CAR-T therapy has transformed treatment for some blood cancers, with seven FDA-approved products and strong clinical responses in hematologic malignancies. However, its limitations remain evident. In solid tumors, engineered T cells often struggle with trafficking, persistence, antigen heterogeneity, and the immunosuppressive tumor microenvironment. Toxicities such as cytokine release syndrome and neurotoxicity remain serious concerns, while autologous manufacturing is slow, expensive, and difficult to scale. These shortcomings have pushed researchers to rethink CAR not as a single-cell solution, but as a broader therapeutic platform. Based on these challenges, deeper research into diverse CAR systems is needed.
In a review (DOI: 10.1093/pcmedi/pbag007) published on March 13, 2026, in Precision Clinical Medicine, researchers from City of Hope National Medical Center and the University of California, Irvine, outlined how CAR technology is rapidly evolving beyond traditional CAR-T cells. Their analysis covers 13 engineered cell platforms and argues that future progress will depend on matching the right cellular platform to the right disease, potentially extending CAR-based therapy from cancer into autoimmune, infectious, fibrotic, and senescence-related disorders.
The review makes clear that αβ CAR-T cells remain the field's benchmark, with complete remission rates of 40%–85% in relapsed or refractory B-cell acute lymphoblastic leukemia and response rates above 80% in multiple myeloma. Yet the same platform also brings major limitations, including cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), weak solid-tumor performance, and manufacturing costs that can reach $300,000–$500,000 per patient. That is why researchers are diversifying. CAR-NK cells offer rapid killing and lower risks of GvHD, CRS, and ICANS. CAR-γδ T cells bring natural tumor tropism and allogeneic potential; in an early study of ADI-001 for B-cell malignancies, response rates reached 78% without severe GvHD, CRS, or ICANS. CAR-macrophages may be better suited to solid tumors and fibrosis because they can penetrate tissue, phagocytose targets, and remodel hostile microenvironments. CAR-Tregs, by contrast, are being developed to induce immune tolerance in transplantation and autoimmune disease. The review also highlights next-generation strategies such as off-the-shelf production from donors, HSCs, or iPSCs, in vivo CAR generation, logic-gated designs, and combination therapies that could improve precision, safety, and access.
The authors suggest that the future of CAR therapy may lie in treating it as a modular platform rather than a single cancer technology. In that view, the central question is not whether CAR-T still matters, but which engineered cell type best fits a specific biological problem. A macrophage may be a better fit in fibrosis, a regulatory T cell in autoimmunity, and NK or γδ T cells in faster off-the-shelf applications, as well as the potential for combining multiple cell therapies and integrating them with non-cell-based therapies
The broader significance of this review is strategic as much as scientific. A diversified CAR ecosystem could make cell therapy more precise, more scalable, and more adaptable to real clinical needs. Off-the-shelf products may reduce cost and delay. In vivo engineering may eventually bypass labor-intensive manufacturing. Most importantly, disease-matched CAR platforms could push engineered-cell medicine beyond oncology into lupus, infection, cardiac or liver fibrosis, and senescence-associated disorders. Even so, the authors caution that most alternative platforms remain early in development and will require disease-specific evaluation and long-term safety monitoring before they can reshape routine care.
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References
DOI
10.1093/pcmedi/pbag007
Original Source URL
https://doi.org/10.1093/pcmedi/pbag007
About Precision Clinical Medicine
Precision Clinical Medicine (PCM) commits itself to the combination of precision medical research and clinical application. PCM is an international, peer-reviewed, open-access journal that publishes original research articles, reviews, clinical trials, methodologies, opinions in the field of precision medicine in a timely manner. By doing so, the journal aims to provide new theories, methods, and evidence for disease diagnosis, treatment, prevention and prognosis, so as to establish a communication platform for clinicians and researchers that will impact practice of medicine. The journal covers all aspects of precision medicine, which uses novel means of diagnosis, treatment and prevention tailored to the needs of a patient or a sub-group of patients based on the specific genetic, phenotypic, or psychosocial characteristics. Clinical conditions include cancer, infectious disease, inherited diseases, complex diseases, rare diseases, etc. The journal is now indexed in ESCI, Scopus, PubMed Central, etc., with an impact factor of 5.0 (JCR2024, Q1).