IMR Press / FBL / Volume 26 / Issue 12 / DOI: 10.52586/5033
Open Access Editorial
Current status and perspectives on CAR-T therapy
Show Less
1 Biopharmaceutical Chemistry Major, School of Applied Chemistry, Kookmin University, 02707 Seoul, Republic of Korea
*Correspondence: (Sukmook Lee)
Academic Editor: Graham Pawelec
Front. Biosci. (Landmark Ed) 2021, 26(12), 1393–1395;
Submitted: 25 November 2021 | Revised: 26 November 2021 | Accepted: 26 November 2021 | Published: 30 December 2021
Copyright: © 2021 The Author(s). Published by BRI.
This is an open access article under the CC BY 4.0 license (

Adoptive cell therapy is a treatment modality that leverages the power of the immune system to combat cancer. Cell-based therapies are constantly evolving, and rapidly providing new therapeutic approaches for cancer patients. Since the U.S. Food and Drug Administration approved Tisageniecleucel (CTL019, Kimriah) in 2018, chimeric antigen receptor (CAR) T cell therapy has ushered in a new era of personalized cancer treatment, becoming a powerful therapeutic strategy for effective cancer therapy [1].

CAR-T cells are engineered T lymphocytes with hybrid receptors comprising a tumor antigen-binding moiety, typically a single-chain variable fragment (scFv), a hinge region, a transmembrane domain, and various combinations of intracellular signaling domains. Several generations of CAR have been developed in an effort to enhance the immune response against programmed targets. For example, first-generation CAR includes the endodomain of the cluster of differentiation 3ζ (CD3ζ) but exhibited limited clinical efficacy. Second- and third-generation CARs have one or more costimulatory endodomains, such as CD28 and/or 4-1BB, to enhance T cell activation. More recently, fourth-generation CARs are further modified to express cytokines or immunomodulatory molecules (Fig. 1A) [2].

Fig. 1.

Schematic representation of CAR structures as well as known and potential therapeutic targets for CAR-T cell therapy in cancers. (A) CARs consist of a monoclonal antibody-derived scFv, a hinge region, a transmembrane domain, and intracellular signaling domains containing one or more endodomains of costimulatory molecules and/or a TCR. The four generations of CAR are shown. (B) Known, and potential, therapeutic targets in hematological and solid cancers for CAR-T cell therapy are provided. These include B-cell maturation antigen (BCMA), carcinoembryonic antigen (CEA), epidermal growth factor receptor variant III (EGFRvIII), the disiaoganglioside GD2, glypican-3 (GPC-3), human epidermal growth factor receptor 2 (HER2), and interleukin 13 receptor subunit alpha 2 (IL13RA2).

Various therapeutic targets in hematological tumors have been validated for CAR-T cell therapy through extensive preclinical and, subsequent, clinical trials. For the treatment of B-cell malignancies, currently approved CAR-T products include Tisageniecleucel and axicabtagene ciloleucel (KTE-C19, Yescarta). Other CAR-T products presently under development include lisocabtagene maraleucel (JCAR017) and UCART19, also specifically target the B-cell antigen CD19 [3]. Furthermore, CD20 and CD22 are other potential therapeutic targets for CAR-T development to treat B-cell malignancies [4, 5]. More recently, several potential therapeutic targets for treating hematological tumors other than B-cell malignancies have been identified. For example, B-cell maturation antigen (BCMA) for multiple myeloma, CD30 for Hodgkin’s lymphoma, and CD123 for acute myeloid leukemia are promising targets for CAR-T cell development (Fig. 1B) [6, 7].

One of the persistent challenges in immuno-oncology is targeting solid tumors. While the groundbreaking clinical success of CAR-T cell therapy in treating hematological tumors is clear, using this approach to treat solid tumors has presented numerous challenges. While preclinical and clinical studies in solid tumors have revealed many potential therapeutic targets, including carcinoembryonic antigen (CEA), human epidermal growth factor receptor 2 (HER2), mesothelin, disiaoganglioside GD2 (GD2), glypican-3 (GPC-3), CD133, epidermal growth factor receptor variant III (EGFRvIII), and interleukin 13 receptor subunit alpha 2 (IL13RA2) [8, 9, 10, 11, 12, 13, 14], CAR-T therapy in solid tumors has yet to prove efficacious and improve clinical outcomes for patients with solid tumors (Fig. 1B) [15].

Another challenge to the use of CAR-T cell therapy are life-threatening toxicities, such as cytokine release syndrome and neurotoxicity. Despite limiting CAR-T cell therapy to patients who have failed other therapeutic options, efforts to improve CAR-T cell safety profiles are currently being conducted with therapeutic antibodies specifically targeting interleukin-6 or interleukin-6 receptors to promptly mitigate such side effects. Another major limitation in the CAR-T field is cost and clinical effectiveness. In this regard, recent studies have focused on the development of off-the-shelf CAR-T cells using an allogeneic engraftment approach. Simultaneously, T cell receptor (TCR) modulation strategies, such as gene editing or knockout, are currently being investigated to reduce TCR-mediated graft-versus-host disease, a form of allogeneic transplantation rejection [2].

At present, CAR-T technology is one of the fastest-growing markets in the field of immuno-oncology. Although current technologies are not yet optimized to address unmet needs in both clinical and commercial development of CAR-T cell therapy, this cell-based therapy remains a promising therapeutic approach and offers hope for terminally-ill cancer patients. Additionally, as CAR-T strategies and potential solutions continue to evolve, new avenues for more effective and safer cell-baseed therapies are likely to be identified.

1. Author contributions

JWK and SL collected and analyzed the information, discussed and commented on the manuscript, and wrote the paper. SL supervised the project. All authors have read and agree with the published version of the manuscript.

2. Ethics approval and consent to participate

Not applicable.

3. Acknowledgment

The authors acknowledge the contribution of the investigators whose experimental work has been cited in this article. Images were created using

4. Funding

This research was supported by a grant from the Bio & Medical Technology Development Program of the National Research Foundation funded by the Korean government (2019M3E5D5065844, 2020M3A9I2107093).

5. Conflict of interest

The authors declare no conflicts of interest. The funders have no role in the design of the study, nor in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. SL is serving as one of the Editorial Board members and Guest editors of this journal. We declare that BR had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to GP.


BCMA, B-cell maturation antigen; CAR, Chimeric antigen receptor; CAR-T, cells Chimeric antigen receptor T cells; CD, Cluster of differentiation; CEA, Carcinoembryonic antigen; EGFRvIII, Epidermal growth factor receptor variant III; GD2, Disiaoganglioside GD2; GPC-3, Glypican-3; HER2, Human epidermal growth factor receptor 2; IL13RA2, Interleukin 13 receptor subunit alpha 2; ScFv, Single-chain variable fragment; TCR, T cell receptor.

June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018; 359: 1361–1365.
Coscia M. Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives. Frontiers in Bioscience-Landmark. 2019; 24: 1284–1315.
Mueller KT, Waldron E, Grupp SA, Levine JE, Laetsch TW, Pulsipher MA, et al. Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. Clinical Cancer Research. 2018; 24: 6175–6184.
Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008; 112: 2261–2271.
Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, et al. CD22-targeted CAR T cells induce remission in B-all that is naive or resistant to CD19-targeted CAR immunotherapy. Nature Medicine. 2018; 24: 20–28.
Cohen AD, Garfall AL, Stadtmauer EA, et al. Safety and Efficacy of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma (MM). Blood. 2017; 130:505.
Ramos CA, Ballard B, Zhang H, Dakhova O, Gee AP, Mei Z, et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. The Journal of Clinical Investigation. 2017; 127: 3462–3471.
Thistlethwaite FC, Gilham DE, Guest RD, Rothwell DG, Pillai M, Burt DJ, 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 Immunology, Immunotherapy. 2017; 66: 1425–1436.
Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, et al. Human Epidermal Growth Factor Receptor 2 (her2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of her2-Positive Sarcoma. Journal of Clinical Oncology. 2015; 33: 1688–1696.
Mount CW, Majzner RG, Sundaresh S, Arnold EP, Kadapakkam M, Haile S, et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nature Medicine. 2018; 24: 572–579.
Zhai B, Shi D, Gao H, Qi X, Jiang H, Zhang Y, et al. A phase i study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3+ hepatocellular carcinoma (r/r GPC3+ HCC). Journal of Clinical Oncology. 2017; 35: 3049.
Wang Y, Chen M, Wu Z, Tong C, Dai H, Guo Y, et al. CD133-directed CAR T cells for advanced metastasis malignancies: a phase i trial. Oncoimmunology. 2018; 7: e1440169.
O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Science Translational Medicine. 2017; 9
Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang W, et al. Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma. Clinical Cancer Research. 2015; 21: 4062–4072.
Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal. 2021; 11: 69.
Back to top