CAR-T cell therapy: current limitations and potential strategies
Open accessAbstract
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.
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T cell-engaging bispecific antibodies and TCR/CAR-T engineered T cells, contingent on the target, could result in significant off-target tissue destruction, leading to associated morbidity and mortality.
“Despite their general tolerability, immune checkpoint inhibitors (ICIs) may induce cytokine storms in patients, and T cell-engaging bispecific antibodies and TCR/CAR-T engineered T cells, contingent on the target, could result in significant off-target tissue destruction, leading to associated morbidity and mortality (Sterner and Sterner, 2021; Johnson et al., 2022).”
From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Sterner and Sterner, 2021
The “On-target off-tumor effects” section (page unavailable) explains that CAR-T cells may target antigens also present on normal tissue, causing toxicity; “CAR-T cell-associated toxicities” reports severe events and some fatalities. The copy does not establish the same tissue-destruction risk for T cell-engaging bispecific antibodies or TCR-engineered T cells, nor does it specifically link the reported fatalities to off-tumor tissue damage. (LLM, conf=0.85)
Experimental — accuracy not yet measuredVarious immunotherapeutic strategies have emerged, including adoptive cell transfer, primarily utilizing genetically modified T cells expressing chimeric antigen receptors (CAR T-cells), and adjuvant therapies such as dendritic cell, mRNA, and peptide-based vaccinations, which have the potential to convert 'cold' tumors into immunogenic 'hot' tumors by generating potent cytotoxic T lymphocyte (CTL
“To address this, various immunotherapeutic strategies have emerged, including adoptive cell transfer, primarily utilizing genetically modified T cells expressing chimeric antigen receptors (CAR T-cells) to recognize and eliminate cancer cells directly (Sterner and Sterner, 2021). Adjuvant therapies, such as dendritic cell, mRNA, and peptide-based vaccinations, aim to boost the patient’s anticancer”
From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Sterner and Sterner, 2021
Immune checkpoint inhibitors may induce cytokine storms in patients.
“Despite their general tolerability, immune checkpoint inhibitors (ICIs) may induce cytokine storms in patients, and T cell-engaging bispecific antibodies and TCR/CAR-T engineered T cells, contingent on the target, could result in significant off-target tissue destruction, leading to associated morbidity and mortality (Sterner and Sterner, 2021; Johnson et al., 2022).”
From Microphysiological systems as models for immunologically ‘cold’ tumors (2024) · cites this paper as Sterner and Sterner, 2021
The CAR-T cell-associated toxicities section attributes cytokine-release syndrome to CAR-T cells, not to immune checkpoint inhibitors. The Immunosuppressive microenvironment section discusses checkpoint blockade in combination with CAR-T therapy but does not address whether checkpoint inhibitors induce cytokine storms; searches for checkpoint blockade and cytokine-release toxicity found no such passage. Page numbers were not available in our copy. (LLM, conf=0.76)
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- Authors
- Sterner, R. C., & Sterner, R. M.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Sterner, Rosalie M.
- Venue
- Blood Cancer Journal
- Published
- 2021-04-06
- Volume
- 11
- Issue
- 4
- Pages
- 69-69
- ISSN
- 2044-5385 (ISSN-L)
- PMC
- PMC8024391
- OpenAlex
- W3148729173
- Cited by
- 2,926
- References
- 110
- Citations by year
- 2026: 530 · 2025: 806 · 2024: 726 · 2023: 532 · 2022: 287 · 2021: 42 · 2012: 1
- FWCI
- 48.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Blood Cancer Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Wisconsin-Madison (T32-GM008692)
- Regenerative Medicine Minnesota (RMM 012819 EPC 003)
- National Institute of General Medical Sciences (T32GM008692)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- CAR T-cell therapy, chimeric antigen receptor, solid tumors, hematologic malignancies, CAR-T cell engineering, tumor microenvironment, antigen escape, CAR-T toxicity, tumor infiltration
- MeSH terms
- Receptors, Chimeric Antigen, Animals, Humans, Neoplasms, T-Lymphocytes, Immunotherapy, Adoptive, Hematologic Neoplasms, Tumor Microenvironment
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