Unveiling the promise of CAR-T therapy in cancer treatment: a global analysis of clinical trial trends.

To the Editor: The Chimeric Antigen Receptor T-cell (CAR-T) therapy represents a groundbreaking immunotherapeutic approach that utilizes genetic engineering to modify a patient’s T-cells, transforming them into “supercells” capable of recognizing and attacking specific tumor cells[1]. This revolutionary therapy offers new hope for treating cancers that traditional methods struggle to address. In recent years, cancer incidence has been rising, particularly hematologic cancers such as lymphoma and leukemia, diseases which often show limited therapeutic response and high recurrence rates. Conventional treatments, including chemotherapy, radiotherapy, and surgery, while somewhat effective, are associated with significant side effects and a strong risk of resistance, making long-term efficacy challenging[2]. The biological foundation of CAR-T therapy lies in the genetic modification of T-cells, enabling them to recognize specific antigens on cancer cell surfaces and trigger an immune response to eradicate the tumor cells. Compared to traditional drug therapies, CAR-T offers superior precision and specificity, targeting cancer cells while minimizing damage to normal tissue. Its major advantage lies in its ability to treat late-stage tumors resistant to conventional therapies, offering prolonged therapeutic benefits and renewed hope for cancer patients[3]. Our primary objective was to quantify temporal, geographic, and disease-area trends in registered CAR-T trials from 2016 to 2025. Prespecified outcomes included counts and proportions by trial phase and status, indication (hematologic vs solid; top cancers), therapy type (monotherapy vs combination), treatment line (neoadjuvant, adjuvant, maintenance/consolidation, first-/later-line), and geography, with annual growth metrics summarized for 2016–2025. The reference format in this manuscript complies with the TITAN reference guidelines[4]. In this study, we utilized the INFORMA database (https://pharma.id.informa.com/) to gather data on Chimeric Antigen Receptor T-cell (CAR-T) therapy clinical trials, retrieving 1,544 trials using the MeSH keyword “CAR-T therapy.” We applied inclusion criteria focusing on trials from 2016 to 2025, across various cancer types, and phases (I, I/II, II, II/III, III, IV). The dataset includes information on trial phases, status (Completed, Open, Planned, Closed, Terminated), geographical regions, and targeted malignancies, enabling a comprehensive overview of CAR-T therapy’s application in oncology. Data were initially extracted on June 30, 2025 and verified/locked on September 15, 2025. Inclusion criteria comprised interventional or observational oncology trials of CAR-T registered between 2016 and 2025 (phases I–IV, including I/II and II/III) with analyzable metadata (phase, status, indication, geography); exclusion criteria removed non-oncologic or non-CAR-T studies, expanded-access/compassionate-use entries lacking essential metadata, duplicates, and records missing key identifiers. To ensure transparency and reproducibility, we conducted data screening in three stages: (1) removing duplicate entries based on trial ID and sponsor name, (2) excluding non-oncologic and non-CAR-T-related trials, and (3) cross-validating phase and status data with records from ClinicalTrials.gov for consistency (Supplemental digital content Figure S1, available at: https://links.lww.com/JS9/G584). We also standardized terminology across different regional registries to minimize classification bias. De-duplication further used registry identifiers (e.g., NCT/CTR/ChiCTR) plus sponsor and title with fuzzy-matching for near-duplicates; conflicts were resolved by prioritizing the most recent official registry timestamp, and a 10% random back-check confirmed concordance across sources. The dataset enables a descriptive characterization of the registered CAR-T trial landscape and the quantification of temporal/geographic/disease-area trends, highlighting key trends, such as the growing use of CAR-T in solid tumors and emerging combination therapies. Additionally, we identified research gaps, particularly in optimizing CAR-T therapy for solid tumor treatment, providing valuable insights for future studies. Figure 1A demonstrates the distribution of CAR-T clinical trials across different Trial Phases from 2016 to 2025. These data reveal a steady increase in Phase II and III trials over time, with a sharp rise in these phases after 2023. Figure 1B presents a geographical analysis of the participation of different countries in CAR-T trials, illustrating the varying levels of interest and progress in different regions. Notably, the United States and China lead in the number of trials. Figure 1C illustrates the trial status of top targets, including stages such as Closed, Completed, Open, Planned, and Terminated. It is evident that many targets are still in the open or ongoing phase, reflecting the broad application of CAR-T therapy across multiple targets and the ongoing dynamic exploration in this field. Figure 1D lists the top 10 cancers targeted in CAR-T therapy trials, with lymphoma, acute lymphoblastic leukemia, and multiple myeloma being prominent, indicating CAR-T’s significant role in hematologic cancers. Figure 1.: Global Landscape of CAR-T Therapy Clinical Trials. A: Distribution of CAR-T therapy clinical trials by phase (2016-2025), highlighting the increase in Phase II and III trials, particularly post-2023. B: Geographical distribution of CAR-T therapy clinical trials across the top 10 countries, with the United States and China leading in the number of trials. C: Trial status of the top CAR-T therapy targets, categorized by Closed, Completed, Open, Planned, and Terminated stages, showing ongoing trial activity across multiple targets. D: Ranking of the top 10 cancers targeted in CAR-T therapy research, with hematologic malignancies like lymphoma and leukemia being the most studied. E: Use of CAR-T therapy as monotherapy versus in combination with other treatments, emphasizing the growing trend of combination therapy trials. F: Distribution of CAR-T therapy across different treatment lines, with a focus on its most frequent use in second-line treatment after failure of conventional therapies. Figure 1E analyzes the use of CAR-T therapy in combination with other treatments versus as a monotherapy. These data show a significantly higher number of monotherapy clinical trials, while combination therapies, particularly those involving immunotherapy and targeted therapies, remain a key area of research. Finally, Figure 1F shows the use of CAR-T therapy across different lines of treatment. These data reveal that second-line treatments are the most common, suggesting that CAR-T therapy is primarily being explored as an adjunctive treatment in patients who have failed conventional therapies. In the clinical trial data analyzed, the patient segments for Neoadjuvant, Adjuvant, and Maintenance/Consolidation therapies, which are particularly relevant to surgical oncology, were represented by 6, 11, and 34 trials (Table 1), respectively, highlighting the increasing integration of CAR-T therapy in surgical treatment protocols. Table 1 - Patient segments in CAR-T therapy clinical trials relevant to surgical oncology Patient segments Number Neoadjuvant 6 Adjuvant 11 Maintenance/Consolidation 34 The significance of this study lies in characterizing CAR-T activity relevant to solid-tumor applications, Since 2017, the FDA has approved seven CAR-T therapies for hematologic malignancies, such as leukemia and lymphoma, marking significant progress in the treatment of blood cancers[5]. However, the application of CAR-T in solid tumors has faced challenges. One of the major limitations is the difficulty in achieving sufficient T-cell infiltration into solid tumors, which are often shielded by a dense extracellular matrix and immunosuppressive microenvironment. Additionally, solid tumors frequently exhibit immune evasion mechanisms, such as upregulation of immune checkpoints, which reduce CAR-T efficacy. The lack of suitable tumor-specific antigens also complicates the targeting of solid tumors with CAR-T therapies. Recent studies, including a landmark trial by Peking University, have shown that CAR-T therapies, such as CLDN18.2 CAR-T, when integrated with surgical treatment strategies, can improve therapeutic outcomes for solid tumors like gastric cancer. This combination approach has demonstrated the ability to enhance progression-free survival and overall survival in patients with advanced gastric cancer and gastroesophageal junction cancers, providing hypothesis-generating evidence for CAR-T’s potential in solid tumor treatment. Nevertheless, Chinese research teams have made significant breakthroughs. For instance, the team led by Professor Shen Lin at Peking University conducted the world’s first CLDN18.2 CAR-T gastric cancer clinical trial, demonstrating impressive efficacy in treating advanced gastric cancer and gastroesophageal junction cancers, significantly extending progression-free survival and overall survival. This achievement, published in Lancet in May 2025, has garnered widespread international attention, highlighting CAR-T’s promising role in solid tumor treatment[6]. However, current evidence in solid tumors remains preliminary and is largely derived from early-phase, single-arm studies; broader generalization is not yet warranted. Key hurdles – such as limited T-cell trafficking/infiltration, antigen heterogeneity, on-target/off-tumor toxicity, and an immunosuppressive microenvironment – persist and temper expectations. Accordingly, we present the CLDN18.2 gastric cancer program as an illustrative case rather than generalizable evidence of solid-tumor efficacy. On a broader scale, the advancements in CAR-T therapy have not only injected new momentum into China’s biopharmaceutical sector but have also strengthened the global competitiveness of precision medicine and immunotherapy. With continuous technological advancements, CAR-T holds the promise of revolutionizing cancer treatment, particularly for cancers traditionally resistant to conventional therapies[7]. Future evidence should prioritize multicenter, randomized or well-controlled comparative trials with harmonized endpoints (e.g., PFS/OS, organ-specific toxicity, and quality-of-life), and predefined biomarker strategies to clarify patient selection and treatment sequencing. Clinically, patient selection should prioritize confirmed, high-density and relatively homogeneous target-antigen expression, adequate performance status and organ function, and manageable tumor burden; dynamic biomarkers such as early changes in circulating tumor DNA and imaging/functional response may help guide on-treatment decisions. From a sequencing standpoint, CAR-T may be positioned after failure of standard systemic options or as consolidation following maximal cytoreduction; integration with surgery, radiotherapy, and immunotherapy requires predefined washout intervals and coordinated monitoring for CRS/ICANS to ensure perioperative safety. These peri-operative considerations align with emerging surgical-oncology frameworks advocating rational integration of cellular immunotherapy following maximal cytoreduction to eradicate minimal residual disease (MRD) and reduce recurrence risk[8]. Limitations: This landscape analysis relies on a single proprietary source (INFORMA). Although we cross-validated key fields where feasible, coverage and refresh cadence may differ from primary registries (e.g., ClinicalTrials.gov, ChiCTR, CTR), introducing potential capture bias and registration lag (under-ascertainment of very recent or region-specific trials). Multi-registry postings may not be perfectly harmonized despite de-duplication rules, and geographic attribution (recruiting countries vs sponsor location) may cause misclassification. Accordingly, our findings should be interpreted as a descriptive characterization of registered activity rather than an exhaustive census or an inferential assessment of clinical efficacy. This research enhances our understanding of the evolving CAR-T landscape and its potential to provide novel therapeutic options. However, to fully realize its potential, CAR-T therapy requires more rigorous clinical trials and long-term assessments to ensure its safety and efficacy, which will ultimately benefit patients and drive continued progress in cancer treatment. In conclusion, our study provides a unique and detailed global overview of CAR-T clinical trial trends, highlighting the growing focus on Phase II and III trials, especially in the post-2023 period. It also offers a geographical analysis of CAR-T trials, identifying the United States and China as leaders in this research. In addition to expanding on CAR-T’s role in hematologic cancers, we emphasize its evolving application in solid tumors, despite the challenges it faces. Our research identifies key gaps in CAR-T’s application, especially in combination therapies and the treatment of solid tumors, offering directions for future studies. By addressing these gaps, we contribute to a deeper understanding of CAR-T therapy’s potential, offering valuable insights for clinicians and researchers to guide future trials and innovations in the field.