Research trends in CAR-T cell therapy: A comprehensive bibliometric analysis highlighting cardiovascular toxicity and clinical implications.

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1. Introduction

Chimeric antigen receptor T cell (CAR-T) treatment is one of the most recent developments in oncology, providing patients with some cancer types, especially hematologic malignancies, with promising therapeutic choices. [ 1 , 2 ] This treatment offers a targeted approach to eradicate cancerous cells by genetically altering a patient’s T cells to express a receptor exclusive to cancer cells. [ 3 ] Since its approval by the FDA, CAR-T therapy has garnered significant attention, resulting in a substantial body of research dedicated to understanding its mechanisms, efficacy, and safety. [ 4 ]

Despite its therapeutic potential, CAR-T therapy is not without risks. The treatment has been associated with various adverse effects, among which cardiovascular symptoms are of particular concern. [ 5 ] These symptoms can range from mild arrhythmias to severe cardiotoxicity, which can significantly impact patient outcomes and quality of life. [ 6 , 7 ] Understanding the prevalence, underlying mechanisms, and management strategies for these cardiovascular effects is crucial for optimizing CAR-T therapy and ensuring patient safety. [ 8 ]

Given the fast growth of research in this area, a bibliometric analysis can offer useful insights into the current state of knowledge, research trends, and new areas of interest. Bibliometric studies look at the numbers in academic literature, such as the number of publications, citations, and collaboration networks, to pinpoint important studies, leading authors, and main research topics. [ 9 – 13 ] By utilizing bibliometric tools, we can map out the current state of research on CAR-T cell treatment and its cardiovascular consequences, identify knowledge gaps, and identify areas that need additional research. Our analysis also examines the distribution of studies addressing these cardiac implications, thereby highlighting the need for enhanced cardiovascular monitoring and risk stratification in patients undergoing CAR-T treatment.

This study aims to perform a comprehensive bibliometric analysis of the literature on CAR-T cell therapy and cardiovascular complications. We will examine trends in publication volume, citation patterns, and collaborative efforts within this domain. Additionally, we will identify the most influential articles, authors, and institutions contributing to this field.

2. Methods

2.1. Data collection and search strategies

On June 15, 2024, the Web of Science Core Collection and PubMed were used as the primary databases for researching published articles. The Web of Science Core Collection database is notable for its extensive coverage, encompassing over 12,000 reputable journals. [ 14 – 16 ] A search strategy with multiple terms was created, as detailed in Table S1, Supplemental Digital Content, https://links.lww.com/MD/O815 , to enhance the search’s efficiency. Initially, 881 items were retrieved. The selection was then refined to 808 pertinent papers by excluding conference papers, letters, editorials, book chapters, pre-publication papers, duplicates, and studies not aligned with the objectives. Figure 1 illustrates the study selection and methodology.

2.2. Data analysis

All relevant documents were converted into Microsoft Excel 2019 and plain text formats for analysis with VOSviewer, and CiteSpace. VOS viewer is a powerful instrument for scientometric network analysis. It aids in clarifying the connections in the academic literature by visualization and creation of maps based on network data. With the use of co-citation, co-occurrence, citation, and bibliographic coupling relationships, the software creates network diagrams illustrating a variety of academic entities, including publications, journals, authors, research institutions, nations, and keywords.

VOSviewer provides 3 types of visualization maps: network, overlay, and density visualizations, each serving a specific analytical purpose. [ 17 , 18 ] Its foundational concept is co-occurrence clustering, which shows the relatedness of items within the network. This approach identifies correlations of different strengths and directions, enabling the recognition of distinct groups within the data. Although primarily used for bibliometric analyses, VOSviewer can also create various web data maps. Its standout feature is its ability to produce high-quality visual graphics, making it particularly useful for large-scale academic and scientific visual analyses. [ 19 , 20 ]

CiteSpace is a Java-based tool for citation visualization analysis. With the use of advanced data mining, thorough information analysis, and comprehensive knowledge maps, this tool displays the dynamics, distribution patterns, and structure of scientific knowledge. CiteSpace assists in understanding the evolving context of scientific research by providing a visual representation of citation networks, emphasizing important spots and emerging areas. [ 21 , 22 ]

3. Results

3.1. The annual growth trend of publications

Figure 2 illustrates the annual publication and temporal revolution of research, distinguishing between 2 series: the number of publications each year (Series 1) and the cumulative number of publications (Series 2), commencing in 1991.

From 1991 to 2018, the number of publications remained relatively low and stable. However, there was a noticeable increase from 2018 onwards. By 2021, the annual number of publications exceeded 100, indicating a significant rise in research activity.

The cumulative count remained relatively low until 2020 when it began to increase more substantially. This trend accelerated significantly from 2020 onwards, reflecting the cumulative effect of the growing annual publications.

3.2. Countries and institutions

Several papers involving multiple countries have been coauthored in recent years. The USA (n = 372) has emerged as the top contributor regarding the number of publications, followed by China (n = 124) and Germany (n = 62) (Table 1 ). As shown in Figure 3 , the USA also had the highest centrality (0.62), followed by China (0.47) and Germany (0.30). An elevated degree of centrality signifies the importance of these nations’ studies and their crucial function in this domain. Regarding the institutions, Xuzhou Medical University led with the highest number of publications (n = 245) followed by the University of Pennsylvania (n = 217). Memorial Sloan Kettering Cancer Center ranked third (n = 214) (Table 2 ).

3.3. Journals and co-cited journals

The publications were dispersed throughout a total of 266 scholarly journals. The top 10 leading journals in the field were as follows: Frontiers in Immunology (n = 35), Blood (n = 24), Haematologica (n = 22), British Journal of Haematology (n = 22), Blood Advances (n = 20), Journal of Hematology & Oncology (n = 20), Blood Cancer Journal (n = 18), Clinical Lymphoma, Myeloma & Leukemia (n = 16), International Journal of Molecular Sciences (n = 15), and The New England Journal of Medicine (n = 14) (Fig. 4 and Table 3 ).

The journal with the highest number of citations was Lancet Oncology (n = 1397), followed by Journal of Clinical Oncology (n = 612) and Journal of the National Cancer Institute (n = 498). Other highly cited journals included Cancer Immunology Research (n = 441), Biology of Blood and Marrow Transplantation (n = 126), JACC: Cardio Oncology (n = 120), International Journal of Molecular Sciences (n = 90), Journal of the American College of Cardiology (n = 81), European Journal of Cancer (n = 80), and Biomed Research International (n = 66) (Table 3 ).

A total of 1313 co-cited journals were identified. The journal with the highest number of co-citations was New England Journal of Medicine (n = 350), followed by Blood (n = 223) and Journal of the American College of Cardiology (n = 175). Other highly co-cited journals included Journal of Clinical Oncology (n = 170), Circulation (n = 131), Blood and Marrow Transplantation (n = 106), JACC: Cardio Oncology (n = 97), Lancet (n = 84), Journal for Immunotherapy of Cancer (n = 76), Lancet Oncology (n = 68) (Fig. 5 and Table 3 ).

The analysis identified the top 10 journals that were the most central and influential in the field. The journal with the highest centrality score of 0.27 was the Annals of Internal Medicine. The second most central journal was Alimentary Pharmacology & Therapeutics with a score of 0.26. Other prominent journals included Cancer: A Journal for Clinicians and British Journal of Cancer, both with a centrality score of 0.15 (Fig. 6 and Table 3 ).

Citation dynamics are demonstrated via the dual-map overlay, which shows journal relationships. Citing journals are on the left, and cited journals are on the right. Three primary citation paths (2 in green and 1 in yellow) are shown in Figure 7 , which highlights this illustration. The overlay demonstrated the high citation rate of research articles from Health/Nursing/Medicine journals by publications in the Medicine/Medical/Clinical field. Moreover, both Molecular/Biology/Immunology and Medicine/Medical/Clinical publications regularly mentioned research published in Molecular/Biology/Genetics articles.

3.4. Authors and co-cited authors

A total of 4560 authors contributed to the publication of these articles. As shown in Table 4 , each of the top 10 authors has published at least 13 documents. Saad Z. Usmani and Sham Mailankody were the most active authors, each with 17 publications, followed by Sundar Jagannath with 16 publications. Other leading authors include Adam D. Cohen and Hermann Einsele (each with 15 publications), Jiang Cao, Niels W. C. J. van de Donk, and Nina Shah (each with 14 publications), and Zhenyu Li and Kailin Xu (each with 13 publications) (Fig. 8 ).

Authors who are cited in 1 or more follow-up papers are known as co-cited authors. The top 10 co-cited writers were all co-cited more than 30 times (Table 4 ). The most frequently co-cited author was D.W. Lee (78 co-citations), followed by Sattva.S. Neelapu (66 co-citations) and S.L. Maude (63 co-citations). Other co-cited authors included S. Ganatra (62 co-citations), S.J. Schuster (49 co-citations), R.M. Alvi (44 co-citations), S.A. Rosenberg (37 co-citations), B. Lefebvre (35 co-citations), F.L. Locke (35 co-citations), and J.N. Brudno (33 co-citations) (Fig. 9 ).

3.5. Keyword analysis and hotspots

The keywords of an article can indicate its main focus and direction. Therefore, examining these keywords can provide an understanding of the key research areas and their respective trajectories within the field. A total of 1171 keywords were identified. The top keywords are presented in Figure 10 . The keyword “multiple myeloma” was found to be the most frequently used (n = 189), followed by “immunotherapy” (n = 99) and “cytokine release syndrome (CRS)” (n = 50). Other keywords included “BCMA” (n = 46), “CAR-T” (n = 45), “chimeric antigen receptor” (n = 44), “cardiotoxicity” (n = 34), “management” (n = 27), “cardio-oncology” (n = 25), and “myeloma” (n = 24).

The clustered map reveals several key research areas and trends within the field. The clusters are identified by specific keywords or phrases, each representing a focal point in the research. In this study, the largest cluster, labeled “#0 multiple myeloma,” was characterized by a dense network of connections, indicating a high volume of related research. Another significant cluster was “#1 combination therapy,” which showed substantial activity in studies exploring therapeutic combinations. Cluster “#2 CAR T-cell therapy” highlighted an important area of research focused on this specific cancer treatment approach. Cluster “#3 cardiovascular magnetic resonance assessment” reflected studies centered around the use of cardiovascular magnetic resonance imaging (MRI). Cluster “#4 cardiac function” encompassed research on cardiac health and its assessment. The cluster “#5 sustained complete responses” pointed to research on achieving and maintaining complete responses in treatment. Clusters “#6 novel” and “#7 novel molecular target” represented areas focused on new and emerging therapies and targets (Fig. 11 ).

4. Discussion

In recent years, remarkable advancements have been made in immune-based cancer therapies, offering the promising future of long-term remission and even potential cures for cancer patients. [ 23 , 24 ] One such innovative approach, CAR-T based cell adoptive immunotherapy, is rapidly gaining traction as a personalized and targeted immunotherapeutic option in the ongoing battle against various types of tumors. [ 25 , 26 ] However, the COVID-19 pandemic has significantly impacted cancer care. Besides the bidirectional relation between chronic inflammation and malignancies, [ 27 , 28 ] delays in diagnosis and treatment can also have a detrimental effect on patient outcomes and may defer CAT-T cell therapy in patients likely to benefit from curative treatments. [ 29 ] Even while CAR-T cell therapy has made advances, it can still have serious side effects, including immune effector cell-associated neurotoxicity syndrome (ICANS) and CRS, which can be fatal. [ 30 , 31 ]

One of the most notable adverse events is cardiovascular toxicity. Prior research has demonstrated that cardiovascular toxicities associated with immunotherapy represent a substantial risk of morbidity and mortality. As a result, the advancement and broad implementation of CAR-T cell therapy in clinical settings are ultimately limited. [ 32 , 33 ] The specific scope and nature of the cardiovascular toxicities linked to CAR-T cell therapy, however, are still poorly understood despite multiple investigations into this topic. [ 34 – 36 ]

Our study’s results indicate a growing focus on assessing the cardiovascular implications of CAR-T therapy in recent years, as evidenced by an increasing number of publications. The surge in articles, especially after 2018, underscores the expanding interest and rapid progress in this field. This heightened research activity is likely driven by the positive therapeutic outcomes of CAR-T cell therapy in treating blood cancers, coupled with the need to address the associated cardiovascular issues. From 1990 to 2009, the annual number of publications was low, reflecting the early stage of CAR-T cell technology. Between 2009 and 2015, there was a gradual increase in publications, indicating rising interest in this topic. Since 2015, there has been a steady annual increase in the number of articles, signifying a substantial rise in attention to this area.

The surge in the number of publications related to CAR-T therapy after 2018 can be attributed to the growing recognition and acceptance of this innovative treatment approach during that time period. For example, In 2017, the FDA approved 2 CAR-T therapy treatments for the management of advanced or treatment-resistant forms of lymphoma and acute lymphoblastic leukemia. [ 37 ] In 2018, CAR-T therapy for adult relapsed/refractory diffuse large B-cell lymphoma was confirmed. [ 38 ]

According to bibliometric trends, the need for standardized cardiac diagnostic techniques is growing along with the use of CAR-T cell treatments. Advanced imaging techniques, along with biomarkers and novel risk scores, are emerging as promising tools for early detection and management of adverse events. [ 39 – 41 ] Recent studies have used various statistical models for determining the prognosis of cardiovascular issues. [ 42 – 44 ] Furthermore, the improvements in artificial intelligence and machine learning models have deeply enhanced precision medicine in the cardiovascular field improving diagnostic, prognostic, and therapeutic strategies. These inventions emerge as valuable strategies to refine these risk assessments and develop predictive models tailored to this patient population. [ 13 , 45 , 46 ] In order to improve early detection and intervention techniques, future research should seek to evaluate and incorporate these novel approaches into clinical practice.

The United States had the highest number of publications, followed by China and Germany. As the leading contributor to research in CAR-T cell therapy, the United States plays a crucial role in shaping the current understanding and future advancements in this field. The high centrality of the USA in global research networks underscores its pivotal role in fostering international collaborations and disseminating innovative discoveries.

Renowned organizations like the Memorial Sloan Kettering Cancer Center, the University of Pennsylvania, and the National Institutes of Health have been at the forefront of CAR-T cell research. [ 47 ] Furthermore, 5 CAR-T cell treatments have been approved by the Food and Drug Administration (FDA) for commercialization in the US to date. Research in this field has significantly increased in China in the last few decades. [ 48 ] According to our research, developed countries make up the majority of the top countries with the highest publication outputs. The main driving force behind these advancements is the substantial cost needed for CAR-T therapy research and development. [ 49 ] Moreover, CAR-T cell therapy is an expensive treatment method. For instance, the cost of using Kymriah to treat acute lymphocytic leukemia is approximately $475,000. [ 50 ] The high costs associated with research and development, as well as clinical usage, impose limitations on the clinical promotion and implementation of this treatment. Addressing the challenge of reducing these expenses and making CAR-T cell treatment more accessible at a reasonable cost is a complex issue. [ 51 , 52 ]

The cluster analysis revealed that “multiple myeloma” was the largest cluster, characterized by a dense network of connections. This indicates a substantial amount of research focused on multiple myeloma, showcasing significant enthusiasm for developing and enhancing CAR-T cell therapy for this particular blood cancer. Research within this cluster concentrates on understanding the disease’s pathophysiology, therapeutic responses, and long-term outcomes of CAR-T cell therapy in patients with multiple myeloma. [ 53 ] Studies like the CARTITUDE-1 and KarMMa trials have shown that patients with poor prognoses can achieve better outcomes. [ 54 – 57 ]

The “combination therapy” cluster was identified as the second most crucial, focusing on research into various therapeutic combinations. This involves integrating CAR-T cell therapy with other treatments, such as chemotherapy, which improves the tumor environment for CAR-T cells by reducing immunosuppressive cells and promoting inflammation; radiotherapy, which enhances CAR-T effectiveness by causing DNA damage in cancer cells, leading to antigen release and immune activation; immune checkpoint inhibitors, which, when combined with CAR-T cells, have shown promising results, particularly in solid tumors; oncolytic viruses, which, when loaded onto CAR-T cells, have demonstrated synergistic effects in preclinical studies; and immunomodulatory drugs, which enhance CAR-T cell proliferation, persistence, and cytokine production. Research in this area underscores the potential of these combination strategies to increase the effectiveness and longevity of CAR-T cell therapy. [ 58 – 62 ]

The research conducted in the “#3 cardiovascular magnetic resonance assessment” cluster focuses on utilizing cardiovascular MRI to observe and measure the cardiovascular impacts of CAR-T cell treatment. This imaging technique is essential for identifying cardiotoxicity, evaluating heart performance, and providing guidance for therapeutic intervention to reduce cardiovascular risks. [ 63 ]

5. Limitations

Although, to the best of our knowledge, this is the first bibliometric study assessing the cardiac implications of CAR-T therapy, it is important to acknowledge certain limitations. First, our study relied exclusively on data from 2 databases, potentially overlooking relevant papers published elsewhere. Utilizing additional datasets might provide a more comprehensive view of the research landscape. Additionally, bibliometric data can be influenced by intrinsic biases, such as citation practices and publishing delays, which may impact the interpretation of research trends and the assessment of author impact. Moreover, tools like CiteSpace and VOSviewer cannot entirely replace systematic retrieval methods. The grouping of keywords and co-citation networks relies on computational processes, which, while generally reliable, may not accurately represent the complex relationships between study subjects. Our study presents a current snapshot of CAR-T cell therapy research, a field that is continually evolving. Ongoing advancements may alter the patterns and areas of focus we have identified. To overcome these limitations and gain a more comprehensive understanding, future research should incorporate longitudinal analyses and utilize multiple databases.

6. Conclusion

This comprehensive bibliometric analysis has provided a detailed assessment of the research landscape on CAR-T cell therapy and its cardiovascular implications. The study has identified the key countries, authors, journals, and institutions driving the progress in this field, as well as the emerging research hotspots and future directions. Understanding the research landscape and identifying key trends and gaps is important for the scientific community. As CAR-T cell therapy continues to evolve and gain widespread clinical application, the cardiovascular implications of this treatment cannot be overlooked. The findings from this bibliometric study underscore the need for a heightened focus on the cardiac safety and management of patients undergoing CAR-T therapy. By addressing the emerging research areas identified, the scientific community can work towards developing more effective strategies to mitigate the cardiovascular risks associated with CAR-T cell therapy, ultimately improving patient outcomes and quality of life.

Author contributions

Conceptualization: Ehsan Amini-Salehi, Sandeep Samethadka Nayak, Alexis Pudimat.

Data curation: Ashraf Ahmed, Seyedeh Fatemeh Hosseini Jebelli, Azin Alizadeh Asl.

Formal analysis: Ehsan Amini-Salehi, Daniyal Ameen.

Investigation: Ehsan Amini-Salehi, Sandeep Samethadka Nayak, Anthony Loc Nguyen.

Project administration: Ashraf Ahmed, Seyedeh Fatemeh Hosseini Jebelli.

Resources: Sandeep Samethadka Nayak.

Software: Sandeep Samethadka Nayak.

Supervision: Ehsan Amini-Salehi, Sandeep Samethadka Nayak, Anthony Loc Nguyen.

Validation: Daniyal Ameen, Kaveh Hosseini, Anthony Loc Nguyen.

Visualization: Daniyal Ameen, Azin Alizadeh Asl, Amir Nasrollahizadeh.

Writing – original draft: Alexis Pudimat, Amir Nasrollahizadeh, Anthony Loc Nguyen.

Writing – review & editing: Ehsan Amini-Salehi, Daniyal Ameen, Sandeep Samethadka Nayak, Kaveh Hosseini, Seyedeh Fatemeh Hosseini Jebelli, Anthony Loc Nguyen.

Supplementary Material

Abbreviations: BCMA B-cell maturation antigen CAR-T chimeric antigen receptor T cell CRS cytokine release syndrome FDA Food and Drug Administration ICANS immune effector cell-associated neurotoxicity syndrome ICI immune checkpoint inhibitor MRI magnetic resonance imaging

The authors have no funding and conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

Supplemental Digital Content is available for this article.

How to cite this article: Ameen D, Amini-Salehi E, Nayak SS, Ahmed A, Pudimat A, Nasrollahizadeh A, Hosseini K, Hosseini Jebelli SF, Alizadeh Asl A, Nguyen AL. Research trends in CAR-T cell therapy: A comprehensive bibliometric analysis highlighting cardiovascular toxicity and clinical implications. Medicine 2025;104:20(e42314).

Contributor Information

Daniyal Ameen, Email: Daniyal_ameen@hotmail.com.

Sandeep Samethadka Nayak, Email: dr.sandeepnayak@gmail.com.

Ashraf Ahmed, Email: Ashrafo2017@hotmail.com.

Alexis Pudimat, Email: AlexisPudimat@gmail.com.

Amir Nasrollahizadeh, Email: nasrollahi.amir@yahoo.com.

Kaveh Hosseini, Email: Kaveh_hosseini130@yahoo.com.

Seyedeh Fatemeh Hosseini Jebelli, Email: sfhoseini.mail@gmail.com.

Azin Alizadeh Asl, Email: alizadeasl@gmail.com.

Anthony Loc Nguyen, Email: Aln019@health.ucsd.edu.

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