INTRODUCTION
In recent years, the landscape of cancer therapy has been transformed by the advent of immunotherapy, an innovative approach harnessing the body’s immune system to combat cancer. Among the various immunotherapeutic strategies, Chimeric Antigen Receptor (CAR) therapy stands out as a groundbreaking paradigm, offering unprecedented opportunities for targeted cancer treatment ( Choi et al ., 2022 ; Pan et al ., 2022 ). By genetically engineering a patient’s own immune cells to recognize and attack tumor cells, CAR therapy has revolutionized the field with its remarkable efficacy and potential to redefine the standard of care for a myriad of malignancies ( Zhang et al ., 2022a ).
The foundation of CAR therapy lies in the fusion of antibody-based targeting with T cell-mediated cytotoxicity. This precise targeting mechanism not only enhances the selectivity of therapy but also minimizes off-target effects, paving the way for personalized and tailored interventions. The clinical success of CAR therapy has been most prominently demonstrated in hematologic malignancies, where groundbreaking outcomes have been achieved in patients with refractory or relapsed disease ( Zhang et al ., 2022b ). Approved CAR-T cell therapies, such as Tisagenlecleucel (KYMRIAH ® ) and Axicabtagene ciloleucel (YESCARTA ® ), have showcased remarkable response rates with 50-80% and durable remissions in individuals with B cell malignancies, heralding a new era of hope for patients previously considered incurable ( Locke et al ., 2019 ; Maude et al ., 2018 ; Schuster et al ., 2019 ).
The expanding landscape of CAR constructs and the exploration of novel target antigens hold promise for extending the applicability of CAR therapy to a broader spectrum of cancers, including solid tumors that have traditionally posed significant therapeutic challenges. However, despite its unprecedented success, CAR therapy is not devoid of challenges and limitations. Cytokine release syndrome (CRS), neurotoxicity, and tumor antigen escape represent formidable hurdles that necessitate ongoing research and refinement of therapeutic strategies ( Dagher and Posey, 2023 ). The most notable adverse events include CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), both of which can result in severe morbidity if not promptly managed ( Morris et al ., 2022 ). CRS is characterized by early symptoms such as fever, chills, and malaise, which can escalate to hypotension, hypoxia, vascular leakage, and multi-organ dysfunction in severe cases. The risk of CRS is strongly associated with high tumor burden and elevated baseline inflammatory markers, underscoring the importance of patient selection and monitoring. ICANS typically manifests after or concurrent with CRS, presenting with confusion, language disturbances, impaired motor skills, or somnolence in mild cases, and progressing to seizures, cerebral edema, or coma in more severe instances. Its pathophysiology involves blood–brain barrier disruption, endothelial activation, and increased permeability, allowing cytokines and immune cells to enter the central nervous system. Current clinical practice has established mitigation strategies, such as IL-6 receptor blockade with tocilizumab and corticosteroid administration, which have substantially improved the safety profile of these therapies. Nevertheless, both CRS and ICANS remain major considerations in trial design and patient management, as their severity and incidence can vary depending on CAR construct design, lymphodepletion regimen, and individual patient characteristics.
Another critical issue with CAR therapy is their limited applicability to solid tumors, primarily due to the complex and immunosuppressive tumor microenvironment (TME) ( Wang, 2024 ). Identifying suitable target antigens is particularly difficult, as truly tumor-specific antigens are rare and many candidate targets are also expressed in normal tissues, raising concerns of on-target, off-tumor toxicity. Antigen expression is frequently heterogeneous within and across tumors, enabling subsets of cancer cells to evade CAR recognition and leading to antigen escape. The TME further restricts CAR-T efficacy through multiple mechanisms, including immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells (MDSCs), inhibitory cytokines (e.g., TGF-β, IL-10), metabolic stress from hypoxia and nutrient deprivation, and physical barriers such as dense extracellular matrix and abnormal vasculature that impede T cell infiltration. CAR-T cell persistence is also compromised by continuous antigen stimulation and tonic signaling, which can induce T cell exhaustion and reduce proliferation, cytotoxicity, and memory formation. Together with additional tumor immune evasion strategies, including antigen loss and intratumoral heterogeneity, these factors collectively limit the effectiveness of CAR-based therapies in solid tumors.
Additionally, the accessibility and affordability of CAR-based therapies remain significant challenges, particularly in resource-limited settings. The individualized nature of autologous CAR-T cell production requires specialized facilities, complex manufacturing processes, and stringent quality control, all of which contribute to high costs and extended treatment preparation times. These logistical and financial barriers can limit patient access, particularly in low- and middle-income countries or in healthcare systems with constrained infrastructure. Furthermore, the need for comprehensive supportive care to manage potential toxicities, such as cytokine release syndrome and neurotoxicity, adds to the overall resource burden. Together, these factors underscore the urgent need for strategies that reduce production complexity, lower costs, and improve global accessibility, ensuring equitable delivery of CAR-based therapies across diverse healthcare settings. ( Choi et al ., 2022 ; Fiorenza et al ., 2020 ; Lyman et al ., 2020 ).
In light of these considerations, this review provides a comprehensive overview of current clinical development trends in CAR-based cell and gene therapies by systematically analyzing clinical trials registered on ClinicalTrials.gov. A total of 1,744 trials initiated up to 2024 were identified and examined. This analysis highlights the advancements, challenges, and future prospects of CAR therapies in oncology. By integrating perspectives from molecular biology, immunology, clinical oncology, and health economics, the study aims to elucidate the multifaceted nature of CAR therapeutics and contribute to the progression of precision medicine and enhanced patient outcomes. Overall, this review summarizes the current landscape of clinical development in CAR-based therapeutics.
DATA SOURCES AND SEARCH
We searched the ClinicalTrials.gov database using the keyword “CAR” without any restrictions. The initial extraction, conducted on January 15, 2024, identified 2,703 registered trials. Studies were excluded if (i) “CAR” did not refer to chimeric antigen receptor, (ii) “CAR” was not listed in the Interventions field, or (iii) “CAR” was not used as a therapeutic modality (e.g., for diagnostic purposes). Additionally, two trial types represented by a single case each—CAR-tumor-infiltrating lymphocyte (TIL, conducted in 2021) and cytokine-induced killer (CIK, conducted in 2017)—were excluded. After applying these exclusion criteria, 1,467 trials remained, with start dates ranging from 1997 to 2026. To minimize bias in year-by-year trend analyses due to incomplete datasets, 46 trials starting in 2024 and one trial starting in 2026 were further excluded, resulting in 1,418 clinical trials initiated between 1997 and 2023. To supplement the 2024 dataset, a second extraction was conducted on May 21, 2025, using the same methodology. This search identified 2,354 trials, of which 326 met the inclusion criteria. Consequently, the final dataset comprised 1,744 clinical trials initiated between 1997 and 2024.
CAR-BASED CELL AND GENE THERAPY BIOLOGY AND STRUCTURE
The CAR was initially developed for T cells and remains most extensively studied in this context. Accordingly, the CAR structure is fundamentally based on domains essential for T cell activation in vivo . A typical CAR-T construct comprises an extracellular single-chain variable fragment (scFv) for antigen binding, a hinge region, a transmembrane domain, one or more co-stimulatory domains, and an intracellular activation domain such as CD3ζ ( Dagher and Posey, 2023 ; Honikel and Olejniczak, 2022 ) ( Fig. 1A ). Although each domain is derived from distinct immune molecules, variations in amino acid sequences can significantly influence CAR-T activity ( Li et al ., 2024 ; Mhaidly and Verhoeyen, 2020 ; Pan et al ., 2022 ; Xu et al ., 2019 ). In CAR-T therapy, co-stimulatory domains such as CD28 and 4-1BB are predominantly employed, with evidence suggesting differential functional outcomes depending on their pairing with the CD3ζ activation domain. Specifically, the 4-1BB/CD3ζ combination enhances memory T cell differentiation and persistence, whereas CD28/CD3ζ may promote more immediate effector memory responses. Consequently, current CAR-T therapeutics utilize diverse core domain sequences to optimize efficacy ( Fig. 1B ) CAR-NK cell therapy involves genetic modification of natural killer (NK) cells to confer antigen specificity. Most CAR-NK constructs to date adopt CAR-T-derived structural frameworks, particularly first-generation CARs incorporating CD3ζ alone or second-generation CARs with additional co-stimulatory domains such as 4-1BB ( Fan et al ., 2017 ; Imai et al ., 2005 ; Jensen and Riddell, 2014 ; Kruschinski et al ., 2008 ). The inclusion of 4-1BB has been shown to enhance NK cell activation, cytotoxicity, and secretion of cytokines including interferon-gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) ( Pan et al ., 2022 b). However, NK cells possess a distinct regulatory network involving activating and inhibitory receptors, prompting recent efforts to integrate NK-specific intracellular signaling domains for improved functional mimicry. Notably, domains such as DAP10, DAP12, and 2B4 have emerged as critical for optimizing CAR-NK activity ( Billadeau et al ., 2003 ; Lanier et al ., 1998 ; Nakajima and Colonna, 2000 ; Tangye et al ., 2000 ). Comparative studies have demonstrated that CAR constructs containing DAP10 enhance NK cell responsiveness to tumor cells expressing NKG2D ligands within the TME ( Daher and Rezvani, 2021 ; Imai et al ., 2005 ). Furthermore, CAR-NK cells engineered with an NKG2D-derived transmembrane domain, a 2B4 co-stimulatory domain, and a CD3ζ activation domain exhibit potent antigen-specific cytotoxicity. Constructs employing the 2B4-CD3ζ configuration show superior cytotoxicity, elevated cytokine production, and improved in vivo antitumor efficacy compared to 4-1BB-CD3ζ-based CAR-NK cells ( Li et al ., 2018 ; Xu et al ., 2019 ). Additionally, CAR-NK cells incorporating DAP12 demonstrate enhanced antitumor activity in both primary NK cells and NK-92 cell lines relative to CD3ζ-only constructs, underscoring DAP12’s role via ITAM-mediated signaling in sustaining NK cell cytotoxicity (Töpfer et al ., 2015). Therefore, CAR-NK design transcends simple adaptation of CAR-T architectures, emphasizing tailored selection and combination of signaling domains that align with NK cell biology to induce more potent and sustained immune responses. Future progress in CAR-NK therapy will depend on rational and precise engineering of constructs incorporating NK-specific intracellular signaling motifs ( Davies et al ., 2014 ).
TRENDS IN CAR-BASED CELL AND GENE THERAPY DEVELOPMENT BY IMMUNE CELL TYPE
Since the approval of KYMRIAH ® , the first CAR-T cell therapy, in 2017, CAR-based cell and gene therapies have emerged as promising therapeutic alternatives for addressing various unmet medical needs. Consequently, the number of clinical trials has significantly increased, and clinical research in this area has become increasingly active. From the initiation of the first CAR clinical trial in 1997 to 2024, a total of 1,744 CAR-related clinical trials have been identified. Among these, 1,621 trials involve T cell–based CAR therapies, including 24 trials CAR-gamma-delta T (CAR-γδT) cell therapies and 2 trials CAR-regulatory T (CAR-Treg) cell therapies ( Fig. 2A , Supplementary Fig. 1 ). Additionally, 111 trials are based on NK cells, 8 on CAR-Natural killer T cell (CAR-NKT), 5 on CAR-macrophages (CAR-M), and 3 on CAR-dendritic cells (CAR-DC). While the development of CAR-T therapies remains dominant, the exploration and development of other CAR-based immune cell therapies continues to expand. Each immune cell platform possesses unique advantages and limitations. CAR-T cells, the most widely studied and utilized, demonstrate strong antigen-specific recognition and cytotoxic activity, making them highly effective against hematologic malignancies. These cells also show long-term persistence and memory T cell formation. The clinical efficacy of CAR-T therapies has been validated through multiple FDA-approved products such as KYMRIAH ® and YESCARTA ® . With this proven clinical efficacy, CAR-T therapies continue to be the most actively developed platform. Indeed, CAR-T consistently accounts for the largest number of newly initiated trials each year, and notably progresses into late-phase clinical trials (Phase 2/3 or Phase 3) at a rate of approximately 3 to 5 trials per year, reflecting advancements toward commercialization ( Fig. 2B ). However, CAR-T therapies are frequently associated with severe adverse effects such as CRS and neurotoxicity. Several CD19-directed CAR-T trials have reported ≥ grade 3 CRS, highlighting the clinical significance of these safety concerns ( Sheth and Gauthier, 2021 ). For instance, the NCT02435849 trial in adults with acute lymphoblastic leukemia (ALL) observed severe CRS and ICANS, with some patients requiring intensive care. Pediatric and adolescent ALL patients in NCT01593696 experienced neurotoxic events, such as altered consciousness, speech difficulties, and seizures, most of which were manageable with steroids. Similarly, CD22-directed CAR-T therapy in NCT02315612 resulted in severe CRS and neurotoxicity in adults, typically within 1–2 weeks post-infusion. BCMA-targeted CAR-T therapies have also been associated with neurotoxicity and prolonged cytopenias, underscoring the need for optimized monitoring and management strategies across CAR-T applications ( Garfall et al ., 2016 ). Collectively, these findings emphasize the importance of early recognition and timely intervention to mitigate treatment-related toxicities. Additionally, in the case of autologous CAR-T, the manufacturing process is time-consuming and expensive. Importantly, their therapeutic efficacy in solid tumors is limited due to the immunosuppressive characteristics of the TME. Excluding CAR-T, the development of CAR-NK therapies has been increasing at a relatively rapid pace. However, the majority of CAR-NK trials are still in early clinical stages (Phase 1 or 2), suggesting that further time and development will be needed before commercialization can be achieved ( Fig. 2C ). CAR-NK cells possess MHC-independent tumor recognition, allowing for application across a broad range of tumor types. They also carry a lower risk of CRS and neurotoxicity and are well-suited for the development of allogeneic, “off-the-shelf” cell therapies. Indeed, compared to CAR-T cells, CAR-NK cells are predominantly being developed using allogeneic rather than autologous approaches, as evidenced by trends observed in clinical trials ( Supplementary Fig. 2 ). Despite these advantages, CAR-NK therapies face significant challenges, including limited in vivo persistence and proliferation, and relatively low genetic modification efficiency, making large-scale production and consistent therapeutic performance difficult ( Wu and Matosevic, 2022 ). Additionally, their tumor infiltration and survival in solid tumors are reported to be suboptimal ( Shin et al ., 2023 ). CAR-NKT cells, which combine features of both T cells and NK cells, represent a hybrid immune platform ( Kriegsmann et al ., 2018 ). These cells have the potential to exert cytotoxic effects on tumor cells and regulate immunosuppressive cells in the TME, including MDSCs and regulatory T cells (Tregs) ( Li et al ., 2024 ). Accordingly, CAR-NKT therapies are being considered as a promising strategy for overcoming solid tumor resistance ( Hadiloo et al ., 2023 ). Nonetheless, their clinical application faces major limitations due to their low natural frequency in the body, difficulties in large-scale expansion, poor genetic modifiability, and the limited number of clinical trials to date ( Zhang et al ., 2023 ). CAR-M exhibit strong tumor infiltration capabilities and are capable of direct phagocytosis of tumor cells, offering a distinct mechanism of action from CAR-T or CAR-NK cells ( Morva et al ., 2025 ). In particular, M1-polarized macrophages can induce anti-tumor immune responses, making them advantageous for overcoming the immunosuppressive TME. However, they present technical challenges, including difficulty in genetic engineering and the risk of in vivo polarization into tumor-promoting M2-type macrophages ( Na et al ., 2023 ). As such, ensuring safety and functional stability remains a critical issue. Moreover, CAR-M therapies are still in early-stage clinical development, and it may be premature to discuss their potential for commercialization at this stage. Finally, CAR-DCs represent an emerging cell-based immunotherapy platform, leveraging the potent antigen-presenting capabilities of dendritic cells ( Perez and De Palma, 2019 ). Unlike cytotoxic effector cells, CAR-DCs are primarily designed to modulate the adaptive immune system by presenting tumor antigens and activating endogenous T cell responses. This approach may provide durable anti-tumor immunity through indirect mechanisms. Preclinical studies have shown that CAR-DCs can effectively home to lymphoid tissues, stimulate cytotoxic T lymphocytes (CTLs), and reshape the TME toward immune activation ( Yang et al ., 2019 ). However, CAR-DC therapies remain in the very early stages of development, with no active clinical trials to date ( Perez and De Palma, 2019 ). Major challenges include limited lifespan and scalability of DCs, difficulties in genetic modification, and the need for precise control of their immunostimulatory activity. Despite these hurdles, CAR-DCs hold potential as complementary therapies that may synergize with existing CAR-T or checkpoint blockade strategies, particularly in tumors with low immunogenicity.
TRENDS IN CAR-BASED CELL AND GENE THERAPY DEVELOPMENT BY SPONSOR AND COUNTRY
The analysis focused on the types of sponsors, their annual distribution trends, and the leading countries involved in clinical trials of CAR-T and CAR-NK cell therapies, two of the most prominent modalities in the field. This provides valuable insights into the current landscape of financial support, sponsorship patterns, and the commercial outlook for CAR-T and CAR-NK therapy development. Notably, the types of clinical trial sponsors differ between CAR-T and CAR-NK cell therapies, potentially reflecting the distinct developmental strategies and stages of commercialization associated with each platform. As shown in Fig. 3A , hospitals account for the largest proportion of CAR-T clinical trial sponsorship (41%), followed by industry (36%) and academic institutions (17%). A similar pattern is observed in CAR-NK trials, with hospitals leading at (49%), followed by industry (32%) and academia (17%). While our categorization assigned each trial to a single sponsor group based on the “Sponsor” field, we also examined whether industry collaborators were listed in trials formally sponsored by hospitals or universities. Of the 1,011 CAR-T and CAR-NK trials with hospital or academic sponsors, 370 (approximately 36.6%) included industry collaborators in the “Collaborator” field. This indicates that, although categorized as hospital- or university-led, a subset of these trials may still involve industry participation. Accordingly, the actual proportion of trials with industry involvement may be somewhat higher than suggested by our primary sponsor classification. Government or public agencies represent only a small fraction of sponsorship—5% in CAR-T and merely 1% in CAR-NK—indicating that most clinical development is being driven by private and medical institutions.
Interestingly, when examined over time, a clear trend emerges: since 2014, there has been a sharp rise in industry-sponsored CAR-T research and development efforts, while CAR-NK therapies, which began emerging after 2016, have consistently involved industry sponsorship ( Fig. 3B , 3C ). This marked shift in sponsorship patterns—from hospital-led efforts prior to 2014 to an increasing dominance of industry-sponsored research—likely reflects the interplay of scientific advancements, technological maturation, evolving regulatory frameworks, and growing commercial interest in CAR-based gene and cell therapies.
First, the clinical success of CAR-T therapies in the early 2010s, particularly the striking remission rates observed in trials led by the University of Pennsylvania and Novartis, garnered global attention ( Badar and Shah, 2020 ; Maude et al . 2014 ). This momentum culminated in 2014 when the FDA granted Breakthrough Therapy designation to CTL019 (later approved as KYMRIAH ® ), signaling strong regulatory support and encouraging broader investment ( Rodriguez-Cartagena et al ., 2018 ). As a result, industry players began to recognize the therapeutic and commercial potential of CAR-based therapies, shifting the developmental focus from academia to the private sector. Second, by 2014, key enabling technologies—such as viral vector-based gene transfer, scalable T/NK cell expansion protocols, and closed-system GMP manufacturing—had reached sufficient maturity to support industrial-scale production ( Giorgioni et al ., 2024 ; Iyer et al ., 2018 ). This technological advancement allowed companies to transition CAR therapies from small-batch academic platforms to scalable and standardized therapeutic products. Third, the increasing feasibility of commercializing CAR therapies became evident. CAR-T therapies, in particular, offered curative potential in certain hematologic malignancies with single-dose treatments, presenting a high-reward profile despite their complexity ( Maude et al ., 2018 ). The ability to secure orphan drug designation, benefit from expedited approval pathways, and command premium pricing further strengthened their appeal as viable biopharmaceutical products ( Giorgioni et al ., 2023 ; Mariz et al ., 2016 ). Finally, hospitals and academic centers, while well-equipped for early-phase, patient-specific development, often lacked the infrastructure and resources necessary for late-stage clinical trials, global regulatory filings, and commercial distribution ( Priesner and Hildebrandt, 2022 ). In contrast, biopharmaceutical companies were better positioned to undertake these activities, enabling them to accelerate product development, pursue broader market access, and establish sustainable manufacturing pipelines. Together, these interrelated developments catalyzed a major turning point in the CAR therapy field post-2014, paving the way for a surge in industry-led innovation and clinical activity ( Mitra et al ., 2023 ). In addition, an analysis of the major countries involved in CAR-based cell and gene therapy development reveals that the majority of research and clinical activity is concentrated in China and the United States ( Fig. 3D ). An analysis of the global landscape of CAR-based cell and gene therapy development reveals that the United States and China are the two dominant countries driving research, clinical trials, and commercialization. This leadership can be attributed to a convergence of scientific, regulatory, financial, and market-based factors. First, both countries possess highly developed research and clinical infrastructures. In the United States, institutions such as the University of Pennsylvania, MD Anderson Cancer Center, and City of Hope have played pioneering roles in CAR-T cell therapy development ( Maude et al ., 2014 ; Rafiq et al ., 2020 ). These academic centers benefit from substantial public research funding, particularly from the National Institutes of Health (NIH), enabling them to lead in early discovery and translational research ( Moses et al ., 2015 ; Packalen and Bhattacharya, 2020 ; Selker and Califf, 2011 ). Similarly, China has made CAR-based therapies a national strategic priority, with major investments through government-led initiatives such as Made in China 2025 and Healthy China 2030 ( Du et al ., 2024 ; Hu et al ., 2022 ; Wu et al ., 2020 ). Leading academic hospitals and military-affiliated research institutes, including Peking University and the Chinese PLA General Hospital, have been instrumental in advancing CAR-T and CAR-NK therapies. Second, favorable regulatory environments in both countries have supported the rapid advancement of CAR therapies. The FDA has established expedited regulatory pathways, including Breakthrough Therapy designation, the Regenerative Medicine Advanced Therapy (RMAT) program, and Orphan Drug status, which provide development incentives for innovative cell and gene therapies. In China, a relatively flexible and responsive regulatory framework—particularly in the early 2010s—enabled hospitals to initiate CAR-T trials under simplified Investigational New Drug Application (IND) procedures, contributing to the rapid proliferation of early-stage clinical trials ( Wei et al ., 2021 ; Yin et al ., 2022 ). Third, robust financial support and a thriving industrial ecosystem have accelerated commercial development ( Litvinova et al ., 2024 ). In the U.S., the biotechnology sector has attracted significant venture capital, and major pharmaceutical companies have made large-scale acquisitions of CAR-T innovators, such as Gilead’s $11.9 billion purchase of Kite Pharma and Bristol Myers Squibb’s $74 billion acquisition of Juno Therapeutics ( BLOOMBERG, 2019 ; Mullin, 2017 ). In parallel, China has experienced a surge in biotech investment, with large technology conglomerates like Baidu, Alibaba, and Tencent entering the life sciences sector ( Gale, 2022 ). Domestic CAR-T companies such as Legend Biotech, CARsgen Therapeutics, and JW Therapeutics have received substantial public and private funding, enabling them to advance pipelines and expand manufacturing capabilities. Fourth, large patient populations and substantial market potential have further supported clinical development in both countries. In the United States, the healthcare system’s capacity to accommodate high-cost precision therapies—particularly for hematologic malignancies—makes it a favorable environment for CAR therapy adoption ( Cao et al ., 2025 ). In China, the vast number of patients with B-cell malignancies and other CAR-T-suitable indications provides a large pool for clinical trial enrollment, facilitating rapid study execution ( Du et al ., 2024 ; Wei et al ., 2021 ). The country’s extensive hospital network also allows for broad implementation of trials across multiple regions. Finally, both the United States and China have adopted global expansion strategies to extend the reach of their CAR-based platforms. U.S.-based companies benefit from well-established global regulatory expertise, GMP-certified manufacturing, and commercial distribution networks, allowing them to dominate international markets. In contrast, Chinese developers have increasingly pursued international clinical trials and cross-border licensing deals to expand their presence in the U.S. and European markets, signaling a more outward-facing commercialization strategy ( Du et al ., 2024 ; Wei et al ., 2021 ). Taken together, these factors underscore why the United States and China continue to lead the global field of CAR-based cell and gene therapy development. Their combined strengths in research, regulation, investment, clinical capacity, and commercialization form a powerful foundation that is likely to shape the future trajectory of this rapidly evolving therapeutic area.
TRENDS IN CAR-BASED CELL AND GENE THERAPY DEVELOPMENT BY INDICATION
An analysis of indications associated with 1,744 CAR-based cellular gene therapies revealed that hematologic malignancies accounted for the majority (1,140 cases, 65%), followed by Solid tumor indications (456 cases, 26%) and Non-tumor indications (137 cases, 8%) ( Supplementary Fig. 3A ). Temporal trends further demonstrate that, with the exception of 1997 and 2003, Hematologic malignancies have consistently represented the largest proportion of CAR therapy indications through 2024 ( Supplementary Fig. 3B ). Notably, since 2014, there has been a clear expansion of research into solid tumors, a shift likely driven by the high unmet medical need in this area due to the complex TME, heterogeneous antigen expression, fibrosis, and hypoxia, which render conventional therapies less effective. CAR therapies are thus increasingly considered as promising alternatives in this challenging landscape. Additionally, from 2017 onwards, research has gradually expanded to non-cancer indications—primarily autoimmune diseases—though these are not explicitly annotated in the dataset. These trends collectively highlight the growing interest in applying CAR-based therapies beyond cancer, including to various intractable diseases. Further analysis of immune cell–based CAR therapies stratified by indication revealed that both CAR-T and CAR-NK therapies predominantly target hematologic malignancies, accounting for 66% (1,075 trials) and 56% (62 trials), respectively, followed by solid tumors at 26% (414 trials) and 31% (34 trials), showing comparable overall distributions ( Fig. 4A ). However, indication-specific differences were evident upon further stratification ( Fig. 4B ). For CAR-T therapies, Multiple myeloma (MM) and B-cell acute lymphoblastic leukemia (B-ALL) were the leading targets with 213 (22%) and 133 (13%) trials, respectively. In contrast, CAR-NK therapies demonstrated a different trend, with AML and B-cell lymphoma accounting for 19 (28%) and 9 (13%) trials, respectively. A similar divergence was observed in solid tumor indications ( Fig. 4C ): excluding pan-tumor or carcinoma categories, CAR-T therapies were primarily directed toward liver cancer (53 trials, 14%) and pancreatic cancer (42 trials, 11%), while CAR-NK therapies were more frequently explored in ovarian cancer (7 trials, 26%) and pancreatic cancer (6 trials, 22%). These differences in indication profiles between CAR-T and CAR-NK therapies across both hematologic and solid tumors likely arise from their distinct biological and technical properties. CAR-T cells are highly effective when targeting well-defined tumor-associated antigens, such as CD19 in B-ALL, BCMA in MM, and Claudin 18.2 in pancreatic cancer, as well as the tumor-specific antigen GPC3 in liver cancer ( Supplementary Fig. 4 ). However, in malignancies such as AML or ovarian cancer, where target antigens (e.g., CD33, CD123, FRα) are also expressed on normal tissues, CAR-T therapies pose a higher risk of on-target/off-tumor toxicity due to their potent cytotoxic responses. In such cases, CAR-NK cells offer a safer alternative due to their shorter in vivo persistence, self-limiting cytokine release, and reduced risk of severe adverse events ( Marofi et al ., 2021 ). Moreover, NK cells utilize innate immune mechanisms, including recognition of MHC class I deficiency and stress-induced ligands (e.g., NKG2D ligands), enabling a broader and more flexible response in antigenically heterogeneous or immunosuppressive environments such as those found in AML and ovarian cancer ( Paul and Lal, 2017 ). From a risk-benefit perspective, CAR-T therapies are typically deployed in indications where high cytotoxic potency justifies potential toxicity, whereas CAR-NK cells are better suited to contexts requiring greater safety margins or where target antigen expression is less well-defined ( dos Reis et al ., 2025 ; Peng et al ., 2024 ). Finally, manufacturing strategies further differentiate the two platforms: CAR-T therapies rely predominantly on autologous patient-derived T cells, requiring individualized and logistically complex production, while CAR-NK therapies can be generated from scalable allogeneic sources—such as NK-92 cell lines, umbilical cord blood–derived NK cells, or iPSC-derived NK cells—enabling off-the-shelf manufacturing and more accessible clinical development ( Peng et al ., 2024 ; Zhang et al ., 2022 ; Zhu et al ., 2024 ). Collectively, these factors explain why CAR-T therapies are more heavily concentrated in indications with well-characterized antigens and expected therapeutic benefit, such as B-ALL, MM, liver and pancreatic cancers, while CAR-NK therapies are preferentially applied to more antigenically ambiguous or immunosuppressive malignancies, including AML, B-cell lymphomas, and ovarian cancer.
TRENDS IN CAR-BASED CELL AND GENE THERAPY DEVELOPMENT BY DISEASE TARGET
A detailed analysis of disease targets in CAR-based cellular gene therapy clinical trials revealed clear differences between CAR-T and CAR-NK platforms, particularly in hematologic malignancies versus solid tumor applications. In hematologic malignancies, CAR-T therapies were overwhelmingly directed toward CD19 (592 trials) and BCMA (173 trials), together comprising the majority of CAR-T targets in this category (N=996) ( Fig. 5A ). Other antigens such as CD33, CLL1, and CD123 were represented to a much lesser extent, highlighting the preferential use of CAR-T cells in diseases like B-ALL and MM, where these antigens are well-characterized and lineage-specific. By contrast, CAR-NK therapies in hematologic malignancies (N=67) showed a more diversified but less concentrated target distribution, with the most frequent being CD19 (37 trials), followed by BCMA, CD33, and CLL1 at much lower frequencies (under 10 trials each). This relatively broader but less focused pattern reflects the exploratory nature of CAR-NK research in this space, especially in diseases such as AML, where safety considerations make NK-based therapies more attractive due to their reduced cytokine release and transient persistence.
In solid tumors, or “pan-tumor” categories, CAR-T trials (N=386) were again dominated by specific targets such as Mesothelin (54 trials), GPC3 (41 trials), and Claudin18.2 (36 trials), along with GD2 (25 trials) and B7-H3 (31 trials) ( Fig. 5B ). These data are consistent with the shift toward solid tumors noted since 2014, especially in tumors like liver, pancreatic, and lung cancers, where unmet clinical need is high. CAR-NK solid tumor targets (N=27), though fewer in number, presented a distinct profile with TROP2 (5 trials) and NKG2D-based CARs (5 trials) leading the group, suggesting an emphasis on broad-spectrum tumor-associated antigens or ligands upregulated in stress or immunoevasive contexts, such as ovarian, pancreatic and colon cancers ( Supplementary Fig. 5 ).
These trends collectively reinforce findings from broader indication-based analyses. The strong clustering of CAR-T therapies around well-defined antigens such as CD19 and BCMA reflects their suitability for precise targeting in hematologic malignancies ( Mansoori et al ., 2024 ). Meanwhile, the distribution of CAR-NK targets—particularly in difficult-to-treat tumors with antigen heterogeneity or limited safety margins—demonstrates the field’s adaptation to the inherent strengths of NK cell biology ( Jørgensen et al ., 2025 ; Peng et al ., 2024 ).Thus, the disease target landscape visualized in Fig. 5 illustrates how biological characteristics of immune effector cells, antigen safety profiles, and disease context collectively inform the strategic deployment of CAR-based therapies. These results underscore the complementary roles of CAR-T and CAR-NK platforms in addressing distinct therapeutic niches across cancer types.
CAR-BASED CELL AND GENE THERAPY TARGETING PLATFORM
The targeting platform employed in CAR-based cell and gene therapies plays a critical role in determining the breadth, specificity, and flexibility of tumor recognition. An analysis of targeting configurations revealed that the majority of CAR therapies to date have adopted conventional monospecific platforms, though various advanced targeting strategies are gradually being explored ( Fig. 6A ).
Among CAR-T therapies (N=1,621), a substantial 86% employed monospecific CARs, indicating that most clinical trials have focused on single-antigen recognition—typically against well-defined targets such as CD19, BCMA, or GPC3 ( Fig. 6B ). Beyond this, a small but notable portion of trials utilized alternative formats aimed at improving target coverage and reducing antigen escape. These included dual CARs (6%), which co-express two independent CAR constructs; bispecific CARs (3%), which recognize two antigens via a single receptor; and universal CARs (2%), which rely on adapter molecules or tag-recognizing domains to allow flexible retargeting. Other multi-targeting platforms—such as tri-specific (1%), tandem (1%), and multi-specific CARs—represented less than 1% each, suggesting these more complex designs remain in early stages of clinical translation. Overall, less than 20% of CAR-T trials have employed non-monospecific formats, reflecting both the clinical success of traditional approaches in hematologic malignancies and the technical complexity associated with engineering multifunctional constructs.
In contrast, CAR-NK therapies (N=111) demonstrated an even higher reliance on monospecific platforms (88%), consistent with their relatively recent emergence in the field and exploratory status in clinical development ( Fig. 6C ). Nonetheless, a small number of trials have begun to explore universal (5%), dual (3%), and bispecific (2%) CAR formats in NK cells. The limited use of complex configurations in CAR-NK platforms may be attributable to current challenges in vector delivery, stable transgene expression, and functional integration of synthetic receptors in NK cells, which differ biologically and technically from T cells ( Liu et al ., 2020 ; Rezvani et al ., 2017 ; Zhong and Liu, 2024 ). These results reveal several important trends. First, the strong predominance of monospecific CARs—especially in CAR-T trials—highlights the historical success of this format in targeting lineage-restricted antigens in hematologic malignancies. Second, the emergence of dual, bispecific, and universal platforms reflects ongoing innovation to address limitations in solid tumors and hematologic malignancy, including antigen heterogeneity, immune escape, and TME ( Cho et al ., 2022 ; Majzner and Mackall, 2019 ; Wei et al ., 2022 ). Lastly, the nascent application of these advanced formats in CAR-NK platforms suggests a potential future direction as engineering techniques improve and as NK cells are increasingly leveraged for “off-the-shelf” immunotherapies. Collectively, the targeting platform landscape underscores a maturation trajectory in CAR-based therapies—from monospecific precision in early hematologic applications to multi-specific adaptability for solid tumors and next-generation constructs. As preclinical and translational research continue to optimize receptor designs, balancing efficacy, safety, and manufacturability will be key to expanding the therapeutic reach of CAR-based cell and gene therapies.
CAR-BASED CELL AND GENE THERAPY TREATMENT STRATEGY
The therapeutic application of CAR-based cell and gene therapies has evolved beyond monotherapies to include various combinatorial and sequential strategies, aimed at enhancing anti-tumor efficacy, overcoming immune resistance, and improving safety profiles. An analysis of current treatment approaches highlights distinct patterns in CAR-T versus CAR-NK clinical development. For CAR-T therapies (N=1,621), the overwhelming majority of trials (89%, 1,441 trials) applied CAR-T cells as monotherapy, reflecting the platform’s well-established efficacy, particularly in hematologic malignancies such as B-cell acute lymphoblastic leukemia and multiple myeloma ( Fig. 7A ). However, a growing number of trials have adopted combination strategies, targeting various resistance mechanisms and tumor complexities. Notably, combination with chemotherapy (38 trials) and monoclonal antibodies (39 trials) were among the most frequently explored approaches, indicating a trend toward immune-sensitization or lymphodepletion to enhance CAR-T persistence and expansion. Additionally, 23 trials implemented cell therapy combinations, including co-infusion with other immune effector cells. A smaller subset of trials evaluated protein-based adjuvants (20 trials), including cytokines, fusion proteins, or checkpoint inhibitors, while 13 trials investigated combinations with CAR-T, suggesting a potential synergistic strategy to harness both innate and adaptive immune responses. More advanced approaches, such as multi-modality regimens involving more than two agents (7 trials) and sequential combination therapies with timed administration (6 trials), are still in early clinical investigation. These evolving approaches reflect efforts to overcome solid tumor challenges, such as antigen escape, immunosuppressive TME, and T cell exhaustion.
In contrast, CAR-NK therapies (N=111) were used predominantly as monotherapy (96 trials, 86%), consistent with their exploratory phase in clinical translation. A small number of studies examined combinations with monoclonal antibodies (6 trials), other immune cells (3 trials), and Protein (2 trials), aiming to potentiate NK-mediated cytotoxicity or broaden antigen recognition ( Fig. 7B ). The limited deployment of complex strategies in CAR-NK therapies likely reflects both their safer profile—often sufficient as standalone agents—and the relative nascency of CAR-NK development compared to CAR-T. These patterns reveal a platform-dependent treatment paradigm. CAR-T therapies, having demonstrated high potency but also high toxicity risks (e.g., CRS, neurotoxicity), are increasingly paired with modulatory agents to improve efficacy while managing adverse events. CAR-NK therapies, by contrast, are being tested primarily in monotherapy settings due to their innate cytotoxicity, favorable safety, and compatibility with off-the-shelf use ( Jørgensen et al ., 2025 ; Peng et al ., 2024 ; dos Reis et al ., 2025 ). As CAR-based therapies continue to diversify, the integration of combination strategies—especially in solid tumor contexts—will be critical. Future directions may include rational sequencing, synergistic immune-cell co-infusion, and TME modulation. The development of biomarker-guided personalized regimens and modular CAR systems may further enhance the adaptability and therapeutic reach of these cellular therapies.
DEVELOPMENT STATUS OF PHASE III CLINICAL TRIALS
As of 2024, a total of 16 Phase 3 clinical trials involving CAR-T therapies for hematologic malignancies have been identified, reflecting continued clinical momentum and maturation of this therapeutic modality ( Table 1 ). These trials are exclusively focused on hematologic malignancies, consistent with the strong track record of efficacy observed in earlier-phase studies for diseases such as B-ALL and MM. The most frequently targeted antigens in these trials are CD19 (8 trials) and BCMA (8 trials), underscoring their clinical relevance and biological specificity. CD19 has long been a foundational target in B-cell malignancies, while BCMA has become central in CAR-T development for relapsed or refractory MM. The majority of these trials (14 out of 16) are sponsored by biotechnology or pharmaceutical companies, indicating sustained commercial interest, while 2 are led by academic or hospital-based research groups. Chronological data show a steady increase in trial initiation from 2014 through 2024, highlighting the evolving and expanding clinical landscape of CAR-T therapies. Collectively, this trend demonstrates that CAR-T therapies for hematologic malignancies are now entering a pivotal stage of late-phase development, with particular emphasis on CD19 and BCMA-targeted platforms. The concentration of Phase 3 activity in this area highlights the clinical maturity and therapeutic confidence surrounding these targets, paving the way for expanded indications and potential label extensions in the near future.
DISCUSSION & CONCLUSION
This review systematically analyzes clinical trials to provide an in-depth overview of ongoing clinical development trends in CAR-based cell and gene therapies. A total of 1,744 clinical trial records were extracted from ClinicalTrials.gov and analyzed, while data from other major registries, such as European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) and International Clinical Trials Registry Platform (ICTRP), were not included. Although exclusive reliance on ClinicalTrials.gov may overrepresent the dominance of the United States and China in CAR-based therapy development, incorporating EudraCT and ICTRP would offer a more geographically balanced perspective by capturing European academic- and hospital-led trials, as well as additional studies from Asia (e.g., Korea, Japan, India) and other regions. Nevertheless, because the majority of CAR trials are concentrated in the United States and China, the overall pattern of regional leadership is unlikely to change, although the relative contributions of other regions would be more accurately reflected.
CAR-based cell and gene therapies have reshaped the oncology landscape, particularly in hematologic malignancies where they demonstrate exceptional efficacy. The growing diversification of platforms—including CAR-NK, CAR-M, and CAR-NKT—along with advancements in target selection and multi-antigen designs, reflects the field’s progression toward broader applicability. While most therapies are still applied as monotherapy, an increasing number of clinical trials are exploring rational combinations to overcome resistance in solid tumors. Despite the challenges of manufacturing, toxicity, and limited persistence in some platforms, global efforts led by the United States and China are accelerating late-phase development, especially for CD19- and BCMA-targeted therapies. As CAR-based therapies continue to mature, future success will depend on optimizing safety, accessibility, and scalability, thereby fulfilling their potential across a wider range of cancers and potentially non-cancer indications.
ACKNOWLEDGMENTS
This research was supported by Duksung Women’s University Research Grants 2023-3000009004.
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