A bibliometric and knowledge-map study on the treatment of hematological malignancies with CAR-T cells from 2012 to 2023

ABSTRACT

Recently, CAR-T cell therapy in hematological malignancies has received extensive attention. The objective of this study is to gain a comprehensive understanding of the current research status, development trends, research hotspots, and emerging topics pertaining to CAR-T cells in the treatment of hematological malignancies. Articles pertaining to CAR-T cell therapy for hematological malignancies from the years 2012 to 2023 were obtained and assessed from the Web of Science Core Collection (WoSCC). A bibliometric approach was employed to conduct a scientific, comprehensive, and objective quantitative analysis, as well as a visual analysis, of this particular research domain. A comprehensive analysis was conducted on a corpus of 3643 articles, which were collaboratively authored by 72 countries and various research institutions. CAR-T cell research in treating hematological malignancies shows an increasing trend each year. Notably, the study identified the countries and institutions displaying the highest level of activity, the journals with the most citations and output, as well as the authors who garnered the highest frequency of citations and co-citations. Furthermore, the analysis successfully identified the research hotspots and highlighted six emerging topics within this domain. This study conducted a comprehensive exploration and analysis of the research status, development trends, research hotspots, and emerging topics about CAR-T cells in the treatment of hematological malignancies from 2012 to 2023. The findings of this study will serve as a valuable reference and guide for researchers seeking to delve deeper into this field and determine the future direction of their research.

KEYWORDS:

• CAR-T cells
• hematological malignancies
• bibliometric
• development trends
• research hotspots
• emerging themes

Introduction

Hematological malignancies refer to malignant tumors that arise from the abnormal proliferation of white blood cells or lymphocytes. Conventional treatment approaches have demonstrated limited effectiveness, necessitating the exploration of novel therapeutic strategies. One such emerging approach is CAR-T cell therapy, which involves the genetic modification of the patient’s own T cells to generate CAR-T cells possessing specific antigen receptors (CAR). The CAR protein comprises an external antigen recognition structure known as a single chain variable fragment (scFv), a transmembrane domain, and an internal signal transduction structure. CAR-T cell therapy has demonstrated significant advancements in the management of hematological malignancies, with notable success observed in the treatment of B-cell acute lymphoblastic leukemia (ALL) and B-cell lymphomas through targeting the CD19 antigen. In addition to CD19 and BCMA, other tumor antigens have garnered attention in the context of CAR-T cell therapy. For instance, the therapeutic potential of CD20 in non-Hodgkin lymphoma using CAR-T cells has been extensively investigated.¹ Similarly, the efficacy of CD22 in the treatment of B-ALL with CAR-T cells has been widely explored.^2,3 Furthermore, novel targets including CD30,⁴ CD33,⁵ CD38,⁶ CD133,⁷ and Siglec-6⁸ have garnered significant interest in recent research.

Despite the promising outcomes of CAR-T cell therapy in the management of hematological malignancies, several obstacles and constraints persist. Notably, treatment-related complications, such as cytokine release syndrome (CRS) and neurotoxicity, pose significant challenges. Additionally, the durability and resistance of CAR-T cells necessitate further enhancement. To surmount these hurdles, researchers are diligently endeavoring to refine CAR-T cell therapy. Several strategies can address these challenges, encompassing the optimization of CAR design to enhance the anti-tumor activity and longevity of CAR-T cells,⁹ the development of novel antigen targets to broaden the applicability of CAR-T cell therapy,¹⁰ and the exploration of combined treatment approaches involving immune checkpoint inhibitors,¹¹ radiotherapy,¹² or chemotherapy¹³ to augment the therapeutic efficacy.

Currently, a substantial quantity of global clinical trials pertaining to CAR-T cell therapy have been conducted. As of December 2023, the American Clinical Trials Database (ClinicalTrials.gov) has documented the registration of 1,509 clinical trials involving CAR-T cell therapy. In recent times, the utilization of CAR-T cell therapy has assumed a significant role in the treatment of hematological malignancies. Bibliometric analysis is a quantitative research methodology that entails the utilization of statistical techniques and analytical tools to examine various aspects of scientific literature. This approach can identify trends in research fields, draw network maps, evaluate research impacts, and extract other relevant information. Furthermore, by conducting extensive statistical and quantitative analyses on a substantial corpus of literature data, bibliometric analysis facilitates the attainment of a comprehensive understanding and an objective evaluation of the research field under investigation.¹⁴ This study aims to employ this research method to carry out scientific, comprehensive, and objective metrological analysis and visual analysis in this field.

Materials and methods

Data collection

Pertinent data were retrieved and downloaded from WoSCC. The search strategy, inclusion, and exclusion criteria for this study are explicated in Annexes 1. A total of 3643 eligible articles were obtained.

Data analysis and visualization

CiteSpace and VOSviewer are the most common bibliometrics software. The former offers an experimental platform conducive to the exploration of novel concepts and the comparison of diverse methodologies.¹⁵ The latter primarily emphasizes the visualization of scientific knowledge and exhibits advantages in handling extensive maps.¹⁶ In data management and analysis, Microsoft Excel 2019 is employed. Additionally, for the purposes of bibliometric analysis and visualized analysis, GraphPad Prism 8, CiteSpace, and VOSviewer are utilized.

Results

Analysis of annual publication volume

Based on the annual publishing volume within this particular field, a growth trend chart has been constructed. Figure 1 illustrates a consistent increase in the annual publishing volume over time. By analyzing the data, the growth trend can be categorized into three distinct stages: a slow stage spanning from 2012 to 2017, a high-speed growth stage from 2018 to 2021, and a stable growth stage from 2022 to 2023. During the second stage, a total of 1627 articles (accounting for 44.7% of the total) were published, while the third stage saw the publication of 1471 articles (representing 40.1% of the total). Currently, only 10 months’ worth of articles from 2023 have been acquired, resulting in a slightly lower publication volume compared to 2022. In conjunction with the developed annual publication quantity fitting equation (y = 70.12*x − 141168, correlation coefficient R² = 0.8784, p ≤.0001) (Figure S1), it is anticipated that the publication volume in 2023 will marginally surpass that of 2022. Despite the current sustained high level of annual publications in this field, growth has decelerated and is projected to reach its peak in the forthcoming years. Furthermore, the 3643 articles garnered a total of 157,925 citations, resulting in an average of 39.74 citations per article. These publications possess an H-index of 172.

Figure 1. Trends in publication production and citation frequency in this research field.

It shows the number of publications per year.

Countries and institutions

The study yielded a total of 3643 articles, which were collaboratively authored by numerous countries and institutions. As depicted in Table 1, the United States emerged as the most prolific publisher in this domain, with a substantial count of 1942 articles, surpassing all other nations by a significant margin. China followed suit with 902 articles, while Germany trailed behind with 446 articles. Interestingly, the number of publications between the first and fourth places shows a multiple relationship, that is, the number of publications from the United States is twice that of China, and so forth. Centrality serves as an index employed for the quantification of node significance within a network. A higher centrality value signifies a more pronounced role of the node in terms of connectivity. At the national level, Finland exhibited the highest centrality measure of 0.84, trailed by Austria at 0.67 and Venezuela at 0.57. The University of Pennsylvania emerged as the most prolific research institution, having published 279 articles, followed by Pennsylvania Medicine (n = 250) and the University of Texas System (n = 250). It is noteworthy that all of the top 10 research institutions are from the United States. In addition, the institutions with the highest centrality were UTMD Anderson Cancer Center (0.47) and Washington University (0.47). The national cooperation network map (Figure 2a) indicates that while there has been some level of cooperation among countries in the preceding two years, the top ten countries primarily engage in cooperation within their own borders and exhibit a lack of collaboration with other nations. Conversely, the collaborative network diagram of institutions (Figure 2b) reveals the presence of robust collaborative relationships among institutions, predominantly observed prior to 2021, with a notable decline in cooperation during the recent two-year period.

Figure 2. The co-occurrence map of countries (a) and institutions (b) about this research field. The order of countries and institutions is arranged clockwise according to the number of articles from large to small.

Table 1. The top 10 countries and institutions about t this research field.

Rank	Country	Counts	Centrality	Institution	Counts	Centrality
1	USA	1942	0.1	University of Pennsylvania (USA)	279	0
2	CHINA	902	0.05	Pennsylvania Medicine (USA)	250	0.06
3	GERMANY	446	0.05	University of Texas System (USA)	233	0.03
4	UK	219	0.14	Harvard University (USA)	218	0.15
5	FRANCE	202	0.05	UTMD Anderson Cancer Center (USA)	201	0.47
6	ITALY	180	0.1	Memorial Sloan Kettering Cancer Center (USA)	199	0
7	SPAIN	177	0	University of California System	169	0.12
8	CANADA	130	0.23	National Institutes of Health (USA)	158	0.12
9	JAPAN	130	0.05	University of Washington (USA)	155	0.07
10	SWITZERLAND	128	0	Fred Hutchinson Cancer Center (USA)	142	0.1

Journals

A total of 3643 articles were published across 652 academic journals. The publication volume, citation frequency, impact factor, and JCR partition of these journals were subjected to scientific statistical analysis (Table 2). The concept of cited journals pertains to the occurrence where a journal article is referenced by other journal articles, serving as a metric for gauging a journal’s influence within a specific field. According to Table 2, the New England Journal of Medicine exhibited the highest citation frequency (n = 223,56) within this research domain, followed by Blood (n = 14,317) and Nature Medicine (n = 8,471). The New England Journal of Medicine, despite publishing a relatively small number of 22 articles in this research field, exhibits a significantly higher citation frequency compared to other journals, thus signifying its substantial academic influence. Notably, Frontiers in Immunology takes the lead with 162 articles, followed by Blood with 147 articles and Blood Advances with 27 articles. The density map depicted in Figure 3a presents journals that have published more than 15 articles, providing researchers with a tool for journal selection. Furthermore, Figure 3b showcases the results of a cluster analysis conducted in these journals. Periodical clustering, as an analytical approach, facilitates the grouping of related periodicals, thereby unveiling the interconnections between discipline structure and specific fields of study.

Figure 3. The density map of journals (a) and cluster analysis of journals (b) about this research field.

Journals with more than 10 publications are included.

Table 2. The top 10 journals and co-cited journals about this research field.

Rank	Cited Journal	Citations	Counts	IF (2022)	JCR (2022)	Journal	Counts	IF (2022)	JCR (2022)
1	New England Journal of Medicine	22356	22	158.50	Q1	Frontiers in Immunology	162	7.30	Q1
2	Blood	14317	141	20.30	Q1	Blood	141	20.30	Q1
3	Nature Medicine	8471	42	82.90	Q1	Blood Advances	122	7.50	Q1
4	Science Translational Medicine	8264	28	17.10	Q1	Journal for Immunotherapy of Cancer	110	10.90	Q1
5	Molecular Therapy	6477	84	12.40	Q1	Transplantation and Cellular Therapy	85	3.20	Q2
6	Journal of Clinical Oncology	6228	40	45.30	Q1	Molecular Therapy	84	12.40	Q1
7	Clinical Cancer Research	5645	72	11.50	Q1	Cytotherapy	81	4.50	Q1
8	Leukemia	4500	65	11.40	Q1	Clinical Cancer Research	72	11.50	Q1
9	Cancer Discovery	4136	19	28.20	Q1	Cancers	70	5.20	Q2
10	Journal of Clinical Investigation	4019	23	15.90	Q1	Frontiers in Oncology	70	4.70	Q2

Authors

A total of 23,852 authors coauthored these articles. To further explore the cooperative network between influential researchers and authors in this research field, we analyzed the cited authors and co-cited authors. The findings, presented in Table 3, reveal that Carl H. June is the most frequently cited researcher with a count of 17,177, followed by Stephan A. Grupp (n = 12,858), Bruce L. Levine (n = 12,396), and David L. Porter (n = 10,305). The inclusion criteria for this study involved researchers who have published a minimum of 10 articles. Subsequently, a cooperative network diagram was constructed to visualize the relationships among these researchers, resulting in the identification of approximately 16 major research groups (Figure 4a). These research teams hold significant academic influence within the field under investigation. Furthermore, also shows that there is cooperation among different research groups. Notably, the top 5 most frequently cited authors are all affiliated with the same research group (orange). The co-cited author analysis indicates that numerous authors are cited together within the same document. Table 3 presents the findings that Shannon L. Maude is the most frequently cited author (n = 2013), followed by Daniel W. Lee (n = 1676) and James N. Kochenderfer (n = 1434). To construct a co-cited network diagram (Figure 4b), only researchers with a minimum of 150 co-cited frequencies were included. This diagram illustrates the citation relationship among co-cited authors. Furthermore, based on the correlation and similarity between co-cited authors, four distinct clusters were identified, with Shannon L. Maude, Daniel W. Lee, James N. Kochenderfer, and Sattva S. Neelapu serving as representatives in each cluster.

Figure 4. The visualization map of authors (a) co-cited authors (b) about this research field.

(a) Minimum number of documents of an author ≥ 10; (b) Minimum number of citations of an author ≥ 150.

Table 3. The top 10 authors and co-cited authors about this research field.

Rank	Author	Citations	Counts	Rank	Co-cited author	Co-citations
1	Carl H. June	17177	59	1	Shannon L. Maude	2013
2	Stephan A. Grupp	12858	49	2	Daniel W. Lee	1676
3	Bruce L. Levine	12396	26	3	James N. Kochenderfer	1434
4	David L. Porter	10305	27	4	Sattva S. Neelapu	1433
5	Simon F. Lacey	9904	26	5	Stephen J. Schuster	1175
6	Stanley R. Riddell	8193	36	6	Cameron J. Turtle	868
7	James N. Kochenderfer	8021	26	7	Frederick L. Locke	854
8	Michel Sadelain	7847	33	8	David L. Porter	836
9	Michael C. Jensen	7512	38	9	Renier J. Brentjens	790
10	Cameron J. Turtle	7093	37	10	Jennifer N. Brudno	715

Cluster and evolution of keywords

The analysis of keywords holds considerable importance in bibliometric analysis as it unveils the research emphasis within a particular field of study. After the process of cleaning and merging the original keyword data, a total of 8099 keywords were obtained. The top 20 keywords are presented in Table 4, with CAR-T (n = 1028) being the most frequently occurring, followed by immunotherapy (n = 986) and CAR (n = 894). To provide a more visual representation of keywords with varying frequencies, a density map (Figure 5a) was constructed, incorporating keywords that appeared at least 50 times. The keyword network diagram (Figure 5b) incorporates the keywords (130 in total) that occur at least 30 times. Subsequently, cluster analysis yielded three distinct clusters, each representing a primary research area. The most substantial cluster, denoted as cluster 1 (red), encompasses keywords such as CAR, immunotherapy, adoptive cell therapy, cancer, leukemia, solid tumors, efficacy, persistence, exhaustion, resistance, expansion, cytotoxicity, checkpoint inhibitors, and TME. Cluster 2 (green) includes CAR-T, ALL, NHL, MM, BCMA, bone marrow transplantation (BMW), survival, safety, term-follow-up, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), diagnosis, tocilizumab, and management. Cluster 3 (blue) includes CD19, lymphoma, hematological malignancies, CLL, clinical trials, and adverse events.

Figure 5. The co-occurrence density map (a) and network (b) of keywords about this research field.

(a) Minimum number of occurrences of keywords ≥ 50. (b) Minimum number of occurrences of keywords ≥ 30.

Table 4. Top 20 keywords about this research field.

Rank	Keyword	Count	Rank	Keyword	Count
1	CAR-T	1028	11	leukemia	291
2	immunotherapy	986	12	CD19	289
3	CAR	894	13	remission	270
4	expression	504	14	children	260
5	ALL	458	15	efficacy	244
6	cancer	454	16	hematological malignancies	241
7	lymphoma	422	17	management	230
8	CRS	377	18	outcomes	211
9	adoptive cell therapy	336	19	survival	209
10	BMW	325	20	AML	194

By utilizing the Timeline viewer of keywords, researchers can discern the dynamic trends and evolutionary patterns of keywords within the research field over time. This can help researchers understand the development of research fields, changes in research hotspots, and the evolution of disciplines. Utilizing the aforementioned keywords, we have built a timeline viewer (Figure 6a) that provides a comprehensive depiction of the progression of keywords within this research domain since 2012, along with the primary research themes associated with each phase. Furthermore, this viewer has successfully generated 6 distinct clusters, which will be thoroughly elucidated in the subsequent discussion section. Additionally, Figure 6b visually presents the temporal dynamics of this field by employing a scientific approach to quantify the various keyword categories.

Figure 6. The timeline viewer of keywords about this research field.

The circle represents a keyword and the horizontal line represents a cluster. The size of the circle represents the frequency of keyword occurrences

Co-cited articles and reference burst

When multiple articles reference the same article, a co-citation relationship emerges among these articles. Such co-cited articles can be considered influential and significant, as they have been cited by numerous independent researchers or research teams. To investigate the prominent areas of interest and significant research topics within this field, we conducted a co-citation analysis of these articles. Table 5 presents a compilation of the ten articles exhibiting the highest citation frequency, encompassing the period from 2014 to 2020. Among these articles, the one that has garnered the most frequent citations (n = 781) is “Tisagenlecleucel in children and young adults with B-cell lymphotropic Leukemia,” authored by Maude et al. and published in 2018.¹⁷

Table 5. The top 10 co-cited articles r about this research field.

Rank	Author	Title	Journal	Year	Co- Citation	Centrality
1	Shannon L Maude et al.^Citation17	Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia	N Engl JMed	2018	781	0.24
2	Sattva S Neelapu et al.^Citation18	Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma	N Engl JMed	2017	689	0.18
3	Stephen J Schuster et al.^Citation19	Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma	N Engl JMed	2019	668	0.10
4	Jae H Park et al.^Citation20	Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia	N Engl JMed	2018	462	0.05
5	Frederick L Locke et al.^Citation21	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	411	0.04
6	Shannon L Maude et al.^Citation22	Chimeric antigen receptor T cells for sustained remissions in leukemia	N Engl JMed	2014	409	0.09
7	Daniel W Lee et al.^Citation23	T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukemia in children and young adults: a phase 1 dose-escalation trial	Lancet	2015	391	0.21
8	Cameron J Turtle et al.^Citation24	CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients	J Clin Invest	2016	327	0.08
9	Jeremy S Abramson et al.^Citation25	Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study	Lancet	2020	320	0.02
10	Marco L Davila et al.^Citation26	Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia	Sci Transl Med	2014	280	0.11

To delve deeper into the burgeoning research areas within this particular field of study, we conducted a comprehensive citation burst analysis on the relevant scholarly papers. A total of 493 articles exhibiting citation bursts were identified, with 92 of them being in an urgent state, constituting 18.7% of the overall corpus (as depicted in Annexes 2). This finding implies that the field in question will continue to garner significant attention in the foreseeable future. The publication timeline of these papers predominantly spans from 2017 to 2021. Subsequently, the 92 papers were meticulously examined, and 23 articles published post-2019 were meticulously selected, summarized, and subjected to further analysis (Table 6).

Table 6. The references (in the state of citation burstiness) about this research field.

NO.	Year	Author	Targets	Associated Tumors	Title	Strength
1	2020	Loretta J Nastoupil et al.^Citation27	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	20
2	2020	Caron A Jacobson et al.^Citation28	CD19	relapsed aggressive B-cell non-Hodgkin lymphoma	Axicabtagene Ciloleucel in the Non-Trial Setting: Outcomes and Correlates of Response, Resistance, and Toxicity	11.8
3	2020	Nirav N Shah et al.^Citation29	CD19 CD20	refractory B cell malignancies	Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial	9.03
4	2020	Erin A Dean et al.^Citation30	CD19	large B-cell lymphoma	High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B-cell lymphoma	8.42
5	2020	Nirali N Shah et al. ^Citation31	CD22	relapsed/refractory CD22+ B-cell malignancies	CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial	7.47
6	2020	Jennifer N Brudno et al.^Citation32	CD19	B-cell lymphoma	Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma	6.43
7	2020	Kevin R Parker et al.^Citation33	CD19	-	Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies	6.43
8	2021	Jennifer M Logue et al.^Citation34	CD19	B-cell lymphoma	Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma	6.27
9	2021	Stephan Kadauke et al ^Citation35	CD19	relapsed or refractory B-cell acute lymphoblastic leukemia	Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial	6.27
10	2020	Edward A Stadtmauer et al.^Citation36	-	refractory advanced myeloma, refractory metastatic sarcoma	CRISPR-engineered T cells in patients with refractory cancer	6.11
11	2020	Chuan Tong et al.^Citation37	CD19 CD20	refractory/relapsed B-cell lymphoma	Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B-cell lymphoma	5.97
12	2020	Carlos Fernández de Larrea et al.^Citation38	GPRC5D BCMA	multiple myeloma	Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent BCMA Escape-Driven Relapse in Multiple Myeloma	5.84
13	2020	Rakesh Awasthi et al.^Citation39	CD19	relapsed/refractory diffuse large B-cell lymphoma	Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL	5.51
14	2020	Hanren Dai et al.^Citation40	CD19 CD22	relapsed or refractory B cell acute lymphoblastic leukemia	Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia	5.51
15	2020	Sagar Lonial et al. ^Citation41	BCMA	multiple myeloma	Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomized, open-label, phase 2 study	5.2
16	2020	Jordan Gauthier et al.^Citation42	CD19	elapsed or refractory (R/R) chronic lymphocytic leukemia	Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure	5.05
17	2020	Alyssa Sheih et al.^Citation43	CD19	-	Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy	5.05
18	2020	Michael Klichinsky et al.^Citation44	HER2	Solid tumors	Human chimeric antigen receptor macrophages for cancer immunotherapy	4.44
19	2020	Mukta Asnani et al.^Citation45	CD19	-	Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19	4.3
20	2020	Zachary Jackson et al.^Citation46	CD19	non-Hodgkin lymphoma	Automated Manufacture of Autologous CD19 CAR-T Cells for Treatment of Non-Hodgkin Lymphoma	4.3
21	2020	Na Tang et al.^Citation47	MSLN	Pancreatic cancer	TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors	4.3
22	2020	Enli Liu et al.^Citation48	CD19	Lymphoid	Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors	4.2
23	2020	Na Wang et al.^Citation49	CD19 CD22	refractory/relapsed B-cell malignancies	Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies	4

Discussion

With the breakthrough of CAR-T cell therapy in the treatment of hematological malignancies, this therapy has occupied an important position in the treatment of hematological malignancies. Currently, a large number of articles about CAR-T cells in the treatment of hematological malignancies are published every year. The related data and knowledge in this research field are increasing year by year. To help researchers better grasp the general situation of this research field, determine the research direction, focus on research hotspots, and improve research efficiency, this study carried out bibliometrics analysis and knowledge-map analysis on related research fields in the field of CAR-T cell therapy for hematological malignancies. It aims to provide scientific and objective references for researchers to explore the general situation and development trend of this research field, focus on research hotspots, and explore emerging research topics.

General information

CAR-T cell therapy has achieved remarkable success in the treatment of hematological malignancies. The advancement of CAR-T cell technology has been rapid, leading to the approval of six CAR-T cell therapies by the US Food and Drug Administration (FDA). This development has instilled newfound hope among numerous patients afflicted with hematological malignancies. Notably, the mature CAR-T cell therapies primarily target CD19 (2/3) and subsequently BCMA (1/3). Furthermore, China has also authorized two domestic CAR-T cell therapies specifically designed for CD19. Since 2018, there has been a significant surge in the registration of clinical trials within this particular research domain.⁵⁰ To date, a total of 1509 clinical trials about CAR-T cells have been registered on ClinicalTrials.gov. Our investigation reveals a consistent upward trajectory in the exploration of CAR-T cells for the treatment of hematological malignancies. While it is anticipated that the number of articles published in 2023 may marginally surpass that of 2022, amounting to a total of 788 articles, the overall trend is expected to gradually stabilize and reach a plateau. Currently, a substantial number of clinical trials continue to be registered annually in this domain. As pertinent clinical experimental data is obtained, a significant volume of associated scholarly articles will persistently emerge in the forthcoming period.

Through the analysis of countries, institutions, periodicals, and authors, important information related to this field has been obtained. Notably, the United States has emerged as the unequivocal frontrunner in this realm, both in terms of national contributions and research establishments. Our research showed that the United States and the University of Pennsylvania contributed the most publications. First, the United States has strong scientific research capabilities and financial support in the fields of scientific research and biomedicine. The American government, private foundations, and biotechnology companies have invested heavily in biomedical research, which provides sufficient resources and support for the advancement of CAR-T cell therapy. Secondly, the University of Pennsylvania has a first-class medical research team and facilities. The Abramson Cancer Center of the school has been devoted to the research of cancer immunotherapy, with a wealth of clinical expertise and scientific achievements. Notably, the center has made an important breakthrough in CAR-T cell therapy, and its research team is in an international leading position in clinical trials and technical improvement of CAR-T cell therapy. Moreover, the scientific research environment and legal system in the United States are relatively open, which is conducive to scientists and research institutions to carry out cutting-edge scientific research and clinical practice. This environment provides favorable conditions for the research and application of CAR-T cell therapy. In conclusion, the United States and the University of Pennsylvania are in a leading position in the field of CAR-T cell therapy due to their strong scientific research capabilities, financial support, first-class research team, and research environment, as well as rich clinical experience and scientific achievements. These factors make them the leaders in the field of CAR-T cell therapy.

Presently, China has registered a total of 749 clinical trials associated with CAR-T cells, constituting 49.6% of the overall count, whereas the United States accounts for 541 trials, representing 35.9% of the total (ClinicalTrials.gov). However, the United States surpasses China in terms of sample size, experimental scale, and experimental time span. Additionally, our findings indicate that the collaboration among the top ten countries in this research domain is primarily limited to their respective nations, with minimal engagement with other countries. Over the past two years, these countries have exhibited a dearth of new collaborative efforts with external counterparts. This phenomenon can potentially be attributed to factors such as technical conservatism, patent protection, and economic considerations. Consequently, the absence of inter-country cooperation may impede the progress and advancement of this field to a certain extent. Furthermore, we obtained a list of important journals and some authors in this field (see Tables 2 and 3). For example, our research indicates that the New England Journal of Medicine is the most frequently cited journal within this particular research field. By reviewing the related articles of the journal, we found that this journal published some important clinical studies related to this research field. These studies have been widely referenced by researchers due to their significant guidance and reference value. Through the analysis of journals and cited journals, we can better understand the influence, characteristics, and development trends of journals and better evaluate the influence of research. By searching the literature of these authors, we can quickly understand the development trend, research direction, and research hotspots in this research field.⁵¹

Research hotspot analysis

To delve deeper into the prevailing areas of research and significant research subjects within this domain, we undertook a co-citation analysis of these articles, ultimately yielding the articles with the most notable co-citation frequency (Table 5) ,^17–20 This collection of 10 studies primarily focuses on the application of CD19-CAR-T cells in the treatment of hematological malignancies (ALL and large B-cell lymphoma). Out of these, 6 studies specifically address the use of CD19-CAR-T cells in ALL,^17–26 while 4 studies explore their efficacy in large B-cell lymphoma.^18,19,21,25 Additionally, 2 studies investigate the long-term follow-up and safety of CD19-CAR-T cells in the treatment of hematological malignancies,^20,21 while another study examines the management of toxic reactions associated with CD19-CAR-T cell therapy.²⁶ The CD19-CAR-T cells employed in the aforementioned ten studies are all FDA-approved CAR-T cell products, namely tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel. These studies mainly focus on the efficacy, safety, long-term follow-up, and toxic reaction management of CD19-CAR-T cells in hematological malignancies. These are research hotspots and important research topics in this field.

It has been proved that CAR-T cell therapy has a significant remission rate for hematological malignancies. Several meta-analysis studies have reported that a) For patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), the total remission rate is found to be 76% (95% CI, 0.71–0.81), accompanied by a median survival time of 36.2 months⁵²; b) CD19-CAR-T cells demonstrate a favorable curative effect on B-cell lymphoma, with an overall remission rate of 63% (95% CI, 0.41–0.85)⁵³; c) In patients with relapsed or refractory acute myeloid leukemia (RR-AML), the total remission rate achieved with CD19-CAR-T cell therapy reaches 65.2% (95% CI, 0.36–0.91)⁵⁴; d）BCMA-CAR-T cells exhibit significant efficacy in patients with multiple myeloma (MM), resulting in a remarkable total remission rate of 80.5% (95% CI, 0.74–0.86).⁵⁵ Nonetheless, the persistent issue of high recurrence rate remains a significant concern that demands attention. A meta-analysis explored this area.⁵⁶ The findings revealed that following the administration of CAR-T cell therapy, the overall recurrence rate within one year was approximately 61% (95% CI, 43%-78%). Furthermore, the overall recurrence rate after one year was determined to be 24% (95% CI, 11%-42%). Multiple factors, including drug resistance, CAR-T cell failure, immune evasion, and the loss or down-regulation of tumor cell surface antigen, may contribute to this phenomenon,^57–59 Finding and identifying predictive biomarkers associated with long-term relapse-free survival following CAR-T cell infusion (e.g., CAR-T cell copy number and minimal residual disease) is important for early intervention in patients with poor prognosis.⁶⁰ Furthermore, several challenges persist in the application of CAR-T cells in hematological malignancies, including tumor heterogeneity, absence of tumor-specific antigens (TSA), and CAR-T cell exhaustion.⁵⁴

The assessment of efficacy and safety has consistently served as the primary metrics for evaluating the caliber of CAR-T cell therapy. During the administration of CD19-CAR-T cell therapy, patients typically experience varying degrees of toxic responses, including CRS, neurotoxicity, B cell dysplasia, CAR-T cell infusion-related infection (CTI), and hematological toxicity.^61,62 Enhancing the safety of CAR-T cells while concurrently enhancing their therapeutic efficacy represents the principal avenue for optimizing this therapeutic approach. Researchers have concentrated their efforts on refining the structure of CAR to enhance the efficacy and/or safety of CAR-T cells, which has remained a focal point within this realm of research.⁵¹ Since its proposal in 1989, the concept of CAR has developed into the fifth generation CAR. The first generation of CARs lacked the necessary second signal for cell proliferation within their intracellular domain, resulting in limited in vivo persistence and proliferation capabilities. However, the subsequent second generation CARs incorporated an active domain of costimulatory signaling within their intracellular domain, thereby enhancing the proliferation and persistence of CAR-T cells. Building upon this progress, the third generation CARs added two costimulatory signaling active domains. The inclusion of an anti-tumor cytokine receptor gene or suicide gene in the intracellular domain of the fourth generation CAR enhanced the anti-tumor efficacy and safety of CAR-T cells. The fifth generation of CARs (universal CARs) was to further transform its extracellular domain to enable it to recognize different tumor antigens. Despite the current global approval of CAR-T cells primarily based on second-generation CAR-T technology, researchers continue to actively optimize and enhance the structure of CARs. With the further development of CAR-T cell therapy, the third, fourth, and fifth generation CAR-T cells, and other innovative therapeutic strategies are expected to achieve more obvious advantages. Some CARs with special structures or systems can also improve the efficacy and safety of CAR-T cells, such as serial CAR, AND-gate CAR, ON/OFF-switch CAR, and inhibitory CAR.⁹ Furthermore, the advent of CRISPR/Cas9 technology offers a convenient and efficient method for designing and optimizing CAR-T cell therapy,^63–65 In recent years, the concomitant utilization of CAR-T cell therapy in conjunction with other therapeutic modalities has demonstrated favorable therapeutic outcomes.^66,67 These modalities encompass radiotherapy,⁶⁸ immune checkpoint inhibitors,^11,69 small molecule drugs (e.g., lenalidomide), and nanotechnology.⁷⁰ Nevertheless, additional research and extensive clinical experimentation are imperative to ascertain the efficacy and safety of these CAR structures’ design and the approach to combined therapy.

Hotspot evolution and emerging topics

By analyzing keywords, we can understand the scope and characteristics of the research topics and fields. The application of keyword network analysis yielded three distinct clusters. The first cluster primarily encompasses investigations into adoptive cell therapy for cancer, specifically focusing on CAR-T cell therapy. The second cluster centers around CAR-T cell research in hematological malignancies, encompassing inquiries into therapeutic efficacy, long-term prognostic outcomes, safety considerations, and toxic reactions. The third cluster pertains predominantly to research concerning CD19-CAR-T cells in lymphoma and chronic lymphocytic leukemia (CLL).

The keyword timeline viewer (Figure 6a) offers insights into the progression of research hotspots within this field and highlights the focal points of investigation during specific periods. This tool yields a wealth of valuable information. Notably, clusters #1, #2, #4, and #5 have exhibited a heightened generation of novel keywords in the past three years, signifying these research fields have high activity. Additionally, the evolution of thematic trends can also be discerned through this analysis. For example, in cluster#2, it is evident that the emergence of concerns regarding cytokine release syndrome (CRS) in the context of CAR-T cell therapy for acute lymphoblastic leukemia (ALL) occurred around 2013, followed by an increased focus on the safety aspects of CAR-T cell therapy around 2014. Since 2015, there has been a notable emphasis on investigating strategies to alleviate and manage the toxic reactions induced by CAR-T cells, which has become a significant area of research. Furthermore, in approximately 2019, immune effector cell-associated neurotoxicity syndrome (ICANS) also gained attention as an independent research topic. Presently, the long-term follow-up of CAR-T cell therapy in 2021 has emerged as a prominent research area.

This study has acquired a total of 23 references with strong citation bursts (Table 6), and through our inductive analysis, we have identified six emerging topics about this research domain, as outlined below:

1. Study on drug resistance related to CAR-T cells^28,45;

2. CD19-CAR-T cell transfusion-related infections (CTI)³⁴;

3. Combination of CD19-CAR-T cells and Ibrutinib in the treatment of CLL⁴²;

4. Application of CRISPR/Cas9 technology in CAR-T cells^36,47;

5. Application of chimeric antigen receptor macrophages (CAR-M) and CAR-NK cells in the treatment of hematological malignancies^44,48;

6. The application of tandem CAR-T cells in hematological malignancies, such as CD19-CD20-CAR-T for NHL and CLL,^29,37 CD19-CD22-CAR-T for ALL,⁴⁰ and BCMA-GPRC5D-CAR-T for MM.³⁸

Based on scientific statistics and analysis, six emerging topics have been obtained, offering researchers a valuable point of reference. Despite the notable remission rates of CAR-T cells in treating hematological malignancies, their propensity for recurrence remains considerably elevated. The drug resistance of CAR-T cells is a significant factor that hinders their efficacy. Enhancing the curative potential of CAR-T cells necessitates addressing this drug resistance. Approaches to overcome drug resistance include optimizing the structure of CAR, enhancing the durability of CAR-T cells, mitigating the inhibitory impact of TME, and combining with other therapies.⁷¹ CTI refers to an infection event that occurs in patients receiving CAR-T cell therapy. The incidence of CTI may be influenced by various factors, such as pre-treatment immunosuppression, lymphocyte depletion during treatment, post-treatment CRS, and neurotoxicity. These factors have the potential to compromise the patient’s immune system, thereby increasing the susceptibility to infections.^62,72 One study indicated that the overall occurrence of CTI was as high as 33.8%, with severe infections accounting for 16.2% of cases, predominantly bacterial or viral in nature.⁷³ Consequently, it is imperative to diligently monitor infection-related complications, implement effective preventive measures, and gain further insights into the underlying mechanisms. Ibrutinib, a small molecule BTK (Bruton tyrosine kinase) inhibitor, functions by obstructing the B cell receptor signaling pathway, thereby impeding the proliferation and survival of malignant cells. Several clinical trials have demonstrated that the concurrent administration of CD19-CAR-T cells and ibrutinib exhibits a synergistic effect, leading to a reduction in adverse events and partially overcoming ibrutinib drug resistance in the treatment of CLL, small lymphocytic lymphoma (SLL), and mantle cell lymphoma.^42–76 Consequently, the combination of these two therapeutic approaches can further augment efficacy and safety, ultimately improving tumor remission rates.

The CRISPR/Cas9 technology is a highly efficient and accurate gene editing tool that offers cost-effective advantages. Currently, this technology has gained widespread application in cancer treatment. The utilization of CRISPR/Cas9 editing technology to enhance and refine CAR-T cells represents a highly promising area of research.⁶³ CRISPR/Cas9 technology has unique advantages in improving the function of CAR-T cells, including knocking out immune checkpoint genes to eliminate the inhibitory effect of immune checkpoints, enhancing the anti-exhaustion ability of CAR-T cells and assisting in the construction of universal CAR-T cells.⁷⁷ Dötsch et al.⁷⁸ found that the knockout of the PD-1 gene did not damage the function and life span of CAR-T cells. Following PD-1 knockout in CAR-T cells, the presence of CAR-T cells was consistently observed in vivo for a period exceeding 390 days. These findings suggest that PD-1 gene knockout can be applied to engineered T cell-based immunotherapies to overcome immune checkpoint suppression. Good et al.⁷⁹ discovered a novel mechanism leading to CAR-T cell exhaustion, namely the conversion of CD8 +T cells to NK-like T cells, and identified the transcription factors ID3 and SOX4 as key contributors to cell dysfunction. They further showed that CRISPR/Cas9 technology-mediated knockouts of ID3 and SOX4 can delay CAR-T cell exhaustion. Moreover, CRISPR/Cas9 technology can also indirectly reduce the treatment cost of CAR-T cells by shortening the manufacturing time of CAR-T cells (reducing the culture cost of CAR-T cells) and improving the persistence/proliferation ability (reducing the dosage of subsequent CAR-T cells).^65,77 Consequently, it is of great practical value to construct CAR-T cells based on CRISPR/Cas9 technology. Furthermore, CAR-M cells^80,81 and CAR-NK cells,^82,83 as extensions of CAR-T cell technology, have also demonstrated efficacy in the treatment of hematological malignancies and solid tumors. For example, researchers from The University of Texas MD Anderson Cancer Center conducted a phase I/II clinical trial.⁸⁴ In this latest clinical trial, 37 patients with recurrent or refractory B-cell malignant tumors received cord blood-derived CAR-NK cell therapy targeting CD19. The results showed that the overall response rate was 48.6% after 100 days of treatment, and the one-year progression-free survival rate and overall survival rate were 32% and 68% respectively. The clinical trial reported excellent safety without severe cytokine release syndrome, neurotoxicity, or graft-versus-host disease.⁸⁴ In recent years, the tandem chimeric antigen receptor (CAR) structure has gained significant popularity in the design of CAR-T cells due to its distinct advantages. This structure expands the recognition range of tumor antigens of CAR-T cells, and it will produce synergistic stimulation when recognizing and combining two tumor antigens at the same time, further enhancing the anti-tumor effect of CAR-T cells.

Furthermore, two articles about solid tumors were identified through citation burst analysis (Table 6).^44,47 This phenomenon is due to the fact that these two documents have been cited many times by researchers in the field of “CAR-T cell therapy for hematological malignancies” in a short time. This indicates that these articles may hold significant research and reference value within this specific field, resulting in their frequent citation. These two studies involve the field of CAR-M cells and the application of CRISPR/Cas9 technology in the construction of CAR-T cells respectively. Klichinsky et al.³⁹ showed that CAR-M cells can specifically phagocytize tumor cells and exhibit good infiltration ability in solid tumors. Moreover, CAR-M cells can stimulate the anti-tumor immune activity of T cells by shaping the inflammatory tumor microenvironment. Tang et al.⁴² knocked out endogenous TGF-β receptor II (TGFBR2) in CAR-T cells by CRISPR/Cas9 technology, which not only reduced the exhaustion of CAR-T cells but also improved the anti-tumor activity of CAR-T cells in tumor microenvironment rich in TGF-β. After analysis, we found that although these two articles involved solid tumor research, their core content was still close to the emerging topics 4 and 5 summarized above.

CAR-T cell therapy exhibits significant promise and potential, as evidenced by its notable achievements in the management of hematological malignancies. In the future, CAR-T cell therapy is expected to be extended to other types of cancer and play a greater role in individualized treatment. Furthermore, the technical improvement of CAR-T cell therapy and the accumulation of clinical experience will further improve the therapeutic effect and safety. Nevertheless, several challenges persist in the realm of CAR-T cell therapy, including drug resistance, elevated recurrence rates, toxic reactions, and limited in vivo persistence. Thus, further research and development are needed to solve these problems to further improve CAR-T therapy.

Conclusion

Miao et al.⁵¹ have done bibliometrics research on the whole field of CAR-T cells. They included related articles and reviews from 2009 to 2021. Different from them, this study focuses on the related research of CAR-T in the treatment of hematological malignancies (excluding the literature related to solid tumors) and only includes relevant articles. Consequently, the literature retrieval strategy of this study is more targeted. Additionally, this study also included the studies in 2022 and 2023. Due to different research directions and emphases, the information obtained in this study, especially the research hotspots and emerging topics, is different from the research of Miao et al.⁵¹ (readers can read and compare themselves).

CAR-T cell therapy has emerged as a prominent approach for the treatment of hematological malignancies, leading to a substantial increase in the number of scholarly publications dedicated to this area of research. Consequently, our study aimed to comprehensively analyze this research domain through bibliometric analysis. Our study indicates a steady growth in related publications within this research field over the years. The countries, research institutions, journals, and scientists that contributed the most to publications are the United States, the University of Pennsylvania, Frontiers in Immunology, and Carl H. June. The most frequently cited journal is the New England Journal of Medicine. The scientists with more cited frequency and co-cited frequency are Carl H. June and Shannon L. Maude respectively. We not only shed light on its overall landscape but also investigated its developmental trajectory and the evolution of prominent research areas. Furthermore, we identified the prevailing research hotspots and delineated six emerging themes, which may provide more targeted guidance and more valuable reference for researchers in the field of CAR-T cell therapy for hematological malignancies.

Author contributions

Q.H.: Writing-Original draft preparation, manuscript, investigation, and figure preparation. H.L.: 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/10.1080/21645515.2024.2371664

Additional information

Funding

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