A bibliometric and knowledge-map study of CAR-T cell-related cytokine release syndrome (CRS) from 2012 to 2023

ABSTRACT

CAR-T cell therapy has demonstrated efficacy in treating certain hematological malignancies. However, the administration of CAR-T cells is accompanied by the occurrence of adverse events. Among these, cytokine release syndrome (CRS) has garnered significant attention. In this descriptive study, we set the search criteria to retrieve and obtain articles regarding CAR-T cell-related CRS from the Web of Science Core Collection (WoSCC). The bibliometric and knowledge-map analysis of these documents was conducted using Microsoft Excel 2019, GraphPad Prism 8, CtieSpace, and VOSviewer. 6,623 authors from 295 institutions in 49 countries coauthored a total of 1,001 publications. The leading country in this field was the United States. The most productive institution was the University of Pennsylvania. Carl H. June had the most citations, while Daniel W. Lee had the most co-citations. Research hotspots primarily concentrated on the pathogenesis, serum biomarkers, management, and therapeutic drugs of CRS, alongside neurotoxicity. Emerging topics within this discipline encompassed the following: a. Drugs for effective treatment and intervention of CRS; b. Conducting pertinent clinical trials to acquire real-world data; c. Management of toxicity (CRS and neurotoxicity) associated with CAR-T cell therapy; d. The study of BCMA-CAR-T cells in multiple myeloma (MM); e. Optimizing the CAR framework structure to enhance the effectiveness and safety of CAR-T cells. A bibliometric and scientific knowledge-map analysis provided a unique and objective perspective for exploring the field of CAR-T cell-related CRS, and may provide some new clues and valuable references for researchers.

KEYWORDS:

• CAR-T cells
• CRS
• research hotspots
• emerging trends
• bibliometric

Introduction

The ultimate goal of CAR-T cell therapy is to apply it to clinical treatment. Therefore, the efficacy and safety are important parameters to evaluate this treatment. Evidence has demonstrated its remarkable effectiveness in managing certain hematological malignancies. Nevertheless, adverse events can occur during the process of receiving CAR-T cells,^1–3 such as CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), and hematological toxicity. In some cases, these adverse events can be severe and potentially life-threatening. Researchers have made a lot of efforts to improve the anti-tumor effect of CAR-T cells and reduce their adverse events. These measures include finding tumor-specific antigens (TSAs) as targets,⁴ optimizing the structure of CARs (e.g., synNotch CARs^5,6 and ON/OFF-switch CARs^7,8), constructing special CARs (e.g., CARs that need special light⁹ or ultrasound¹⁰ to be activated), adding suicide genes,¹¹ and designing CD8α hinge and/or transmembrane domain with the best length.^12,13

A better understanding of the underlying mechanism of CAR-T cell-related adverse events contributes to effective prevention and treatment. In recent years, numerous scholars have conducted in-depth research and summary on the diagnosis, mechanism and management of these adverse events from multifaceted perspectives.^1,3,14 CRS has garnered significant attention as the most prevalent adverse event.^15,16 It is a super physiological reaction caused by excessive release of cytokines in the body.¹⁷ The primary clinical presentations encompass fever, fatigue, headache, and joint pain. In more severe cases, hypotension, shock, capillary leakage, and multiple organ dysfunction syndrome (MODS) may transpire, posing a potential threat to life.^17,18 Presently, the relevant mechanism of CRS remains unclear. A multitude of investigations have been conducted to explore various facets of CRS, including pathogenesis, prediction, diagnosis, classification, and management.^19–24

The study of CAR-T cells has emerged as a hot field in recent years.²⁵ The study and new knowledge of CAR-T cell-related CRS are also increasing rapidly. Bibliometrics can not only reflect the development trends and research hotspots in various fields, but also help researchers to obtain important information in a certain field by comprehensively and systematically analyzing the scientific literature in the field.^26,27 Bibliometric analysis plays a crucial role in academia by facilitating various aspects of research. Firstly, it aids researchers in identifying research hotspots, frontier directions, and development trends within a specific field. This enables researchers to gain a comprehensive understanding of the research direction, avoid redundant work, and enhance research efficiency. Secondly, it serves as a tool for evaluating the quality and impact of research outcomes. Thirdly, it enables researchers to explore potential collaboration opportunities, partners, and institutions through the author cooperation network. Lastly, it provides a solid foundation and support for scientific research planning and decision-making processes. Currently, This field lacks bibliometric studies. This paper was the first to use a combination of bibliometrics and knowledge-map to analyze articles in this field. It aims to explore and seek the research overview, development trends, research hotspots, and new topics in this field.

Materials and methods

Data collection

The pertinent data was obtained and downloaded from WoSCC. The search strategy, inclusion, and exclusion criteria of this study are obtained in Annexes 1. A total of 1001 eligible articles were identified.

Data analysis and visualization

CiteSpace provides a test platform to study new ideas and compare existing approaches.²⁸ VOSviewer is a software for bibliometric mapping, which pays more attention to the visualization of scientific knowledge.²⁹ GraphPad Prism 8 and Microsoft Excel 2019 were used for data management and analysis. Furthermore, CiteSpace (version 6.2.R4) and VOSviewer (version 1.6.17) were used for bibliometric and visual analyses. Two researchers independently analyzed and extracted the required data.

Results

The annual growth trend of publication outputs

Based on the aforementioned retrieval strategy, 1001 related articles were identified. The number of articles published each year reflects the development trend of the field. Figure 1 shows that the number of articles and citations in this field is increasing annually. From 2012 to 2015, publication output was extremely low and almost stagnant. There were only 16 papers (accounting for 1.60%) in this stage. From 2016 to 2018, the number of publications showed a slowly increasing trend. Publications increased rapidly from 2019 to 2022. In this period, 707 papers (70.63%) were published. By August 25, 2023, 165 articles (16.48%) had been published. Only nine months of articles could be counted in 2023, so the current volume of publications was lower than in 2022. These articles were cited 67,374 times, with an average of 67.31 citations per paper. The H-index of these publications was 106. Based on the fitting equation (y = 22.56*x − 45423, correlation coefficient R² = 0.8067) derived from the annual publication data, it is projected that the publication volume in 2023 will exceed that of 2022.

Figure 1. The growth trend and citation trend of publications related to CAR-T cell-related CRS.

Note: It shows the number of publications and the total number of citations per year. The fitting equation Y = 22.56*X 45,423 is constructed based on the annual publication data, and the correlation coefficient R² = 0.8067, p < .0001.

Countries/regions and institutions

1001 articles were coauthored by 295 institutions from 49 countries (one paper may be completed by several countries or organizations, so it will be counted more than once). According to Table 1, the country with the most publications was the United States (n = 521, accounting for 35.06%), far exceeding other countries, followed by China (n = 336, 22.61%) and Germany (n = 73, 4.91%). Centrality refers to the intermediary role of a node in information transmission between other nodes. The higher the centrality of a node, the more important the node plays in information transmission. France, Italy, and Canada had a relatively high centrality of 0.46, 0.45, and 0.36, respectively. It is suggested that these countries have a strong bridge role in this field. The most productive institution was the University of Pennsylvania (n = 98, 2.85%). Notably, the top 10 institutions were all from the United States. Figure 2a illustrates the limited connections between the United States and China with other nations. Conversely, Austria has exhibited greater cooperation with certain countries over the preceding two years. In Figure 2b, it is evident that despite the close collaboration among numerous institutions, overall cooperation has been scarce during the aforementioned period.

Figure 2. The co-occurrence map of countries (a) and institutions (b) in the CAR-T cell-related CRS field.

Note: The larger the circle, the greater the publication volume of the country or institution in the field. The countries or institutions in the figure are arranged according to the size of the publication volume. Besides, the thicker the line, the closer the cooperation.

Table 1. The top 10 countries and institutions involved in CAR-T cell-related CRS.

Rank	Country	Counts	Centrality	Institution	Counts	Centrality
1	USA	521 (35.06%)	0.23	University of Pennsylvania (USA)	98 (2.85%)	0.01
2	CHINA	336 (22.61%)	0	Pennsylvania Medicine (USA)	89 (2.59%)	0
3	GERMANY	73 (4.91%)	0.28	University of Texas System (USA)	88 (2.56%)	0.28
4	FRANCE	64 (4.31%)	0.46	Harvard University (USA)	87 (2.53%)	0.01
5	ITALY	63 (4.24%)	0.45	Memorial Sloan Kettering Cancer Center (USA)	81 (2.35%)	0.07
6	UK	58 (3.90%)	0.04	UTMD Anderson Cancer Center (USA)	75 (2.18%)	0.19
7	SPAIN	48 (3.23%)	0.01	H Lee Moffitt Cancer Center & Research Institute (USA)	54 (1.57%)	0.12
8	CANADA	40 (2.69%)	0.36	Dana-Farber Cancer Institute (USA)	52 (1.51%)	0.02
9	JAPAN	39 (2.62%)	0.18	Fred Hutchinson Cancer Center (USA)	50 (1.45%)	0
10	SWITZERLAND	30 (2.02%)	0.12	Massachusetts General Hospital (USA)	49 (1.42%)	0

Journals and co-cited journals

1001 articles were published in 303 academic journals. The most cited journal was the New England Journal of Medicine (n = 19950), far more than any other journal, followed by Blood (n = 4894) and Journal of Clinical Oncology (n = 4234) (Table 2). 80% of the top 10 journals were in the Q1 Journal Citation Reports (JCR) section, with the New England Journal of Medicine (IF = 158.499) having the highest impact factor. The journal with the most publications was Frontier in Immunology (n = 45, 4.5%), followed by Blood (n = 38, 3.8%) and Journal for Immunotherapy of Cancer (n = 37, 3.7%). 8 journals had over 20 publications. The density map of the publication volume of these journals is shown in Figure 3a. Through it, we can find all the journals with more than five articles published, which provides convenience for selecting journals.

Figure 3. The density map of journals (a) and co-cited journals (b) in the CAR-T cell-related CRS field.

Note: Figure A shows journals with a number of publications ≥ 5; Figure B shows the journals with citations ≥ 120. The darker the color, the more articles the journal has published in the field.

Table 2. The top 10 journals and co-cited journals related to CAR-T cell-related CRS.

Rank	Journal	Citations	Counts	IF（2022）	JCR（2022）	Co-cited journal	Co-Citations	IF（2022）	JCR（2022）
1	New England Journal of Medicine	19950	18	158.499	Q1	Blood	4991	20.30	Q1
2	Blood	4894	38	20.30	Q1	New England Journal of Medicine	3077	158.499	Q1
3	Journal of Clinical Oncology	4234	25	45.301	Q1	Journal of Clinical Oncology	1838	45.301	Q1
4	Nature Medicine	2951	18	82.899	Q1	Biology of Blood and Marrow Transplantation	909	4.30	Q1
5	Blood Advances	1218	34	7.50	Q1	Nature Medicine	894	82.899	Q1
6	Clinical Cancer Research	990	22	11.50	Q1	Science Translational Medicine	870	17.10	Q1
7	Journal for Immunotherapy of Cancer	689	37	10.90	Q1	Cancer Discovery	739	28.20	Q1
8	Frontiers in Immunology	522	45	7.30	Q1	Blood Advances	694	7.50	Q1
9	Frontiers in Oncology	353	31	4.70	Q2	Lancet	693	168.902	Q1
10	Transplantation and Cellular Therapy	141	29	3.20	Q2	Leukemia	654	11.40	Q1

When two (or more) journals are cited by one or more papers simultaneously, they are considered to have a co-citation relationship. The most co-cited journal was Blood (n= 4991), followed by the New England Journal of Medicine (n = 3077) and Journal of Clinical Oncology (n = 1838). All three journals have been cited more than 1,000 times (Table 2). The density map of the co-cited amount of these journals is shown in Figure 3b. Through it, we can quickly find high-impact journals in this field. To determine the distribution of academic journals in this field, we constructed the dual-map overlay of journals (Figure 4).³⁰

Figure 4. The dual-map overlay of journals on CAR-T cell-related CRS.

Note: Image parameter: a: 3; Source Circle Size: 80; Target Circle Size: 8; Snap to centroids (< Radius): 0. It shows the three major reference paths (two green paths and one orange path), representing three cited relationships. It indicates that the papers published in “Molecular/Biology/Genetics” journals and “Health/Nursing/Medicine” journals were often cited by the papers published in “Medicine/Medical/Clinical” journals. Moreover, the papers published in “Molecular/Biology/Genetics” journals were often cited by papers published in “Molecular/Biology/Immunology” journals.

Authors and co-cited authors

A total of 6623 authors participated in the publication of these articles. As shown in Table 3, Carl H. June (n = 11151) was cited the most, followed by Bruce L. Levine (n = 10473) and Stephan A. Grupp (n = 9960). He Huang (n = 30) published the most articles. Include the authors who have contributed to a minimum of five scholarly articles, thereby establishing a cooperative network of these authors (Figure 5). It shows that many researchers formed different collaborative groups.

Figure 5. The visualization map of authors (a) co-cited authors (b) involved in CAR-T cell-related CRS.

Note: Minimum number of documents of an author ≥ 5; Minimum number of citations of an author ≥ 40.

Table 3. The top 10 authors and co-cited authors of CAR-T cell-related CRS research.

Rank	Author	Citations	Counts	Rank	Co-cited author	Co-citations
1	Carl H. June	11151	20	1	Daniel W. Lee	1016
2	Bruce L. Levine	10473	14	2	Shannon L. Maude	844
3	Stephan A. Grupp	9960	22	3	Sattva S. Neelapu	758
4	David L. Porter	9035	15	4	Stephen J. Schuster	509
5	Simon F. Lacey	8192	14	5	James N. Kochenderfer	452
6	Jan J. Melenhorst	6796	6	6	Jennifer N. Brudno,	425
7	David T. Teachey	6732	8	7	Frederick L. Locke	395
8	Cameron J. Turtle	6155	19	8	Cameron J. Turtle	371
9	Susan R. Rheingold	6104	5	9	Jae H. Park	299
10	Daniel. Li	5663	10	10	Kevin A. Hay	266

If different authors are cited in one or more papers, these authors are called co-cited authors. The most co-cited author was Daniel W. Lee (n = 1016), followed by Shannon L. Maude (n = 844) and Sattva S. Neelapu (n = 758) (Table 3). The researchers who had been cited together at a minimum of 40 instances were combined, resulting in the creation of a network that shows their co-citation relationships. The co-citation network diagram of co-cited authors and their co-citation relationships is presented in Figure 5b.

Keyword co-occurrence, clusters, and evolution

Keywords reflect the research focus and direction of a paper. To ensure accuracy and relevance, the collected keywords underwent a series of procedures, such as merging synonymous terms and eliminating insignificant ones. Ultimately, we obtained 2429 keywords. Table 4 shows the top 20 keywords, all of which appeared more than 60 times. The most frequent keywords were CRS (n = 378), followed by CAR-T (n = 322) and immunotherapy (n = 199). A density map of keywords was constructed (Figure 6a).

Figure 6. The co-occurrence density map (a) and network (b) of keywords involved in CAR-T cell-related CRS.

Note: The darker the color, the more times the keyword appears.

The larger the circle, the more the papers are published by the author. The lines between circles represent the cooperative relationship between authors. Circles and lines of the same color form a cluster, representing a group.

Table 4. Top 20 keywords related to CAR-T cell-related CRS.

Rank	Keyword	Count	Rank	Keyword	Count
1	CRS	378	11	children	102
2	CAR-T	322	12	adults	88
3	immunotherapy	199	13	outcomes	87
4	management	185	14	cancer	86
5	CAR	172	15	lymphoma	80
6	remissions	124	16	transplantation	80
7	acute lymphoblastic-leukemia	112	17	efficacy	71
8	cd19	107	18	biomarkers	65
9	ICANS	107	19	activation	64
10	b-cell	106	20	expression	64

The network clustering analysis of the keywords revealed 4 clusters, which represented 4 research scopes. As shown in Figure 6b, the largest cluster was cluster 1 (red), followed by clusters 2 (green), 3 (blue), and 4 (yellow). Cluster 1 had 20 keywords, including immunotherapy, CAR, adoptive cell therapy, cancer, hematologic malignancies, leukemia, lymphoma, antitumor-activity, and checkpoint inhibitors. Cluster 2 had 19 keywords, including CAR-T, outcomes, efficacy, survival, safety, transplantation, diffuse large B-cell lymphoma, non-Hodgkin lymphoma, multiple myeloma, BCMA, and rituximab. Cluster 3 had 11 keywords, including CRS, ICANS, toxicity, management, biomarkers, cytokines, IL-6, tisagenlecleucel, axi-cel, and tocilizumab. Cluster 4 had 10 keywords, including acute lymphoblastic leukemia (ALL), CD19, blinatumomab, minimal residual disease, children, adults, and chemotherapy.

The timeline viewer of keywords can cluster the keywords in chronological order. It can display the year when a keyword in a certain research field first appeared, and help to track the evolution of the keyword. The evolution track, important topics, and research hotspots in each stage of the field are shown in Figure 7.

Figure 7. The timeline viewer of keywords involved in CAR-T cell-related CRS.

Note: Minimum number of occurrences of keywords ≥ 5.

Co-cited references and reference burst

When two (or more) references are cited by one or more references simultaneously, they establish a co-citation relationship. The function of co-cited literature is to help researchers better understand the development trend, research direction, and discover new research hotspots in the subject field. It can also help researchers evaluate the importance of literature and help screen literature. Table 5 shows the top 10 most co-cited articles in this field. These articles were co-cited more than 100 times, with the top 3 references co-cited over 300 times. The most co-cited article was published by Neelapu et al.³¹ in 2017, with 334 citations. Notably, 40% of the top 10 most co-cited articles were from the New England Journal of Medicine.

Table 5. The top 10 co-cited articles related to CAR-T cell-related CRS.

Top 10 co-cited articles related to CAR-T cell-related CRS
Rank	Author	Title	Journal	Year	Citation	Centrality
1	Sattva S Neelapu et al.^Citation31	Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma	N Engl J Med	2017	334	0.04
2	Shannon L Maude et al.^Citation32	Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia	N Engl J Med	2018	329	0.08
3	Stephen J Schuster et al.^Citation33	Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma	N Engl J Med	2019	306	0.03
4	Jae H Park et al.^Citation34	Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia	N Engl J Med	2018	199	0.04
5	Frederick L Locke et al.^Citation35	Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial	Lancet Oncol	2019	193	0.04
6	Kevin A Hay et al.^Citation36	Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy	Blood	2017	157	0.05
7	Juliane Gust et al.^Citation37	Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells	Cancer Discov	2017	148	0.1
8	Daniel W Lee et al.^Citation38	T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukemia in children and young adults: a phase 1 dose-escalation trial	Lancet	2015	142	0.07
9	Margherita Norelli et al.^Citation39	Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells	Nat Med	2018	138	0.04
10	Cameron J Turtle et al.^Citation40	CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients	J Clin Invest	2016	138	0.03

78 references with the strongest citation bursts were identified by CiteSpace. Figure 8 shows the top 50 among them. The number one reference was “Chimeric antigen receptor T cells for sustained remissions in leukemia⁴¹” (strength: 59.78). These 50 papers were published between 2013 and 2023, and 19 of them (38%) were published between 2018 and 2023. Currently, there are still eight papers in the state of citation burst.

Figure 8. The top 50 references with the strongest citation bursts involved in CAR-T cell-related CRS.

Notes: The blue bars mean the reference has been published; the red bars mean citation burstiness.

Discussion

General information

The statistical number of annual publications can reflect the development trend of a certain field. The number of papers related to this field is increasing annually. Very few papers were published during the stagnation period. It was primarily because CAR-T technology was still in its infancy at this time, attracting less attention. The number of publications increased slowly during the slow growth period, indicating that the field has begun to attract attention from scientists. The effectiveness of CAR-T cells is a crucial parameter for evaluation, and the assessment of their safety and toxicity are equally significant indicators that warrant attention. As the therapy has been extensively investigated, certain adverse events have gradually surfaced, garnering significant attention. Since 2016, there have been more and more articles in this field, indicating that it is becoming a research hotspot. The fitting model of the annual publication volume we constructed suggests that this research field will continue to receive substantial attention in the future.

Our research found that, at the national level, there has been little new cooperation between countries other than Austria during the last two years. Similarly, at the institutional level, there is a lack of new cooperation among institutions. Generally, there has been a lack of close cooperation between countries or institutions in recent years. We consider that this may be because there are still some barriers to cooperation in this field, and relevant information and technology cannot be well shared. We call for strengthening communication and cooperation to better promote the development of this field and benefit more patients.

Despite publishing only 18 articles, the New England Journal of Medicine has been cited the most, far exceeding any other journal. The main reason is that most of these articles published in this journal are clinical experimental articles, which have very high clinical guidance and reference value. Currently, some relevant clinical trial data are continuously generated, and it is believed that there will be more high-quality literature published in the future. Figure 4 implies that research related to this field is currently focused on basic research and clinical transformation. Our analysis identified Carl H. June as the most-cited author, Daniel W. Lee as the most-co-cited author, and He Huang as the most-published author. By searching and reading the relevant papers of these authors, we can quickly understand the research hotspots, the research directions, and the research degree in this field.

Knowledge base

Co-citation means that two (or more) papers are cited by one or more papers.⁴² It can measure the relationship between papers. This study included 10 articles with the most co-citations in the field^31–40 (Table 5).

By analyzing these articles, we found that these articles mainly focused on the research of CAR-T cell therapy in hematological malignancies. Although CAR-T cell research in solid tumors has developed rapidly in recent years, the clinical practice information provided by CAR-T cell research in hematological malignancies still has extremely important guidance and reference value. The main reason is that the curative effect of CAR-T cell therapy in the treatment of hematological malignancies has been widely recognized, whereas its effectiveness in treating solid tumors remains unsatisfactory,⁴³ and the absence of large-scale clinical trials is evident.

Neelapu et al.³¹ published an important study in 2017. In this multicenter phase 2 clinical trial, 101 patients with refractory large B-cell lymphoma received axicabtagene ciloleucel (axi-cel, CD19-CAR-T cells), and achieved substantial clinical benefits. The results showed that the objective remission rate was 82% and the complete remission rate was 54%. The incidence of total adverse events was 100%, and the common adverse events included myelosuppression (neutropenia (84%), anemia (66%), and thrombocytopenia (58%)), CRS (93%), and ICANS (64%). Furthermore, this study explored CRS-related serum biomarkers, including IL-6, IL-10, IL-15, and IL-2 Rα. Another five studies^32,35,38 focused on investigating the application of CD19-CAR-T cell therapy in hematological malignancies, encompassing the assessment of its efficacy, adverse events, and safety. These studies have yielded significant clinical trial data of utmost importance. Two studies^31,40 explored serum biomarkers (for diagnosis and prediction) related to CRS and neurotoxicity. One study³⁶ discussed the kinetics, independent predictors, and predictive biomarkers of severe CRS (sCRS) after CD19-CAR-T cell therapy. These biomarkers included IFN-γ, IL-6, IL-8, IL-10, IL-15, MCP-1 and TNFRp55. Additionally, angiopoietin-2 and von Willebrand factor (VWF) were identified as biomarkers of endothelial activation. Neurotoxicity following CD19 CAR-T cells was detailed clinically, radiologically, and pathologically (endothelial activation and vascular disruption) in one study,³⁷ and the risk factors were identified. In another study,⁴⁰ researchers found that CRS was prevented by depletion of monocytes or blocking IL-6 receptors with tocilizumab; Anakinra, an IL-1 receptor blocker, could alleviate both CRS and neurotoxicity.

Generally, these 10 articles represent the most popular research topics, and the research scope mainly focuses on the following aspects:

1. Research on CAR-T cells in the treatment of hematological malignancies, including evaluation of efficacy, adverse events, and safety;

2. Studies on serum biomarkers related to CRS, neurotoxicity, and sCRS, such as IL-6, IL-8, IL-10, IL-15, IL-2 Rα, IFNγ, sgp130, sIL6R, ferritin, CRP, MCP-1 (sCRS; sensitivity, 100%; specificity, 95%) and TNFRp55;

3. Pathogenesis and diagnosis associated with CRS and neurotoxicity.

4. Drugs for CAR-T cell-related CRS and neurotoxicity;

5. Studies on the long-term follow-up and long-term toxicity of CD19-CAR-T cell therapy for patients with hematological malignancies.

Currently, the primary areas of research that garner significant attention in this domain encompass the aforementioned five facets. These perspectives are substantiated by recent pertinent literature.^44–51 Serious adverse events hinder the wide clinical application of this therapy. It is inevitable that the toxic reaction will occur when CAR-T cells exert anti-tumor effects for various reasons, such as the specificity of the target and the structure of the cells.² Before the conquest of CRS, the primary focus of forthcoming research in this field continued to revolve around the efficient prevention of CRS, hindering its advancement, alleviating its adverse consequences, and improving its prognosis. With the advancement of related clinical experiments, more and more important clinical data will be published in the future, which will help us to further clarify and conquer CRS.

Hotspot evolution, knowledge structure, and emerging topics

According to the richness of keywords and the frequency of each keyword (Figure 7), the period from 2008 to 2022 can be divided into three stages, namely, 2012–2013, 2013–2019, and 2019–2023. During the second stage, the most keywords appeared, followed by the third stage. In the first stage, there were the fewest keywords. This is because, during this period, the CAR-T cell-related CRS field received little attention. Most keywords, especially the top 20 keywords all appeared in the second stage, suggesting that this field has begun to receive widespread attention. At this stage, the mechanism of CRS and improving the safety of CAR-T cells are important research topics. Furthermore, cluster # 3 shows that researchers have been paying attention to the adverse events of this therapy since 2012. As can be seen from cluster # 2, this research field has received extensive attention since 2014, and its related treatment, management, biomarkers, and ICANS have gradually become important research topics in various stages with the progress of time.

The representative keywords include CRS, CAR-T, immunotherapy, CAR, CD19, cancer, ALL, lymphoma, ICANS, biomarkers, management, remissions, outcomes, and efficacy (Table 4). Based on these representative keywords, the key aspects of this field can be summarized as follows:¹ As anti-tumor immunotherapy, CAR-T cell therapy is mainly used in the treatment of hematological malignancies, with CD 19 as the most commonly used target^2–52–55 the diagnosis (serum biomarkers) and management of CRS and ICANS are research hotspots;^56–58 and³ the efficacy and safety of CAR-T cells are research priorities.^59–61

The network clustering analysis of the keywords identified four clusters (Figure 6b). Cluster 1 keywords are mainly about the research of CAR-T cells in malignant tumors. Cluster 2 keywords are about the research on CAR-T cells in hematological malignancies, including curative effect, safety, and prognosis. Cluster 3 keywords are mainly about the pathogenesis, diagnosis, management, and treatment of CAR-T cell-related adverse events. Cluster 4 keywords are related to research on the treatment of ALL, including CD19-CAR-T cell therapy, targeted therapy,^62–65 and chemotherapy.

References with strong citation bursts refer to a sudden increase in the number of citations for some references within a given period of time. Analysis of such references can reveal emerging topics for a given field.⁶⁶ By analyzing these articles in this study, we found that these articles were frequently cited within 10 years and 5 years. Furthermore, 8 articles remain in citation burst status. All this means that this area may continue to receive attention in the future. We ranked the eight articles according to the citation burst intensity (Table 6). They may represent the emerging topics that have received much attention in this field.

Table 6. The references (in the state of citation burstness) related to CAR-T cell related CRS.

NO.	Year	Author	Article Type	Targets	Associated Tumor	Title	Strength
1	2019	Rebecca A Gardner et al.^Citation67	Article	CD19	B-cell acute lymphoblastic leukemia (B-ALL)	Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy	8.94
2	2020	Loretta J Nastoupil et al.^Citation68	Article	CD19	Relapsed/refractory large B-cell lymphoma (LBCL)	Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium	8.59
3	2019	Sattva S Neelapu et al.^Citation69	Review			Managing the toxicities of CAR T-cell therapy	5.78
4	2019	Jie Xu et al.^Citation70	Article	B-cell maturation antigen (BCMA)	Relapsed and refractory multiple myeloma (MM)	Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma	5.78
5	2020	Marcelo C Pasquini et al.^Citation71	Article	CD19	pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma	Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma	5.43
6	2019	Kevin J Curran et al.^Citation72	Article	CD19	Relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL)	Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL	5.3
7	2020	Caron A Jacobson et al.^Citation73	Article	CD19	relapsed aggressive B-cell non-Hodgkin lymphoma	Axicabtagene Ciloleucel in the Non-Trial Setting: Outcomes and Correlates of Response, Resistance, and Toxicity	5.3
8	2019	Adam D Cohen et al.^Citation74	Article	B-cell maturation antigen (BCMA)	multiple myeloma (MM)	B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma	5.02

Through the analysis and summary of eight articles^67–74 that are in an explosive state, we can learn about the current emerging topics related to this field:

1. Drugs for effective treatment and intervention of CRS;⁶⁷

2. To explore and analyze the efficacy, toxicity, safety, prognosis, and drug resistance mechanism of CD19-CAR-T cells in hematological malignancies through real-world evidence;^68,71–73

3. Management of toxicity (CRS and neurotoxicity) associated with CAR-T cell therapy;⁶⁹

4. The study of BCMA-CAR-T cells in multiple myeloma (MM);^70,74

5. Optimizing the CAR framework structure to enhance the effectiveness and safety of CAR-T cells.⁷⁰

Despite the fact that glucocorticoids, tocilizumab, and anakinra can be used for the prevention and treatment of CRS, they cannot completely eliminate the occurrence of CRS or block its progress.⁴⁴ Consequently, the development of specific drugs remains important. According to recent research, researchers have also employed other strategies. Gong et al.⁷⁵ PEGylated CAR-T cells and attached a layer of spacer to their surfaces. As CAR-T cells proliferated in vivo, this attachment gradually decreased, and CAR-T cells gradually recovered their antitumor effect, which can alleviate the symptoms related to CRS. Li et al.⁷⁶ reduced the incidence of CRS by subcutaneous injection of hydrogel that can adsorb IL-6. Relevant large-scale clinical trials have provided us with real and reliable clinical data, which is of great significance in exploring the efficacy, toxicity, safety, and prognosis of CAR-T cell therapy. Furthermore, these clinical trials will continue to generate new data in the future, which will play an important role in promoting the development of this field. Although neurotoxicity is often discussed with CRS, it is now being paid attention to as a separate topic.^77,78 BCMA is an important therapeutic target for MM. The study of BCMA-CAR-T cells in MM has emerged as a prominent area of research. Recently, the latest related research results have been published.^79–82 Besides finding new targets, optimizing and improving the structure of CAR-T cells to further enhance their anti-tumor effects and safety of CAR-T cells is also a research hotspot.⁸³

With the research and application of CAR-T cells in malignant tumors, its efficacy and prospects have been recognized and affirmed by more and more researchers. As a new type of tumor immunotherapy, its ultimate goal is to be applied to clinical treatment. Thus, while further improving the anti-tumor effect of CAR-T cells, minimizing its toxic reaction is still the research focus. CRS, as one of the most common adverse events of CAR-T cells, has undoubtedly become a research hotspot in this field. It is necessary to have a further and more comprehensive understanding of CAR-T cell-related CRS, which will help researchers overcome it.

Limitations

As a bibliometric analysis, the data used were all from the WoSCC database. For more comprehensive analyses, we obtained all relevant literature as much as possible. However, this study has some limitations. First of all, although the WoSCC database contains most literature, a few kinds of literature are not contained in it. Second, the quality of the collected literature was uneven, which may have led to a certain degree of bias in the analysis.

Conclusion

To our knowledge, this is the first bibliometric analysis of CAR-T cell-associated CRS. Research hotspots primarily concentrated on the pathogenesis, serum biomarkers, management, and therapeutic drugs of CRS, alongside neurotoxicity. Emerging topics within this discipline encompassed the following: a. Drugs for effective treatment and intervention of CRS; b. Conducting pertinent clinical trials to acquire real-world data; c. Management of toxicity (CRS and neurotoxicity) associated with CAR-T cell therapy; d. The study of BCMA-CAR-T cells in multiple myeloma (MM); e. Optimizing the CAR framework structure to enhance the effectiveness and safety of CAR-T cells. In conclusion, this study provides a unique and objective perspective on the field and may provide some new clues and useful references for researchers.

Author contributions

H.L.: Writing-Original draft preparation, manuscript, investigation, and figure preparation. Q.H.: Investigation, figure preparation, manuscript. Y.Z.: Conceptualization, Methodology, Supervision, manuscript. All authors approved the final version of the manuscript and agreed to be accountable for all specs of the work.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2023.2291900

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.