A sweeping trial landscape review shows how CAR T therapy is moving beyond one-target designs toward multifunctional “living drugs” designed to improve safety, overcome tumor escape, and tackle harder-to-treat cancers.
Review: Mapping the clinical landscape of multifunctional CAR T cells: Targets, trends, and synergies
In a recent comprehensive review published in the journal Molecular Therapy, researchers in Germany analyzed 1,801 registered clinical trials to map the evolution of “next-generation” Chimeric Antigen Receptor (CAR) T cell products.
The review reveals that multifunctional CAR T cell therapies accounted for 533 of 1,801 CAR T trials and reached 33% of new CAR T products submitted for clinical testing in 2025, and are rapidly shifting from simple designs toward complex, multifunctional architectures, incorporating auxiliary features to enhance safety, such as “suicide switches” and potency, particularly against solid tumors.
The review concludes that while current efficacy-focused strategies, such as multitargeting, are growing exponentially, emergent combination designs are beginning to show promising preclinical and early clinical potential, but their future impact will depend on overcoming manufacturing, regulatory, and clinical validation challenges.
Next-Generation CAR-T Cell Therapy Background
Chimeric Antigen Receptor (CAR) T cells are a relatively novel therapeutic approach in which immune cells are engineered to recognize and destroy malignant tumors. The first of these “cell therapies” was approved by the US Food and Drug Administration (FDA) for human clinical use in 2017. Since then, these modalities, colloquially termed “living drugs,” have reportedly saved thousands of lives, particularly in blood cancers where they demonstrate the highest efficacy.
However, subsequent research highlighted that classical CAR T cell designs demonstrated several significant drawbacks: 1. A subset of patients exhibited severe immune-mediated toxicities, e.g., Cytokine Release Syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2. Limited efficacy against solid tumors.
Consequently, “classical” CAR designs are being supplemented by research into next-generation “multifunctional” CAR T cells. These emergent modalities are engineered to include safety enhancements such as “suicide switches,” which can be externally triggered if adverse patient reactions are observed. Furthermore, some CAR T cells are engineered to secrete cytokines that support persistence, recruitment, or anti-tumor activity, while others target multiple cancer markers simultaneously to prevent the disease from hiding.
Clinical Trial Review Design and Categories
This review aims to synthesize the evolution of CAR T cells from their classical roots through to emergent multifunctional variants via a data-driven approach. The review dataset was extracted and curated from relevant clinical trials (n = 1,801) registered at ClinicalTrials.gov between 2003 and September 2025.
Shortlisted publications were classified into two primary categories:
Safety enhancement research, which comprises technologies like "on/off switches" or "suicide switches" (such as iCasp9) that allow doctors to monitor patient response and deactivate or control CAR T cells if the patient demonstrates adverse side effects, and Efficacy enhancement strategies such as multitargeting (modalities capable of identifying and subsequently targeting two or more discrete tumor antigens), armored CARs (which endogenously secrete survival-boosting cytokines), and checkpoint modulation studies (which are designed to resist prolonged antigen stimulation (“T cell exhaustion”) and tumor microenvironment-induced immunosuppressive factors).
Statistical analyses involved the generation of UpSet plots (a relatively novel data visualization approach for analyzing multidimensional sets and their intersections) and network analyses, thereby mapping patterns, overlaps, and target combinations across different CAR T technologies (e.g., CARs combined with T Cell Engagers (TCEs) or Chimeric Co-stimulatory Receptors (CCRs)).
Multifunctional CAR-T Trial Trends and Findings
The review revealed that of the 1,801 trials analyzed, 533 (~33%) now investigate multifunctional products. Furthermore, multitargeting CAR T technologies accounted for 52% of multifunctional CAR T approaches in 2025.
Network analysis corroborated these findings, highlighting that while blood cancer targets (e.g., CD19, CD20, and BCMA (B Cell Maturation Antigen)) remain the most common overall, hematological indications still dominate both single-functional and multifunctional CAR T trials, while emergent investigations are increasingly focused on new clusters for Acute Myeloid Leukemia (AML) and solid tumors.
These emergent investigations, particularly those on solid tumors, were found to be much more likely to incorporate combination strategies that leverage potency enhancers alongside suicide switches than their more conventional CAR T counterparts.
When exploring data from trials incorporating suicide switches and similar safety mechanisms (> 100), the review noted that these switches are rarely triggered in clinical practice. However, the authors caution that because switches have been activated in only a small number of reported cases, more clinical evidence is needed before firm conclusions can be drawn about their comparative safety or efficacy.
The review also noted a rapid expansion of CAR T trials for autoimmune diseases, which increased from 35 trials in 2023 to 185 trials in 2025, marking a more than five-fold surge in just two years and highlighting the movement of CAR T technologies beyond oncology.
Future Directions for Multifunctional CAR-T Cells
This review posits that the future of CAR T immunotherapy will likely diverge from conventional "one-size-fits-all" cell designs to complex “tri-functional” cells. However, the authors highlight several main hurdles that need to be addressed before this future can be realized: 1. Difficulties (and associated prohibitive costs) in manufacturing these cells, 2. limited clinical outcome data for many approaches, and 3. Regulatory approval, including the need for frameworks that can accommodate modular or combined CAR T designs.
Improving the efficacy of CAR T interventions against solid tumors and ensuring their safety in human patients will likely form a major focus of CAR T research efforts between now and 2030.
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