Yescarta (4-1BB/CD3ζ costimulatory domain). Preclinical studies have demonstrated the anti-tumor efficacy and persistent activity of CAR T-cells against GC in vitro and in vivo using an animal xenotransplantation model (13-17).

The current review assessed the potential of CAR T-cell immunotherapy for patients with GC and discussed the history of its development, its current status and toxic side effects, as well as the management of these toxicities.

2. The development and characteristics of CAR T-cell therapy

Tumor immunotherapy has been prevalent for >100 years, with CAR T-cell therapy being developed in the last ~30 years. The first-generation CAR, derived from a chimeric TCR, was pioneered and constructed by Eshhar et al in 1993 (18,19). First-generation CARs are modular in nature, containing a single-chain variable fragment (ScFv) and CD3ζ domains, and they inhibit tumor cell escape by downregulating the expression of MHC on the surface of tumor cells (20). To address the poor cytokine production and T-cell expansion observed in first-generation CARs (21), Finney et al (22) constructed a second-generation CAR that incorporated a costimulatory domain. The superiority of this second-generation CAR in cytokine-secretion and in T-cell expansion and persistence has been demonstrated in several studies (23-26) (Fig. 1A). Using second-generation CAR as a foundation, a third-generation CAR was created, which contained two tandem costimulatory molecules. The third-generation CAR exhibited enhanced effector functions and persistence in vivo (27). However, to further enhance targeted anti-tumor and trafficking activities of CARs in solid tumors and to reduce off-target toxicity and immunosuppression, multiform fourth-generation CARs were constructed using novel mechanisms, for example, T-cells redirected for universal cytokine-mediated killing, armored CARs, switchable CARs, bispecific CARs and CARs incorporating a suicide gene have been created (28). In addition, scientists are working to uncover a universal CAR structure to act against all target cells with an optimal outcome.

CAR is an artificially synthesized membrane protein composed of three domains: An extracellular antigen-recognition domain, a transmembrane domain and an intracellular signaling domain (29) (Fig. 1A). The single-chain variable fragment (ScFv) is a recombinant polypeptide derived from the heavy and light chains of a monoclonal antibody, which binds directly to the tumor surface-associated antigens, independently from MHC restriction (30). The hinge region provides ScFv flexibility and is associated with the target-binding capacity of the CAR (31). The transmembrane domain, primarily consisting of CD8 or immunoglobulin G4 molecules, enhances CAR stability and provides a connection between the ectodomain and endodomain (32). In the intracellular domain, CD3ζ or Fc receptor γ provides the first signal for T-cell activation (33). Although the B7-CD28 pathway provides essential signals for T-cell activation, further studies have revealed that CD3ζ has a more optimal signaling efficacy (34,35). Additionally, the endodomain commonly contains costimulatory signal domains that promote T-cell proliferation, lymphokine secretion and effector function, including CD28 (36), inducible T-cell costimulator (34), DNAX-activating protein 10 (DAP10) (37), CD134 (OX40) (38) or CD137 (4-1BB) (39), which have also been studied successively in different generations of CARs (27). CD28 promotes the multiplication of naïve and CD4+ T-cell subsets, whereas costimulatory CD137 promotes the proliferation of memory and CD8+ T-cell subsets preferentially, improving persistence (40). CD28 has been demonstrated to promote the ability of CARs to enhance the resistance of modified T-cells against regulatory T-cells and to reduce antigen-induced cell death (41). However, CD137 enhances the metabolic adaptability and memory potential of CAR T-cells to a greater extent than CD28 (42,43). Despite the aforementioned costimulatory molecules exhibiting antigen-dependent immune-cytolysis in vitro, there is still debate over which costimulatory molecule is most optimal (44). Previous evidence has suggested that the functional activity induced by T-cell-expressed CARs depends on the interaction of endogenous signaling moieties (45).

3. A novel and promising choice of immunotherapy

Based on previous clinical applications of adoptive immunotherapies, including TILs, CAR T-cell therapy was designed for the treatment of various types of cancer. CAR T-cell therapy is a complex and rigorous multi-step adoptive cell transfer therapy as indicated in Fig. 1B (46).

Following a decade of study, the curative effect of CAR T-cells in hematological malignancies has provided valuable information. First-generation anti-CD19 CAR T-cells were demonstrated to persist for 6 months at high levels in peripheral blood and bone marrow. Kochenderfer et al (47) first reported that a chemotherapy-refractory patient with stage IV B-cell non-Hodgkin lymphoma (B-NHL) achieved partial remission lasting for 8 months after receiving anti-CD19 CAR T-cell therapy. Subsequently, a patient with refractory chronic lymphocytic leukemia achieved a 10-month complete remission (CR) (48). CD20, a second form of CAR T-cell treatment administered to patients with B-NHL also demonstrated similar results (32,49). However, a phase II trial of anti-CD20 CAR T-cell therapy achieved promising effects without inducing severe toxicities, with an overall objective response rate (ORR) of 81.8% (8/11) and six patients with B-NHL demonstrating CR (50). The curative efficacy of CAR T-cells in hematological malignancies has improved, with ORR rates increasing from 52 to 92% and CR rates ranging from 43 to 90% (51-55). Furthermore, encouraging results from the use of CAR T-cells for the treatment of B cell malignancies has resulted in the application of this therapy to solid tumors.

The first CAR T-cell therapy clinical trials were performed two decades ago in the USA for the treatment of patients with ovarian cancer and metastatic renal carcinoma (56,57). To date, a total of 692 clinical trials have been registered worldwide on ClinicalTrials.gov, which is over three times the total number of registrations recorded at the end of 2016 (Fig. 2A). Of these clinical trials, >400 are associated with cancer therapy. Currently, the majority of clinical trials are in phase I or II, where appropriate dosage, safety and efficacy is being established. Only 8% of CAR T-cell therapy clinical trials have been completed (Fig. 2B).

4. Promising preclinical results for future clinical investigation

A single high fidelity target antigen is the most critical factor for the successful clinical application of CAR T-cell therapy (58). Previous literature has indicated that an ideal specific antigen must be expressed on the extracellular surface of cancer cells and be preferentially selected for its density and differential expression in tumors rather than in normal tissues (59). If this does not occur, severe or lethal off-target toxicity, in addition to poor curative effects, may occur (59). The expression of surface antigens in GC is highly heterogeneous, providing tumor cells with the ability to escape host immune surveillance (60). Therefore, the design of CAR T-cell immunotherapy for GC poses a great challenge.

However, promising results have been obtained using preclinical models of first-generation CAR T-cells for the treatment of ovarian cancer (57), renal cell carcinoma (57,61) and neuroblastoma (62). Furthermore, the durable efficacy of CAR T-cell therapy has been high in patients with recurrent or end-stage glioblastoma, demonstrating anti-tumor activity with acceptable toxicities in subsequent GD2-targeting trials (62,63). In murine GC models and in vitro experiments, the anti-tumor activity and persistence of CAR T-cells targeting folate receptor 1 (FOLR1), 3H11 and human epidermal growth factor receptor 2 (HER2) has been validated (13-17).

Kim et al (15) constructed a second-generation CAR T-cell consisting of FOLR1-scFv, CD28 and CD3ζ signaling domains. The cytotoxicity of this CAR T-cell construct against GC cells was assessed using a luciferase assay. Furthermore, Western blot analysis and ELISA demonstrated, elevated levels of apoptosis-associated proteins and cytokines, respectively. These proteins and cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor and granzyme B are crucial for T-cell activation, proliferation and differentiation in target GC cells (15).

In a xenograft subcutaneous mouse model, significant tumor-killing abilities of CAR-T cell have been demonstrated in MKN1 cells (16). An additional HER2-specific CAR T-cell construct has exhibited specific and persistent anti-tumor efficacy, along with a strong homing ability against xenografts derived from HER2+ GC cell lines in mice (16). Similarly, specific tumor-killing abilities and high affinities were also verified in primary patient-derived GC cells through intravenous infusion, which also occurred during HER2 expression knockdown, and these positive outcomes were further investigated by constructing humanized chA21-4-1BBz CAR T-cells (13). Additionally, striking tumor inhibition was observed in an established and advanced intraperitoneal metastatic GC model (13). As a major component of the ErbB2 (CD340) family, HER2 is highly expressed on gastrointestinal epithelial cells and has been extensively investigated as a potential immunotherapy target for various solid tumors (64). The monoclonal antibody, trastuzumab, has been approved as first-line treatment following its successful clinical application against advanced GC (65). Furthermore, following the intravenous injection of HER2-directed CAR T-cells, the tumorigenicity of cancer stem cells (CSCs) derived from patients with GC was markedly inhibited in a tumor-bearing mouse model and was efficiently phagocytized and degraded in vitro via a sphere-forming assay (16). Previous studies have indicated that HER2 signaling serves an important role in maintaining CSC populations in GC (66-68). Thus, the eradication of CSCs that possess a capacity for clonal tumor initiation and contribute to carcinogenesis, tumor invasion, recurrence, metastasis and drug resistance, has been identified as a promising immunological approach for cancer treatment (69). Luo et al (17) constructed a bifunctional αHER2/CD3 RNA-engineered CAR T-cell with a more effective and specific tumor-killing capacity to reduce the possibility of tumor antigen escape and to transfer these attributes to bystander T-cells, which exhibited similar effects against HER2+ GC cells. Additionally, the persistence duration of this bispecific αHER2/CD3 CAR T-cell in vivo was 6 days, outlasting other conventional bispecific CAR T-cells (70). Third-generation 3H11-directed CAR T-cells also exhibited similar cytotoxicity and secretion in vitro and in vivo, while poor trafficking was observed by tail intravenous injection (14). The HER2-directed CAR T-cell therapeutic approach has been continually developed and validated in different types of cancer, including breast cancer (71), renal cancer (72) and osteosarcoma (73). It is worth noting that adverse toxicities may occur unnoticed due to the evaluation of therapeutic effect being implemented on diverse tumor-bearing mouse models. However, CAR T-cell therapy is still considered to have great potential in GC treatment and therefore warrants further clinical development.

5. Exploration of GC treatment in the clinic

A major priority for the development of GC CAR T-cell immunotherapy is the discovery and validation of authentic and specific antigens which minimize potential life-threatening complications. Clinically, various antigens have been targeted for CAR T-cell therapy in solid tumors. These include: Epidermal growth factor receptor, mesothelin, GPC3, GD2 and HER2 (Fig. 3A). On account of the constraints applied to the selection of optimizing antigens (74), only 38% of trials are performed on solid tumors, of which 2.96% are for GC (Fig. 3B). There are still no published clinical outcomes of CAR T-cells used for GC treatment. Therefore, the current review summarized the clinical trials registered on ClinicalTrial.gov. As presented in Table I, a total of 12 registered clinical trials, utilizing seven different antigens, are distributed in China and the USA, the majority of which are in the recruitment phase. The eligibility criteria for participants were as follows: Individuals aged between 18 to 75 years, without restrictions of sex or nationality. A good physical condition was required, which was quantified as an Eastern Cooperative Oncology Group score of ≤2 or a Karnofsky score of ≥60 (75,76). Currently, the majority of trials are conducted for orthotopic GC sites via intravenous injection, while only two ongoing trials (trail nos. NCT03563326 and NCT03682744) have investigated the risk and potential benefits of CAR T-cell intraperitoneal infusion for patients with epithelial cell adhesion molecule- and carcinoembryonic antigen-expressing GC with peritoneal metastasis. Despite the support of previous research, each clinical trial is conducted discreetly, with strictly controlled input dosages, interval times and monitoring indicators, to minimize potentially life-threatening accompanying side effects.

Table I

CAR-T cell therapy trials for gastric cancer registered in ClinicalTrials.gov.

Table I

CAR-T cell therapy trials for gastric cancer registered in ClinicalTrials.gov.

Targeted antigenStudy phaseAge (years)Estimated no. of patientsStatusStudy institutionEstimated end dateClinicalTrials number
EPCAMII≤7519RecruitingAnhui Province Hospital, Hefei, China2019 NovNCT02725125
EPCAMI18-7540RecruitingWest China Hospital, Chengdu, China2022 DecNCT03563326
MUC1I18-8020UnknownPersonGen Bio Therapeutics, Suzhou, China2018 NovNCT02617134
CEAI18-8075RecruitingSHTMMU, Chongqing, China2019 DecNCT02349724
HER2I/II18-8060RecruitingSHTMMU, Chongqing, China2019 SepNCT02713984
EPCAMI/II18-8060RecruitingICE of Chengdu Medical College, Chengdu, China2022 DecNCT03013712
MesothelinI/II4-7073RecruitingTFAHZZU, Zhengzhou, China2023 MarNCT03638206
CEAI≥1818RecruitingRutgers Cancer Institute, New Jersey, USA2019 SepNCT03682744
CEAI≥188Not recruitingRWMC, Rhode Island, USA2019 JanNCT02416466
HER2I≥1839Not openBaylor College of Medicine, Texas, USA2037 JanNCT03740256
BPX-601I /II≥18138RecruitingMoffitt Cancer Center Tampa, Florida, USA2020 DecNCT02744287
EGFRI /II18-6520RecruitingShanghai International Medical Center, Shanghai, China2018 MarNCT02862028

[i] Male and female patients were recruited into each listed study. CAR, chimeric antigen receptor; EPCAM, epithelial cell adhesion molecule; MUC1, mucin 1 cell surface associated; CEA, carcinoembryonic antigen; HER2, human epidermal growth factor receptor 2; EGFR, epidermal growth factor receptor; SHTMMU, Southwest Hospital of the Third Military Medical University; ICE, The First Affiliated Hospital of Chengdu Medical College; TFAHZZU, The First Affiliated Hospital of Zhengzhou University; RWMC, Roger Williams Medical Center Providence.

6. Severe side effects

CAR T-cell therapy has produced a durable remission in a subset of patients with relapsed or refractory hematological malignancies (5); however, its efficacy in GC is yet to be fully elucidated. Severe toxicity is a main restriction to the promotion and development of CAR T-cell therapy for patients with GC (47,51). The most common and serious toxicity is cytokine release syndrome (CRS), a non-antigen-specific toxicity that leads to respiratory distress syndrome and multiple organ dysfunction syndrome (MODS). This toxicity occurs due to the rapid and excessive activation of various cytokines, including TNF-α, interleukin (IL)-1, IL-6, IL-8, IL-12, IFN-α, IFN-β and IFN-γ (77). Lymphocyte-depleting chemotherapy regimens, including fludarabine or cyclophosphamide, enhance the activation of CAR T-cells in the human body and are associated with CRS and neurotoxicity (78). In one instance, a patient with colon cancer immediately developed rapid respiratory distress and ultimately died of MODS 5 days following treatment. The death resulted from normal cardiopulmonary tissue with slight HER2 expression being recognized and attacked by high-affinity targeting CAR T-cells (79). Additionally, a clinical trial was suspended due to manufactured anti-CD19-redirected CAR T-cells inducing CRS, resulting in two deaths (80). Clinical symptomatology of CRS, on-target off-tumor toxicity and neurotoxicity of CAR T-cells are summarized in Table II (81-83). The majority of complications are reversible and self-healing. However, fatal complications as a result of CRS and neurotoxicity emphasizes the importance of assessing the preclinical safety of CAR T-cell therapy (79,84,85). Biological informatics analyses that predict target protein distributions in human organs are incomplete and the superior penetrability of CAR T-cells in solid tissue limits the use of safety-associated conclusions drawn from studies with mAbs (86). A patient with chronic lymphoid leukemia was diagnosed with tumor lysis syndrome on day 22 following anti-CD19-redirected CAR T-cell infusion. However, the kidney and hepatic function of the patient recovered after fluid resuscitation and rasburicase treatment (trail no. NCT01029366) (32). Therefore, accumulating evidence has indicated that CAR T-cell-associated toxicities may be minimized or controlled using preventive or protective interventions (87). Furthermore, well-controlled liver toxicity may be achieved by blocking antigenic sites in tumors that are distant to the tumor (88).

Table II

Toxicities of CAR-T cell therapies.

Table II

Toxicities of CAR-T cell therapies.

ToxicityOrgan systemClinical symptomatology
Cytokine release syndromeConstitutionalFever, rigors, fatigue, arthralgias, anorexia, myalgias and malaise
HematologicAnemia, lymphopenia, thrombocytopenia, febrile neutropenia, B-cell aplasia, elevated d-dimer, hypofibrinogenemia, prolonged prothrombin time and activated partial thromboplastin time
CardiovascularTachycardia, arrhythmias, hypotension, Q-T prolongation, widened pulse pressure and variable cardiac output
PulmonaryHypoxia and tachypnea
HepaticTransaminitis and hyperbilirubinemia
RenalAcute kidney injury, hyponatremia, hypokalemia, hypophosphatemia, tumor lysis syndrome and azotemia
GastrointestinalNausea, emesis, vomiting, diarrhea and elevated creatine kinase
MusculoskeletalWeakness and elevated creatine kinase
NeurotoxicityBrainHeadache, mental status changes, confusion, delirium, aphasia, hallucinations, tremor, seizures, somnolence and weakness
LimbsFocal motor and sensory defects and altered gait
Off-target/on- target toxicitiesMulti-organHepatic, gastrointestinal, respiratory, cardiovascular, endocrine, and neurological dysfunctions, fatal pulmonary complications and B cell aplasia
Tumor lysis syndromeMulti-organFatigue, fever, rigors, diaphoresis, anorexia, nausea and diarrhea

[i] CAR, chimeric antigen receptor.

7. Toxicity management and guidelines for future clinical applications

Cancer immunotherapy aims to eradicate malignant cells by harnessing the power of the human immune system. While CAR T-cells attack targets on the surface of tumor cells to exert its therapeutic effect, they also cause inevitable harm to normal tissues in other organs of the body. Therefore, early recognition, vigilant monitoring and timely intervention are necessary to reduce CAR T-cell-associated toxicity (82,89). Thus, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0), toxicity grading systems are considered to be an important measure for standardized treatment (90). Furthermore, according to the Experimental Transplantation and Immunology Branch of the National Cancer Institute (NCI), a normal cardiovascular system and a healthy bone marrow function may reduce the incidence of potential adverse toxicities, demonstrating the necessity for adequate patient condition assessment before receiving CAR-T therapy (82). It has been reported that IL-6 and C-reactive protein can be used as highly sensitive biomarkers for the diagnosis and potential quantification of CRS severity (90,91). Previous studies have also indicated that the IL-6 receptor antagonist, tocilizumab, can attenuate or eliminate CRS toxicities without affecting the efficacy of CAR T-cell infusion (44,92). In addition, corticosteroids and other immunosuppressive drugs (including etanercept, siltuximab and anakinra) have been effectively applied to reduce CRS-associated toxicities (93). However, due to the inhibition of CAR T-cell anti-tumor efficacy and persistence, these drugs are administered second to tocilizumab (93). Neurotoxicity, which may be associated with the increased permeability of cerebrospinal fluid, often occurs concurrently with CRS due to the blood-brain barrier, resulting in the wide usage of dexamethasone and corticosteroids instead of tocilizumab (94).

Despite clinical practice experience being derived from the use of CAR T-cells or treatment against hematological malignancies, previous studies are valuable for the future management of CAR T-cell-associated toxicities in GC therapy.

8. Emerging approaches against GC treatment

Although CAR T-cell therapy is promising, several challenges must be overcome to improve its efficacy for the clinical treatment of GC. Due to the ubiquitous expression of CD19 in the B cell lineage, infections associated with B cell deficiency or hypoplasia can be prevented or alleviated by immunoglobulin intervention, providing the rationale for the use of CD19 CAR T-cells against hematological tumors (95,96). Similarly, the efficacy of CAR T-cell therapy largely depends on the selection of an ideal epitope target unique to GC that will also prevent off-target effects. A single GC-associated surface neo-antigen is optimal but time-consuming. Thus, a multi-targeted approach is advocated as a promising solution for CAR T-cell efficacy and safety in vivo (97). An additional issue to overcome is the limitation of complex tumor microenvironments (TME): GC cells generate a physical and metabolic barrier characterized by hypoxia, nutrient starvation and cytokine secretion, contributing to tumorigenesis and facilitating CAR T-cell tolerance (98). It has been indicated that combined pre-condition treatment, including chemotherapy, radiotherapy, immune checkpoint molecules and other drugs involving small molecules, may contribute to the removal of regulatory T lymphocytes. This makes the TME permissive for immunotherapy and for the improvement of antitumor effects (99,100). However, compared with traditional cell experiments, GC organoids can simulate the GC microenvironment in vitro and accurately assess the specific efficacy and toxicities of CAR T-cells for GC in vitro (101). Traditional subcutaneous tumor implant and patient-derived xenograft models have the disadvantage of not simulating human immunity and human-derived tumors, resulting in different preclinical and clinical study outcomes (102).

Further study assessing GC CAR T-cell therapy should focus on the following aspects: i) Seeking ideal CAR T-cell therapeutic targets with higher positive expression rates in GC tissues; ii) clarifying the specific role of other combined precondition treatments used in CAR T-cell therapy for GC; and iii) developing a novel GC organoid model and humanized tumor implantation model to improve the reliable evaluation of CAR T-cell efficacy and toxicity in preclinical research. Additionally, the development of a generic CAR structure may lead to an increase in the number of patients with GC benefiting from CAR T-cell therapy, causing a reduction in medical costs.

9. Conclusion and perspective

CAR T-cell immunotherapy is confronted with many challenges and difficulties; however, it is still recognized as the most potent cure for GC (103). Although GC CAR T-cell research is in its infancy, the positive results of preliminary trials provides a rationale for the further exploration of its use in clinical practice. This indicates that CAR T-cell therapeutic models are advancing and may eventually improve with continued exploration. Combined with a deeper understanding of the TME, novel target epitopes and scientific-technical progress, CAR T-cell therapy may improve its current standing in the near future. Improving the tumor-killing effect and prolonging the survival time of patients should also be readily solved with future study. Furthermore, combining CAR T-cell therapy with precondition treatment may address its current ineffectiveness. In conclusion, the available evidence strongly supports the potential of CAR T-cells in the treatment of patients with GC.

Funding

The current review was supported by the Fundamental Research Funds of the Central Universities (grant no. lzujbky-2019-cd06), the Cuiying Science and Technology Innovation Project of Lanzhou City (grant no. CY2017-ZD03) and the National Natural Science Foundation of China (grant no. 31670847).

Availability of data and materials

Not applicable.

Authors' contributions

ZJ and BL conceptualized the present review. ZY, LQ and QL drafted the manuscript. BZ and HY designed and finalized the figures. LW and GZ collected and analyzed the data. XJ and ZY designed and finalized the tables. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

Not applicable.

References

1 

Khalil DN, Budhu S, Gasmi B, Zappasodi R, Hirschhorn-Cymerman D, Plitt T, De Henau O, Zamarin D, Holmgaard RB, Murphy JT, et al: The new era of cancer immunotherapy: Manipulating T-cell activity to overcome malignancy. Adv Cancer Res. 128:1–68. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, et al: Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 17:4550–4557. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Schuster M, Nechansky A and Kircheis R: Cancer immunotherapy. Biotechnol J. 1:138–147. 2006. View Article : Google Scholar : PubMed/NCBI

4 

Fesnak AD, June CH and Levine BL: Engineered T cells: The promise and challenges of cancer immunotherapy. Nat Rev Cancer. 16:566–581. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Chow VA, Shadman M and Gopal AK: Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. Blood. 132:777–781. 2018. View Article : Google Scholar : PubMed/NCBI

6 

Grupp SA, Michael K, David B, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, et al: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 368:1509–1518. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM, et al: 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. 33:540–549. 2015. View Article : Google Scholar :

8 

Wang Z, Wu Z, Liu Y and Han W: New development in CAR-T cell therapy. J Hematol Oncol. 10:532017. View Article : Google Scholar : PubMed/NCBI

9 

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI

10 

Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Nikšić M, Bonaventure A, Valkov M, Johnson CJ, Estève J, et al: Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): Analysis of individual records for 37513025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 391:1023–1075. 2018. View Article : Google Scholar : PubMed/NCBI

11 

FDA approves second CAR T-cell therapy. Cancer Discov. 8:5–6. 2018. View Article : Google Scholar

12 

June CH, O'Connor RS, Kawalekar OU, Ghassemi S and Milone MC: CAR T cell immunotherapy for human cancer. Science. 359:1361–1365. 2018. View Article : Google Scholar : PubMed/NCBI

13 

Han Y, Liu C, Li G, Li J, Lv X, Shi H, Liu J, Liu S, Yan P, Wang S, et al: Antitumor effects and persistence of a novel HER2 CAR T cells directed to gastric cancer in preclinical models. Am J Cancer Res. 8:106–119. 2018.PubMed/NCBI

14 

Han H, Wang S, Hu Y, Li Z, Yang W, Lv Y, Wang L, Zhang L and Ji J: Monoclonal antibody 3H11 chimeric antigen receptors enhance T cell effector function and exhibit efficacy against gastric cancer. Oncol Lett. 15:6887–6894. 2018.PubMed/NCBI

15 

Kim M, Pyo S, Kang CH, Lee CO, Lee HK, Choi SU and Park CH: Folate receptor 1 (FOLR1) targeted chimeric antigen receptor (CAR) T cells for the treatment of gastric cancer. PLoS One. 13:e01983472018. View Article : Google Scholar : PubMed/NCBI

16 

Song Y, Tong C, Wang Y, Gao Y, Dai H, Guo Y, Zhao X, Wang Y, Wang Z, Han W and Chen L: Effective and persistent antitumor activity of HER2-directed CAR-T cells against gastric cancer cells in vitro and xenotransplanted tumors in vivo. Protein Cell. 9:867–878. 2018. View Article : Google Scholar :

17 

Luo F, Qian J, Yang J, Deng Y, Zheng X, Liu J and Chu Y: Bifunctional αHER2/CD3 RNA-engineered CART-like human T cells specifically eliminate HER2(+) gastric cancer. Cell Res. 26:850–853. 2016. View Article : Google Scholar : PubMed/NCBI

18 

Gross G, Waks T and Eshhar Z: Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA. 86:10024–10028. 1989. View Article : Google Scholar : PubMed/NCBI

19 

Eshhar Z, Waks T, Gross G and Schindler DG: Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA. 90:720–724. 1993. View Article : Google Scholar : PubMed/NCBI

20 

Jaspers JE and Brentjens RJ: Development of CAR T cells designed to improve antitumor efficacy and safety. Pharmacol Ther. 178:83–91. 2017. View Article : Google Scholar : PubMed/NCBI

21 

Brocker T and Karjalainen K: Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med. 181:1653–1659. 1995. View Article : Google Scholar : PubMed/NCBI

22 

Finney HM, Lawson AD, Bebbington CR and Weir AN: Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J Immunol. 161:2791–2797. 1998.PubMed/NCBI

23 

Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, Kamble RT, Bollard CM, Gee AP, Mei Z, et al: CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 121:1822–1826. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O, et al: Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 118:4817–4828. 2011. View Article : Google Scholar : PubMed/NCBI

25 

Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, et al: CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 5:177ra382013. View Article : Google Scholar : PubMed/NCBI

26 

Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A and June CH: T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 3:95ra732011. View Article : Google Scholar : PubMed/NCBI

27 

Finney HM, Akbar AN and Lawson AD: Activation of resting human primary T cells with chimeric receptors: Costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol. 172:104–113. 2004. View Article : Google Scholar

28 

Knochelmann HM, Smith AS, Dwyer CJ, Wyatt MM, Mehrotra S and Paulos CM: CAR T cells in solid tumors: Blueprints for building effective therapies. Front Immunol. 9:17402018. View Article : Google Scholar : PubMed/NCBI

29 

Ramos CA and Gianpietro D: Chimeric antigen receptor (CAR)-engineered lymphocytes for cancer therapy. Expert Opin Biol Ther. 11:855–873. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Jackson HJ, Rafiq S and Brentjens RJ: Driving CAR T-cells forward. Nat Rev Clin Oncol. 13:370–383. 2016. View Article : Google Scholar : PubMed/NCBI

31 

Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE, et al: CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: Pilot clinical trial results. Blood. 119:3940–3950. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Porter DL, Levine BL, Kalos M, Bagg A and June CH: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 365:725–733. 2011. View Article : Google Scholar : PubMed/NCBI

33 

Jensen MC and Riddell SR: Designing chimeric antigen receptors to effectively and safely target tumors. Curr Opin Immunol. 33:9–15. 2015. View Article : Google Scholar : PubMed/NCBI

34 

McAdam AJ, Greenwald RJ, Levin MA, Chernova T, Malenkovich N, Ling V, Freeman GJ and Sharpe AH: ICOS is critical for CD40-mediated antibody class switching. Nature. 409:102–105. 2001. View Article : Google Scholar : PubMed/NCBI

35 

Lipowska-Bhalla G, Gilham DE, Hawkins RE and Rothwell DG: Targeted immunotherapy of cancer with CAR T cells: Achievements and challenges. Cancer Immunol Immunother. 61:953–962. 2012. View Article : Google Scholar : PubMed/NCBI

36 

Haynes NM, Trapani JA, Teng MW, Jackson JT, Cerruti L, Jane SM, Kershaw MH, Smyth MJ and Darcy PK: Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors. Blood. 100:3155–3163. 2002. View Article : Google Scholar : PubMed/NCBI

37 

Wu J, Song Y, Bakker AB, Bauer S, Spies T, Lanier LL and Phillips JH: An activating immunoreceptor complex formed by NKG2D and DAP10. Science. 285:730–732. 1999. View Article : Google Scholar : PubMed/NCBI

38 

Pulè MA, Straathof KC, Dotti G, Heslop HE, Rooney CM and Brenner MK: A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol Ther. 12:933–941. 2005. View Article : Google Scholar : PubMed/NCBI

39 

Milone MC, Fish JD and Carmine C: Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 17:1453–1464. 2009. View Article : Google Scholar : PubMed/NCBI

40 

Hua Z, Snyder KM, Suhoski MM, Maus MV, Kapoor V, June CH and Mackall CL: 4-1BB is superior to CD28 costimulation for generating CD8+ cytotoxic lymphocytes for adoptive immunotherapy. J Immunol. 179:4910–4918. 2007. View Article : Google Scholar

41 

Friedmann-Morvinski D, Bendavid A, Waks T, Schindler D and Eshhar Z: Redirected primary T cells harboring a chimeric receptor require costimulation for their antigen-specific activation. Blood. 105:30872005. View Article : Google Scholar : PubMed/NCBI

42 

Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, et al: Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 7:303ra1392015. View Article : Google Scholar : PubMed/NCBI

43 

Kawalekar OU, O'Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr, Patel PR, Guedan S, Scholler J, Keith B, et al: Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 44:380–390. 2016. View Article : Google Scholar : PubMed/NCBI

44 

Maude SL, Noelle F, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 371:1507–1517. 2014. View Article : Google Scholar : PubMed/NCBI

45 

Cheadle EJ, Rothwell DG, Bridgeman JS, Sheard VE, Hawkins RE and Gilham DE: Ligation of the CD2 co-stimulatory receptor enhances IL-2 production from first-generation chimeric antigen receptor T cells. Gene Ther. 19:1114–1120. 2012. View Article : Google Scholar

46 

Han S, Latchoumanin O, Wu G, Zhou G, Hebbard L, George J and Qiao L: Recent clinical trials utilizing chimeric antigen receptor T cells therapies against solid tumors. Cancer Lett. 390:188–200. 2017. View Article : Google Scholar : PubMed/NCBI

47 

Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DA, Lanier BJ, et al: Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 116:4099–4102. 2010. View Article : Google Scholar : PubMed/NCBI

48 

Wang Y, Zhang WY, Han QW, Liu Y, Dai HR, Guo YL, Bo J, Fan H, Zhang Y, Zhang YJ, et al: Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. Clin Immunol. 155:160–175. 2014. View Article : Google Scholar : PubMed/NCBI

49 

Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ, et al: Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 112:2261–2271. 2008. View Article : Google Scholar : PubMed/NCBI

50 

Zhang WY, Wang Y, Guo YL, Dai HR, Yang QM, Zhang YJ, Zhang Y, Chen MX, Wang CM, Feng KC, et al: Treatment of CD20-directed Chimeric Antigen Receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: An early phase IIa trial report. Signal Transduct Target Ther. 1:160022016. View Article : Google Scholar : PubMed/NCBI

51 

Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, et al: 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. 119:2709–2720. 2012. View Article : Google Scholar :

52 

Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, Ghobadi A, Budde LE, Bot A, Rossi JM, et al: Phase 1 results of ZUMA-1: A multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 25:285–295. 2017. View Article : Google Scholar : PubMed/NCBI

53 

Kochenderfer JN, Somerville RPT, Lu T, Shi V, Bot A, Rossi J, Xue A, Goff SL, Yang JC, Sherry RM, et al: Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J Clin Oncol. 35:1803–1813. 2017. View Article : Google Scholar : PubMed/NCBI

54 

Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, et al: Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 377:2531–2544. 2017. View Article : Google Scholar : PubMed/NCBI

55 

Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D, et al: Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 377:2545–2554. 2017. View Article : Google Scholar : PubMed/NCBI

56 

Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L, et al: A phase I study on adoptive immuno-therapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 12:6106–6115. 2006. View Article : Google Scholar : PubMed/NCBI

57 

Lamers CH, Sleijfer S, Vulto AG, Kruit WH, Kliffen M, Debets R, Gratama JW, Stoter G and Oosterwijk E: Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: First clinical experience. J Clin Oncol. 24:e20–e22. 2006. View Article : Google Scholar : PubMed/NCBI

58 

Guo Y, Wang Y and Han W: Chimeric antigen receptor-modified T cells for solid tumors: Challenges and prospects. J Immunol Res. 2016:38508392016. View Article : Google Scholar : PubMed/NCBI

59 

Sadelain M, Brentjens R and Rivière I: The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol. 21:215–223. 2009. View Article : Google Scholar : PubMed/NCBI

60 

Fousek K and Ahmed N: The evolution of T-cell therapies for solid malignancies. Clin Cancer Res. 21:3384–3392. 2015. View Article : Google Scholar : PubMed/NCBI

61 

Lamers CH, Langeveld SC, Grootvan Ruijven CM, Debets R, Sleijfer S and Gratama JW: Gene-modified T cells for adoptive immunotherapy of renal cell cancer maintain transgene-specific immune functions in vivo. Cancer Immunol Immunother. 56:1875–1883. 2007. View Article : Google Scholar : PubMed/NCBI

62 

Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z, et al: Virus-specific T cells engineered to coexpress tumor-specific receptors: Persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 14:1264–1270. 2008. View Article : Google Scholar : PubMed/NCBI

63 

Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang WC, Naranjo A, Starr R, Wagner J, Wright C, et al: Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin Cancer Res. 21:4062–4072. 2015. View Article : Google Scholar : PubMed/NCBI

64 

Whilding LM and Maher J: ErbB-targeted CAR T-cell immunotherapy of cancer. Immunotherapy. 7:229–241. 2015. View Article : Google Scholar : PubMed/NCBI

65 

Fanotto V, Ongaro E, Rihawi K, Avallone A, Silvestris N, Fornaro L, Vasile E, Antonuzzo L, Leone F, Rosati G, et al: HER-2 inhibition in gastric and colorectal cancers: Tangible achievements, novel acquisitions and future perspectives. Oncotarget. 7:69060–69074. 2016. View Article : Google Scholar : PubMed/NCBI

66 

Jiang J, Zhang Y, Chuai S, Wang Z, Zheng D, Xu F, Zhang Y, Li C, Liang Y and Chen Z: Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype. Oncogene. 31:671–682. 2012. View Article : Google Scholar

67 

Lo PK and Chen H: Cancer stem cells and cells of origin in MMTV-Her2/neu-induced mammary tumorigenesis. Oncogene. 32:1338–1340. 2013. View Article : Google Scholar

68 

Shah D, Wyatt D, Baker AT, Simms P, Peiffer DS, Fernandez M, Rakha E, Green A, Filipovic A, Miele L and Osipo C: Inhibition of HER2 increases JAGGED1-dependent breast cancer stem cells: Role for membrane JAGGED1. Clin Cancer Res. 24:4566–4578. 2018. View Article : Google Scholar : PubMed/NCBI

69 

Plaks V, Kong N and Werb Z: The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells? Cell Stem Cell. 16:225–238. 2015. View Article : Google Scholar : PubMed/NCBI

70 

Nagorsen D, Kufer P, Baeuerle PA and Bargou R: Blinatumomab: A historical perspective. Pharmacol Ther. 136:334–342. 2012. View Article : Google Scholar : PubMed/NCBI

71 

Sun M, Shi H, Liu C, Liu J, Liu X and Sun Y: Construction and evaluation of a novel humanized HER2-specific chimeric receptor. Breast Cancer Res. 16:1–10. 2014. View Article : Google Scholar

72 

Schönfeld K, Sahm C, Zhang C, Naundorf S, Brendel C, Odendahl M, Nowakowska P, Bönig H, Köhl U, Kloess S, et al: Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Mol Ther. 23:330–338. 2015. View Article : Google Scholar :

73 

Rainusso N, Brawley VS, Ghazi A, Hicks MJ, Gottschalk S, Rosen JM and Ahmed N: Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma. Adv Exp Med Biol. 19:212–217. 2012.

74 

Hartmann J, Schüßler-Lenz M, Bondanza A and Buchholz CJ: Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. 9:1183–1198. 2017. View Article : Google Scholar : PubMed/NCBI

75 

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET and Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 5:649–655. 1982. View Article : Google Scholar : PubMed/NCBI

76 

Schag CC, Heinrich RL and Ganz PA: Karnofsky performance status revisited: Reliability, validity, and guidelines. J Clin Oncol. 2:187–193. 1984. View Article : Google Scholar : PubMed/NCBI

77 

Frey NV and Porter DL: Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2016:567–572. 2016. View Article : Google Scholar : PubMed/NCBI

78 

Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, Brudno JN, Stetler-Stevenson M, Feldman SA, Hansen BG, et al: T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 128:1688–1700. 2016. View Article : Google Scholar : PubMed/NCBI

79 

Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM and 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. 18:843–851. 2010. View Article : Google Scholar : PubMed/NCBI

80 

Kim MG, Kim D, Suh SK, Park Z, Choi MJ and Oh YK: Current status and regulatory perspective of chimeric antigen receptor-modified T cell therapeutics. Arch Pharm Res. 39:437–452. 2016. View Article : Google Scholar : PubMed/NCBI

81 

Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, Pequignot E, Gonzalez VE, Chen F, Finklestein J, et al: Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 6:664–679. 2016. View Article : Google Scholar : PubMed/NCBI

82 

Brudno JN and Kochenderfer JN: Toxicities of chimeric antigen receptor T cells: Recognition and management. Blood. 127:3321–3330. 2016. View Article : Google Scholar : PubMed/NCBI

83 

Brudno JN and Kochenderfer JN: Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management. Blood Rev. 34:45–55. 2019. View Article : Google Scholar :

84 

Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, et al: Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 378:449–459. 2018. View Article : Google Scholar : PubMed/NCBI

85 

Thistlethwaite FC, Gilham DE, Guest RD, Rothwell DG, Pillai M, Burt DJ, Byatte AJ, Kirillova N, Valle JW, Sharma SK, et al: The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity. Cancer Immunol Immunothe. 66:1425–1436. 2017. View Article : Google Scholar

86 

Gross G and Eshhar Z: Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment: Counteracting off-tumor toxicities for safe CAR T cell therapy. Annu Rev Pharmacol Toxicol. 56:59–83. 2016. View Article : Google Scholar : PubMed/NCBI

87 

Kenderian SS, Ruella M, Shestova O, Klichinsky M, Aikawa V, Morrissette JJ, Scholler J, Song D, Porter DL, Carroll M, et al: CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia. 29:1637–1647. 2015. View Article : Google Scholar : PubMed/NCBI

88 

Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, Vulto A, den Bakker M, Oosterwijk E, Debets R and Gratama JW: Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: Clinical evaluation and management of on-target toxicity. Mol Ther. 21:904–912. 2013. View Article : Google Scholar : PubMed/NCBI

89 

Mei H, Jiang H, Wu Y, Guo T, Xia L, Jin R and Hu Y: Neurological toxicities and coagulation disorders in the cytokine release syndrome during CAR-T therapy. Br J Haematol. 181:689–692. 2018. View Article : Google Scholar

90 

Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, Chung SS, Stefanski J, Borquez-Ojeda O, Olszewska M, et al: Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 6:224ra252014. View Article : Google Scholar : PubMed/NCBI

91 

Schultz DR and Arnold PI: Properties of four acute phase proteins: C-reactive protein, serum amyloid A protein, alpha 1-acid glycoprotein, and fibrinogen. Semin Arthritis Rheum. 20:129–147. 1990. View Article : Google Scholar : PubMed/NCBI

92 

Lee DW, Kochenderfer JN, Stetlerstevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, et al: T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. Lancet. 385:517–528. 2015. View Article : Google Scholar

93 

Lee DW, Rebecca G, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA and Mackall CL: Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 124:188–195. 2014. View Article : Google Scholar : PubMed/NCBI

94 

Pardridge WM: CNS drug design based on principles of blood-brain barrier transport. J Neurochem. 70:1781–1792. 1998. View Article : Google Scholar : PubMed/NCBI

95 

Brudno JN, Maric I, Hartman SD, Rose JJ, Wang M, Lam N, Stetler-Stevenson M, Salem D, Yuan C, Pavletic S, et al: T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J Clin Oncol. 36:2267–2280. 2018. View Article : Google Scholar : PubMed/NCBI

96 

Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, et al: Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 378:439–448. 2018. View Article : Google Scholar : PubMed/NCBI

97 

Beatty GL and O'Hara M: Chimeric antigen receptor-modified T cells for the treatment of solid tumors: Defining the challenges and next steps. Pharmacol Ther. 166:30–39. 2016. View Article : Google Scholar : PubMed/NCBI

98 

Sharma P and Allison JP: The future of immune checkpoint therapy. Science. 348:56–61. 2015. View Article : Google Scholar : PubMed/NCBI

99 

Kang TH, Mao CP, Lee SY, Chen A, Lee JH, Kim TW, Alvarez RD, Roden RB, Pardoll D, Hung CF and Wu TC: Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity. Cancer Res. 73:2493–2504. 2013. View Article : Google Scholar : PubMed/NCBI

100 

Shahabi V, Postow MA, Tuck D and Wolchok JD: Immune-priming of the tumor microenvironment by radiotherapy: Rationale for combination with immunotherapy to improve anticancer efficacy. Am J Clin Oncol. 38:90–97. 2015. View Article : Google Scholar : PubMed/NCBI

101 

Nanki K, Toshimitsu K, Takano A, Fujii M, Shimokawa M, Ohta Y, Matano M, Seino T, Nishikori S, Ishikawa K, et al: Divergent routes toward Wnt and R-spondin niche independency during human gastric carcinogenesis. Cell. 174:856–869.e17. 2018. View Article : Google Scholar : PubMed/NCBI

102 

Hidalgo M, Amant F, Biankin AV, Budinská E, Byrne AT, Caldas C, Clarke RB, de Jong S, Jonkers J, Mælandsmo GM, et al: Patient-derived xenograft models: An emerging platform for translational cancer research. Cancer Discov. 4:998–1013. 2014. View Article : Google Scholar : PubMed/NCBI

103 

Lv J, Zhao R, Wu D, Zheng D, Wu Z, Shi J, Wei X, Wu Q, Long Y, Lin S, et al: Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer. J Hematol Oncol. 12:182019. View Article : Google Scholar : PubMed/NCBI

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Spandidos Publications style
Long B, Qin L, Zhang B, Li Q, Wang L, Jiang X, Ye H, Zhang G, Yu Z, Jiao Z, Jiao Z, et al: CAR T‑cell therapy for gastric cancer: Potential and perspective (Review). Int J Oncol 56: 889-899, 2020
APA
Long, B., Qin, L., Zhang, B., Li, Q., Wang, L., Jiang, X. ... Jiao, Z. (2020). CAR T‑cell therapy for gastric cancer: Potential and perspective (Review). International Journal of Oncology, 56, 889-899. https://doi.org/10.3892/ijo.2020.4982
MLA
Long, B., Qin, L., Zhang, B., Li, Q., Wang, L., Jiang, X., Ye, H., Zhang, G., Yu, Z., Jiao, Z."CAR T‑cell therapy for gastric cancer: Potential and perspective (Review)". International Journal of Oncology 56.4 (2020): 889-899.
Chicago
Long, B., Qin, L., Zhang, B., Li, Q., Wang, L., Jiang, X., Ye, H., Zhang, G., Yu, Z., Jiao, Z."CAR T‑cell therapy for gastric cancer: Potential and perspective (Review)". International Journal of Oncology 56, no. 4 (2020): 889-899. https://doi.org/10.3892/ijo.2020.4982