CAR-T Cell Therapy: Current Limitations and Potential Strategies

Overview

Journal Blood Cancer J

Date 2021 Apr 7

PMID 33824268

Citations 873

Authors

Robert C Sterner

Rosalie M Sterner

Affiliations

Soon will be listed here.

Abstract

Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.

Citing Articles

Targeting HER2-Positive Solid Tumors with CAR NK Cells: CD44 Expression Is a Critical Modulator of HER2-Specific CAR NK Cell Efficacy.

Gergely B, Vereb M, Rebenku I, Vereb G, Szoor A Cancers (Basel). 2025; 17(5).

PMID: 40075578 PMC: 11898473. DOI: 10.3390/cancers17050731.

Engineered circular RNA-based DLL3-targeted CAR-T therapy for small cell lung cancer.

Cai J, Liu Z, Chen S, Zhang J, Li H, Wang X Exp Hematol Oncol. 2025; 14(1):35.

PMID: 40075480 PMC: 11905684. DOI: 10.1186/s40164-025-00625-8.

Strategies to Overcome Antigen Heterogeneity in CAR-T Cell Therapy.

Zhang B, Wu J, Jiang H, Zhou M Cells. 2025; 14(5).

PMID: 40072049 PMC: 11899321. DOI: 10.3390/cells14050320.

Nanobody-enhanced chimeric antigen receptor T-cell therapy: overcoming barriers in solid tumors with VHH and VNAR-based constructs.

Guo S, Xi X Biomark Res. 2025; 13(1):41.

PMID: 40069884 PMC: 11899093. DOI: 10.1186/s40364-025-00755-5.

Adipose stromal cells increase insulin sensitivity and decrease liver gluconeogenesis in a mouse model of type 1 diabetes mellitus.

Lai H, Lee Y, Chen P, Tang C, Chen L Stem Cell Res Ther. 2025; 16(1):133.

PMID: 40069851 PMC: 11899698. DOI: 10.1186/s13287-025-04225-5.

References

June C, OConnor R, Kawalekar O, Ghassemi S, Milone M . CAR T cell immunotherapy for human cancer. Science. 2018; 359(6382):1361-1365. DOI: 10.1126/science.aar6711. View

Sadelain M, Brentjens R, Riviere I . The basic principles of chimeric antigen receptor design. Cancer Discov. 2013; 3(4):388-98. PMC: 3667586. DOI: 10.1158/2159-8290.CD-12-0548. View

Neelapu S, Locke F, Bartlett N, Lekakis L, Miklos D, Jacobson C . Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017; 377(26):2531-2544. PMC: 5882485. DOI: 10.1056/NEJMoa1707447. View

Maude S, Laetsch T, Buechner J, Rives S, Boyer M, Bittencourt H . Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018; 378(5):439-448. PMC: 5996391. DOI: 10.1056/NEJMoa1709866. View

Schuster S, Svoboda J, Chong E, Nasta S, Mato A, Anak O . Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017; 377(26):2545-2554. PMC: 5788566. DOI: 10.1056/NEJMoa1708566. View

Sterner R, Hedin K, Hayden R, Nowakowski G, Wyles S, Greenberg-Worisek A . A Graduate-Level Interdisciplinary Curriculum in CAR-T Cell Therapy. Mayo Clin Proc Innov Qual Outcomes. 2020; 4(2):203-210. PMC: 7140137. DOI: 10.1016/j.mayocpiqo.2019.12.006. View

Chailyan A, Marcatili P, Tramontano A . The association of heavy and light chain variable domains in antibodies: implications for antigen specificity. FEBS J. 2011; 278(16):2858-66. PMC: 3562479. DOI: 10.1111/j.1742-4658.2011.08207.x. View

Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot E . Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice. Cancer Res. 2015; 75(17):3596-607. PMC: 4560113. DOI: 10.1158/0008-5472.CAN-15-0159. View

Caruso H, Hurton L, Najjar A, Rushworth D, Ang S, Olivares S . Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity. Cancer Res. 2015; 75(17):3505-18. PMC: 4624228. DOI: 10.1158/0008-5472.CAN-15-0139. View

10.

Hudecek M, Sommermeyer D, Kosasih P, Silva-Benedict A, Liu L, Rader C . The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol Res. 2014; 3(2):125-35. PMC: 4692801. DOI: 10.1158/2326-6066.CIR-14-0127. View

11.

Jensen M, Riddell S . Designing chimeric antigen receptors to effectively and safely target tumors. Curr Opin Immunol. 2015; 33:9-15. PMC: 4397136. DOI: 10.1016/j.coi.2015.01.002. View

12.

Srivastava S, Riddell S . Engineering CAR-T cells: Design concepts. Trends Immunol. 2015; 36(8):494-502. PMC: 4746114. DOI: 10.1016/j.it.2015.06.004. View

13.

Guest R, Hawkins R, Kirillova N, Cheadle E, Arnold J, ONeill A . The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens. J Immunother. 2005; 28(3):203-11. DOI: 10.1097/01.cji.0000161397.96582.59. View

14.

James S, Greenberg P, Jensen M, Lin Y, Wang J, Till B . Antigen sensitivity of CD22-specific chimeric TCR is modulated by target epitope distance from the cell membrane. J Immunol. 2008; 180(10):7028-38. PMC: 2585549. DOI: 10.4049/jimmunol.180.10.7028. View

15.

Wilkie S, Picco G, Foster J, Davies D, Julien S, Cooper L . Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol. 2008; 180(7):4901-9. DOI: 10.4049/jimmunol.180.7.4901. View

16.

Hombach A, Hombach A, Abken H . Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc 'spacer' domain in the extracellular moiety of chimeric antigen receptors avoids 'off-target' activation and unintended initiation of an innate immune response. Gene Ther. 2010; 17(10):1206-13. DOI: 10.1038/gt.2010.91. View

17.

Almasbak H, Walseng E, Kristian A, Myhre M, Suso E, Munthe L . Inclusion of an IgG1-Fc spacer abrogates efficacy of CD19 CAR T cells in a xenograft mouse model. Gene Ther. 2015; 22(5):391-403. DOI: 10.1038/gt.2015.4. View

18.

Bridgeman J, Hawkins R, Bagley S, Blaylock M, Holland M, Gilham D . The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J Immunol. 2010; 184(12):6938-49. DOI: 10.4049/jimmunol.0901766. View

19.

Zhang T, Wu M, Sentman C . An NKp30-based chimeric antigen receptor promotes T cell effector functions and antitumor efficacy in vivo. J Immunol. 2012; 189(5):2290-9. PMC: 3633481. DOI: 10.4049/jimmunol.1103495. View

20.

Dotti G, Gottschalk S, Savoldo B, Brenner M . Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol Rev. 2013; 257(1):107-26. PMC: 3874724. DOI: 10.1111/imr.12131. View