Global research trends in CAR-T cell therapy for solid tumors: A comprehensive visualization and bibliometric study (2012–2023)

ABSTRACT

CAR-T cell therapy has emerged as a significant approach for the management of hematological malignancies. Over the past few years, the utilization of CAR-T cells in the investigation and treatment of solid tumors has gained momentum, thereby establishing itself as a prominent area of research. This descriptive study involved the retrieval of articles about CAR-T cell therapy for solid tumors from the Web of Science Core Collection (WoSCC) database. Subsequently, bibliometric analysis and knowledge map analysis were conducted on these articles. The field under consideration is currently experiencing a period of swift advancement, as evidenced by the escalating number of publications in this domain each year. The United States holds an indisputable position as the foremost leader in this particular field, with the University of Pennsylvania emerging as the most active institution. The authors with the highest citation frequency and co-citation frequency are Carl H. June and Shannon L. Maude, respectively. The research hotspots in this field mainly focus on five aspects. Additionally, 10 emerging themes were identified. This study undertakes a comprehensive, systematic, and objective analysis and exploration of the field of CAR-T cell treatment for solid tumors, utilizing bibliometric methods. The findings of this study are expected to serve as a valuable reference and enlightenment for future research endeavors in this particular domain.

KEYWORDS:

• CAR-T cells
• solid tumors
• bibliometric
• knowledge-map
• hotspots
• emerging topics

Introduction

A new era in cancer treatment has begun with CAR-T cells,¹ offering new hope to cancer patients. Since the concept of CAR was put forward in 1989, it has evolved into the fifth generation. The intracellular structure of the first-generation CAR has only one signaling domain (CD3ζ). Compared to the first-generation CAR, the second-generation adds one costimulatory molecule and the third-generation adds two. Among the frequently employed costimulatory molecules are CD28 and 4-1BB. Extensive research has demonstrated the ability of these costimulatory molecules to enhance CAR-T cell proliferation and persistence.^2–4 In addition to costimulatory molecules, anti-tumor cytokine receptor genes or suicide genes were added to the intracellular domain of the fourth-generation CAR. The fifth-generation CAR modifies the extracellular domain by adding a “third party” intermediate system. Currently, the US Food and Drug Administration (FDA) has approved several CAR-T cell products that specifically target CD19 and BCMA. The success of CAR-T cell therapy in treating hematological malignancies has also piqued interest in treating solid tumors. This is because compared with hematological malignancies, the number of patients with solid tumors is much larger.

However, to date, no CAR-T cell therapy for solid tumors has been marketed. At present, the clinical trials involving CAR-T cells in solid tumors are predominantly in their initial phases and have shown limited antitumor efficacy. This is because CAR-T cells encounter numerous challenges when targeting solid tumors, including tumor antigen heterogeneity, homing disorders of CAR-T cells, and immunosuppression by the tumor microenvironment (TME).⁵ An increasing number of researchers are currently investigating the mechanisms underlying these barriers and putting forth numerous significant strategies.⁶ These strategies encompass further optimizing CAR structure, remodeling TME,⁷ targeting inhibitors in TME (e.g., immune checkpoints, chemokine-receptor networks, and immunosuppressive cells),⁸ combining immune checkpoint inhibitors,^9,10 combining chemotherapy,¹¹ and combining radiotherapy.^12,13 Currently, although CAR-T cells exhibit lower effectiveness in solid tumors compared to hematological malignancies,¹⁴ it is anticipated that once these obstacles are overcome, CAR-T cells will undergo a significant advancement in the treatment of solid tumors.

Research on CAR-T cells in solid tumors is a hot field. Bibliometrics, as a comprehensive, objective, and efficacious approach for analyzing scientific information, offers a superior means to explore the trends, frontiers, hotspots, emerging topics, research topic distribution, as well as the contributions and collaborations among countries, institutions, and authors within this domain.¹⁵ Although there are some bibliometric studies on CAR-T cells, there is no bibliometric analysis specifically for this field. In this study, we carry out bibliometric analysis and knowledge-map analysis in this field.

Materials and methods

Data collection and search strategies

The data utilized in this research is sourced from the WoSCC database, with the retrieval and screening strategies outlined in Annexes 1. A total of 2009 articles were obtained.

Data analysis and visualization

Microsoft Office Excel 2019, GraphPad Prism 8, CiteSpace, and VOSviewer were used for data management, data analysis, and visualization. CiteSpace and VOSviewer are JAVA-based metrology analysis and visualization software. Both of them have various emphases in data analysis and visualization. CiteSpace is better at mining and analyzing potential information in literature, while VOSviewer has powerful visualization capabilities.^16,17

Results

The annual growth trend of publications

The trend chart depicting the number of publications over the course of the past 12 years was generated through the annual tallying of publications. As illustrated in Figure 1, the overall quantity of articles within this field has exhibited an upward trajectory, with a notable surge observed from 2019 to 2021, during which 784 articles were published, constituting 39.02% of the total. The number of publications in 2021, 2022, and 2023 remains relatively consistent. Presently, there have been 306 articles published in 2023, slightly fewer than in 2022. This discrepancy can be attributed to the fact that only 10 months’ worth of relevant articles were collected for 2023, resulting in a total of 306 articles (15.23%). Moreover, we constructed a fitting equation (Y = 31.14*X − 62650, correlation coefficient R² = 0.9253, p <0.0001) based on the annual publication data (Figure S1). Taking into account these findings, we maintain an optimistic outlook on the projected publication volume in 2023. As of now, the cumulative citations for these articles amount to 79,842, with an average of 39.74 citations per article. Additionally, these publications possess an H-index of 138.

Figure 1. Trends in publication output and citation frequency about the CAR-T cell research in solid tumors.

Note. It shows the number of publications per year.

Countries/regions and institutions

Over the course of the past 12 years, a significant number of countries and institutions have collaborated on a total of 2009 articles (as each article may involve multiple countries or organizations, it is counted multiple times). Notably, the United States (n = 1008) has emerged as the leading contributor in terms of publications, followed by China (n = 601) and Germany (n = 222) (see Table 1). The United States stands out as the most active country in this particular field, boasting a considerably higher number of articles compared to other nations. Furthermore, Egypt (0.82, n = 9) exhibited the highest centrality among countries, followed by Norway (0.77, n = 12), and Sweden (0.71, n = 31). High centrality represents the relevant research of these countries and plays a bridge role in this field.

Table 1. The top ten countries and institutions about the research of CAR-T cells in solid tumors.

Rank	country	Counts	Centrality	Institution	Counts	Centrality
1	USA	1008	0.27	University of Pennsylvania (USA)	136	0.11
2	CHINA	601	0.07	Harvard University (USA)	120	0.14
3	GERMANY	222	0.07	Pennsylvania Medicine (USA)	118	0.01
4	UK	101	0.07	National Institutes of Health (USA)	104	0
5	JAPAN	71	0	National Cancer Institute (USA)	98	0
6	ITALY	67	0.11	Harvard Medical School (USA)	82	0.21
7	SWITZERLAND	56	0	Helmholtz Association (GERMANY)	76	0.16
8	CANADA	52	0.03	University of California System (USA)	75	0.06
9	AUSTRALIA	49	0.11	Baylor College of Medicine (USA)	74	0.05
10	SOUTH KOREA	40	0	University of Texas System (USA)	74	0.12

8460 scientific research institutions worldwide have contributed to the body of knowledge on CAR-T cell research in solid tumors by publishing at least one article. Notably, the University of Pennsylvania emerged as the leading contributor with 136 publications, closely followed by Harvard University (n = 120) and Pennsylvania Medicine (n = 118) (Table 1). Nine of the top ten institutions are from the United States. By conducting a visual analysis of the pertinent data, the collaborative network and contributions of countries and institutions in this domain can be visually observed (Figure 2). It can be seen that in recent years, especially in 2021–2023, countries have actively cooperated in this field; Additionally, there is also intensive cooperation among institutions.

Figure 2. The co-occurrence map of countries (a) and institutions (b) about the research of CAR-T cells in solid tumors.

Journals and co-cited journals

These articles were disseminated across a total of 536 academic journals. The most frequently published publications in this field were the Journal for Immunotherapy of Cancer (n = 93), followed by Frontiers in Immunology (n = 85) and Molecular Therapy (n = 70) (Table 2). All of the top 10 journals surpassed the threshold of 30 publications. To construct a comprehensive journal density map, 40 journals with a minimum publication count of 10 were included. The resulting density plot, depicted in Figure 3(a), effectively portrays the prominence of these high-volume journals.

Figure 3. The density map of journals (a) and co-cited journals (b) about the research of CAR-T cells in solid tumors.

Notes: Figure A shows journals with a number of publications ≥ 10; Figure B shows the journals with citations ≥ 300.

Table 2. The top ten journals and co-cited journals about the research of CAR-T cells in solid tumors.

Rank	Journal	Counts	Citations	IF(2022)	JCR(2022)	Co-cited journal	Co-Citations	IF(2022)	JCR(2022)
1	Journal for Immunotherapy of Cancer	93	2089	10.90	Q1	Blood	4710	20.30	Q1
2	Frontiers in Immunology	85	1295	7.30	Q1	Clinical Cancer Research	4446	11.500	Q1
3	Molecular Therapy	70	5886	12.40	Q1	New England Journal of Medicine	4011	158.50	Q1
4	Oncoimmunology	55	2314	7.20	Q1	Cancer Research	3578	11.20	Q1
5	Cancers	54	651	5.20	Q2	Journal of Immunology	3047	4.40	Q2
6	Clinical Cancer Research	52	5621	11.50	Q1	Molecular Therapy	2841	12.40	Q1
7	Cancer Immunology Research	49	3555	10.10	Q1	Journal of Clinical Oncology	2656	45.30	Q1
8	Cancer Immunology Immunotherapy	39	1446	5.80	Q1	Proceedings of the National Academy of Sciences of the United States of America	2464	11.10	Q1
9	Molecular Therapy-Oncolytics	38	1081	5.70	Q2	Nature Medicine	2344	82.90	Q1
10	Frontiers in Oncology	33	396	4.70	Q2	Nature	2150	64.80	Q1

IF: Impact Factor. JCR: Journal citation reports.

The journal with the highest number of citations was Blood (n = 4710), followed by Clinical Cancer Research (n = 4446) and the New England Journal of Medicine (n = 4011) (Table 2). Among the top 10 co-cited journals, these 10 journals received more than 5000 citations. Furthermore, 90% of these journals possess an impact factor exceeding 10. A total of 63 journals with co-citation frequencies ≥ 300 were selected to construct a co-citation density map. The density plot effectively portrays the journals with significant co-citation frequencies (Figure 3(b)). The dual-map overlay of journals visually represents the distribution of academic journals within the field (Figure 4).

Figure 4. The dual-map overlay of journals about the research of CAR-T cells in solid tumors.

It identified two main reference paths, including a green reference path and an orange reference path. This shows that the articles published in “Molecular, Biology, and Genetics” Journals are often cited by the papers published in “Medicine, Medical, and Clinical” Journals.

Authors and co-cited authors

12,897 authors participated in the publication of these articles. As shown in Table 3, each of the top 10 authors was cited at least 2300 times. Carl H. June was the most cited (n = 6561), followed by Gianpietro Dotti (n = 4260) and Stephen J. Forman (n = 3357). Authors with at least five articles published were included and a collaborative network of these authors was constructed (Figure 5a). This network analysis indicates the existence of numerous research groups within this particular field, highlighting a significant level of collaboration among the researchers. However, it is worth noting that there appears to be a lack of close cooperation between these distinct research groups.

Figure 5. The visualization map of authors (a) co-cited authors (b) about the research of CAR-T cells in solid tumors.

Note: Minimum number of documents of an author ≥ 6; Minimum number of citations of an author ≥ 100.

Table 3. The top ten authors and co-cited authors about the research of CAR-T cells in solid tumors.

Rank	Cited author	Citations	Counts	Rank	Co-cited author	Co-citations
1	Carl H. June	6561	42	1	Shannon L. Maude	649
2	Gianpietro Dotti	4260	41	2	Richard A. Morgan	556
3	Stephen J. Forman	3354	26	3	James N. Kochenderfer	528
4	Marcela V. Maus	2886	8	4	Steven A. Rosenberg	501
5	Christine E. Brown	2786	26	5	Christine E. Brown	459
6	Michael C. Jensen	2591	20	6	David L Porter	425
7	Simon F. Lacey	2591	12	7	Nabil Ahmed	405
8	Steven A. Rosenberg	2471	20	8	Renier J. Brentjens	377
9	Hao Liu	2365	11	9	Carl H. June	322
10	Julie R. Ostberg	2318	11	10	Daniel W. Lee	313

Co-cited authors are those who are cited in one or more subsequent papers. As shown in Table 3, the top 10 co-cited authors are all co-cited more than 300 times. Shannon L. was the most frequently co-cited. Maude (n = 649) followed by Richard A. Morgan (n = 556) and James N. Kochenderfer (n = 528). We selected authors with a minimum of 100 co-citations and generated a co-citation network for them (Figure 5b). The co-citation network graph of authors provides a visual representation of the co-cited authors and their co-citation relationships. Furthermore, Carl H. June, Christine E. Brown, and Steven A. Rosenberg appear on both the top ten cited authors and co-cited authors lists, suggesting that these three researchers may have made outstanding contributions to the field.

Keyword co-occurrence, clusters, and evolution

An article’s keywords can reflect its focus and direction. Consequently, by analyzing these keywords, one can gain insight into the prominent areas of research and their corresponding directions within the field. Initially, the acquired keywords are processed, which involves consolidating synonymous terms and eliminating insignificant ones. Ultimately, a total of 5455 keywords were obtained. Table 4 presents the top 20 keywords, each of which has a frequency exceeding 200 occurrences. The keyword “immunotherapy” was found to be the most frequently used (n = 921), followed by “CAR” (n = 679) and “cancer” (n = 563). Additionally, a list of the top ten solid tumors (Table S1) was obtained, with “melanoma” being the most frequent (n = 199), followed by “glioblastoma” (n = 191) and “breast cancer” (n = 100). Overall, brain tumors (glioblastoma and neuroblastoma) appeared the most frequently, with a total of 239 times. A total of 76 keywords with at least 40 occurrences were included and used to construct a density map (Figure 6(a)). Figure 6(a) provides a more visual representation of these high-frequency keywords.

Figure 6. The co-occurrence density map (a) and network (b) of keywords about the research of CAR-T cells in solid tumors.

Note: (a) Minimum number of occurrences of keywords ≥ 40. (b) Minimum number of occurrences of keywords ≥ 30.

Table 4. Top 20 keywords related to the research of CAR-T cells in solid tumors.

Rank	Keyword	Count	Rank	Keyword	Count
1	Immunotherapy	921	11	Melanoma	199
2	CAR	679	12	Glioblastoma	191
3	Cancer	563	13	Solid tumors	171
4	CAR-T	501	14	Efficacy	167
5	Expression	489	15	Checkpoint inhibitors	150
6	Adoptive cell therapy	328	16	Tumor microenvironment (TME)	135
7	Antitumor-activity	236	17	Antibodies	129
8	T cells	229	18	Survival	125
9	Lymphocytes	222	19	NK cells	122
10	Activation	216	20	Persistence	114

To construct a keyword network map, 95 keywords with at least 30 occurrences were included, and five clusters were identified (Figure 6(b)). Cluster 1 (red) has 34 keywords, including immunotherapy, CAR-T, solid tumors, checkpoint inhibitors, chemotherapy, combination, antitumor immunity, tumor microenvironment, inhibition, resistance, mesothelin, B7-H3, PD1, and PD-L1. Cluster 2 (green) has 25 keywords, including lymphocytes, activation, persistence, survival, response, memory, cytotoxicity, identification, proliferation, and mechanisms. Cluster 3 (blue) has 16 keywords, including cancer, glioblastoma, efficacy, radiotherapy, safety, stem cells, HER2, and EGFR. Cluster 4 (yellow) has 11 keywords, including hematological malignancies, CD19, adverse events, (cytokine release syndrome) CRS, and remission. Cluster 5 (purple) has nine keywords, including adoptive cell therapy, CAR, antitumor activity, and melanoma. These clusters roughly represent five important research directions and research areas in this field.

A Timeline viewer for keywords clusters keywords in chronological order. It can help us explore the evolution of these keywords in different topics. By referring to Figure 7, one can visually discern the trajectory of this field’s development and identify the research focal points at each stage.

Figure 7. The timeline viewer of keywords about the research of CAR-T cells in solid tumors.

The circle represents a keyword and the horizontal line represents a cluster.

Co-cited references and reference burst

Table 5 shows the top ten articles that have been co-cited the most in this field. These articles were co-cited more than 60 times, and the top 4 articles were co-cited more than 100 times. The most frequently co-cited article is “A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma¹⁸ (n = 179).”

Table 5. The top ten co-cited articles related to the research of CAR-T cells in solid tumors.

Rank	Author	Title	Journal	Year	Citation	Centrality
1	Donald M O’Rourke et al.^Citation18	A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma	N Engl J Med	2017	179	0.11
2	Christine E Brown et al.^Citation19	Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy	N Engl J Med	2016	147	0.08
3	Nabil Ahmed et al.^Citation20	HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial	JAMA Oncol	2017	98	0.04
4	Nabil Ahmed et al.^Citation21	Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma	Nabil Ahmed	2015	95	0.07
5	Sarwish Rafiq et al.^Citation22	Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo	Nat Biotechnol	2018	84	0.04
6	Keishi Adachi et al.^Citation23	IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor	Nat Biotechnol	2018	81	0.05
7	Leonid Cherkassky et al.^Citation24	Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition	J Clin Invest	2016	77	0.05
8	Justin Eyquem et al.^Citation25	Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumor rejection	Nature	2017	71	0.09
9	Robbie G Majzner et al.^Citation26	CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors	Clin Cancer Res	2019	67	0.04
10	Gregory L Beatty et al.^Citation27	Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial	Gastroenterology	2018	63	0.05

Citation burst refers to the fact that some documents are cited in large numbers in a short time. A total of 596 references with citation bursts were obtained (Figure S2). At present, 168 papers (28.2%) are in an emergency state, with their publication dates ranging from 2017 to 2020. This indicates that these papers have been frequently cited in three years. To identify emerging research topics within this field, a comprehensive analysis was conducted on these 168 papers. Among them, 33 articles (19.6%) were published in 2020 or later, comprising 17 articles, 13 reviews, and 2 case reports about this particular field. Subsequently, the 17 noteworthy articles were meticulously sorted, summarized, and analyzed based on their burst intensity (Table 6).

Table 6. The references (in the state of citation burstiness) related to the research of CAR-T cells in solid tumors.

NO.	Year	Author	Targets	Associated Tumors or Tumor Cell line	Title	Strength
1	2020	Michael Klichinsky et al.^Citation28	HER2	SKOV3 (ovarian cancer)	Human chimeric antigen receptor macrophages (CAR-Ms) for cancer immunotherapy	11.04
2	2020	Enli Liu et al.^Citation29	CD19	NHL, CLL	Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors	9.96
3	2020	Edward A Stadtmauer et al.^Citation30	–	–	CRISPR-engineered T cells in patients with refractory cancer	9.36
4	2020	Donghua Shi et al.^Citation31	GPC3	HCC	Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials	7.75
5	2020	Na Tang et al.^Citation32	Mesothelin TGFBR2	Pancreatic cancer, CRL5826 (lung cancer), OVCAR-3 (ovarian cancer)	TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors	6.86
6	2020	Katharina Reinhard et al.^Citation33	Claudin 6 Claudin 18.2	OV90 (ovarian cancer)	An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors	6.86
7	2020	Dongrui Wang et al.^Citation34	–	Glioblastoma	Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma	4.77
8	2020	Jennifer N Brudno et al.^Citation35	CD19	B-cell lymphoma	Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma	3.83
9	2020	Guangna Liu et al.^Citation36	GPC3 CXCR2	HCC	CXCR2-modified CAR-T cells have enhanced trafficking ability that improves treatment of hepatocellular carcinoma	3.58
10	2020	Nathan Singh et al.^Citation37	CD19	ALL	Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction	3.58
11	2020	Venugopal Gudipati et al.^Citation38	–	–	Inefficient CAR-proximal signaling blunts antigen sensitivity	3.28
12	2020	Prativa Sahoo et al.^Citation39	IL13Rα2	Glioblastoma	Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data	3.28
13	2020	Theodore L Roth et al.^Citation40	–	–	Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies	3.28
14	2020	Yuying Liu et al.^Citation41	–	–	Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome	3.28
15	2020	Le Qin et al.^Citation42	PD-L1	Solid tumors	Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth	3.07
16	2020	Laura Evgin et al.^Citation43	EGFRvIII	–	Oncolytic virus-derived type I interferon restricts CAR T cell therapy	3.07
17	2020	Meijia Yang et al.^Citation44	CD70 B7-H3	solid tumors	Tandem CAR-T cells targeting CD70 and B7-H3 exhibit potent preclinical activity against multiple solid tumors	2.68

ALL: acute lymphoblastic leukemia.

CLL: chronic lymphocytic leukemia.

NHL: non-Hodgkin’s lymphoma.

GPC3: glypican-3.

HCC: hepatocellular carcinoma.

TGFBR2: TGF-β receptor II.

Discussion

General information

In recent years, CAR-T cell therapy has developed rapidly, especially after breakthroughs in the treatment of hematological malignancies. Our previous study showed that the research on CAR-T cells showed a rapid growth trend since 2012.⁴⁵ Hence, we chose 2012 as the starting point of this study. Related research in this field shows an increasing trend year by year, suggesting a growing interest in the application of CAR-T cells for solid tumors. In contrast to hematological malignancies, solid tumors encompass a greater diversity of types. Once CAR-T cells make a substantial breakthrough in solid tumors, it will bring great benefits to patients with solid tumors. This has served as a catalyst for numerous researchers to persistently delve into this field. Our study shows that CAR-T cell research in solid tumors is at a rapid stage of development. Based on the growth rate in 2023 and the fitting equation derived from the annual publication data, it is anticipated that the publication volume in 2023 will surpass that of 2022, indicating positive growth. We remain optimistic about this. With the continuous in-depth study of relevant mechanisms and the continuous overcoming of obstacle factors, it is believed that CAR-T cells will make significant progress in the treatment of solid tumors in the future. This will be the gospel for all solid tumor patients.

Our research findings indicate that the United States is the foremost country in this field and holds a dominant position. In recent years, there has been an increase in collaboration among nations and institutions, which has further facilitated the advancement of this field. Currently, the FDA has approved six CAR-T cell therapies for the treatment of hematological malignancies, all originating from the United States. Additionally, China has introduced two CD19-CAR-T cell therapies to the market. Nevertheless, the high cost of CAR-T cell therapy poses limitations on its clinical dissemination. The current cost of CAR-T cell therapy stands at a minimum of $370,000 per treatment. It is anticipated that as the market expands with the introduction of additional CAR-T cell therapies and advancements in the production process of CAR-T cells,⁴⁶ the initial high price will gradually diminish, offering renewed hope to a larger patient population. Despite the ongoing Phase I/II clinical trials investigating the efficacy of CAR-T cells in solid tumors, no CAR-T cell therapy targeting solid tumors has been commercially available thus far. Claudin18.2, one of the most promising targets for treating solid tumors,^47,48 is also favored in the CAR-T cell field and has published clinical trial results.^49,50

We found that the Journal for Immunotherapy of Cancer, Frontiers in Immunology, and Molecular Therapy had published a large number of articles related to this field. This suggests that these journals have a keen interest in research related to this field. By searching and reviewing the articles of researchers listed in Table 3, we can gain a comprehensive understanding of the current state of this research area.

Knowledge base analysis and hotspot analysis

We made a co-citation analysis of the obtained literature. Frequent co-citation shows that they have a common and related research topic.⁵¹ Through examination of these frequently co-cited documents, prominent research subjects within this field can be identified. Ultimately, the ten most highly co-cited articles about solid tumors were selected^18–27 (Table 5).

These ten articles primarily focus on CAR-T cell therapy in various solid tumors, with clinical experimental studies comprising 50% of the research. Among these ten studies, four are associated with brain tumors,^18–20–26 two with sarcomas,^21,26 one with mesothelioma,²⁴ and one with pancreatic cancer.²⁷ The solid tumors investigated in these studies and their corresponding targets include glioblastoma (targeting EGFRvIII, IL 13α 2, and HER2), medulloblastoma (targeting B7-H3), sarcoma (targeting HER2 and B7-H3), pleural mesothelioma (targeting mesothelin), and pancreatic cancer (targeting mesothelin). Recently, the research on CAR-T cells in the treatment of solid tumors has developed rapidly. Common therapeutic targets for solid tumors include Glypican-3, GD2, HER2, mesothelin and, EGFR. The National Institutes of Health (NIH) database reveals over 200 clinical trial registrations pertaining to this domain, encompassing a wide range of solid tumors and more than 50 targets.⁵² The research of CAR-T cells for the treatment of brain tumors, particularly glioblastoma, has emerged as a prominent area of research interest. There may be the following reasons. Firstly, the intricate location of brain tumors within the central nervous system poses challenges for surgical resection, while conventional radiotherapy and chemotherapy exhibit limited efficacy against certain brain tumors. Consequently, alternative treatment approaches are imperative. Secondly, CAR-T cells demonstrate promising prospects in cancer treatment. Lastly, glioblastoma has some relatively good therapeutic targets, such as IL-13 Rα2, EGFRvIII, HER2 and EphaA2. Significant advancements have yet to be achieved in this particular domain due to the numerous obstacles encountered by CAR-T cells when targeting solid tumors, such as the absence of tumor-specific antigens (TSA). Currently, the majority of targets employed for treating solid tumors are tumor-associated antigens (TAA), including the aforementioned targets. Consequently, there is an imperative need to identify a more effective tumor antigen. Tumor neoantigens are a kind of unique “antigens” of tumor cells, and their main sources are point mutations in the genome of tumor cells. One prominent example is EGFRvIII, the most prevalent EGFR mutation, with an expression rate of approximately 30% in glioblastoma.⁵³ Therefore, it can be used as a therapeutic target for glioblastoma.⁵⁴ The identification of tumor neoantigens broadens the range of potential targets for solid tumor therapies.

Furthermore, there are four studies related to improving the curative effect of CAR-T cells in solid tumors, such as combining CAR-T cells with PD-1 inhibitors,²⁴ integrating CRISPR/Cas9 technology into CAR-T cells,²⁵ optimizing the CAR structure by augmenting cytokine receptor genes in the intracellular domain.^22,23 It is evident that utilizing a single CAR-T cell therapy alone is insufficient to achieve optimal therapeutic outcomes for solid tumors. How to further improve its efficacy and safety in solid tumors has become the research focus. The combination of CAR-T cells with other therapeutic modalities has demonstrated potential for improved efficacy and safety.⁵⁵ commonly employed therapies such as chemotherapy, radiotherapy, and immune checkpoint inhibitors have been investigated in conjunction with CAR-T cell therapy. Chemotherapy has long been recognized as a crucial approach in cancer treatment. Alzubi et al.⁵⁶ observed that the combination of PSMA-CAR-T cells and Docetaxel effectively suppressed tumor progression in a mouse model of prostate cancer, surpassing the individual effects of PSMA-CAR-T cells or docetaxel alone. Radiotherapy is a frequently employed modality for cancer treatment. In recent times, there has been a gradual rise in research pertaining to the combination of CAR-T cells and radiotherapy. Radiotherapy can improve tumor microenvironment (TME) to some extent, such as inducing the release of chemokines, increasing the expression of immune factors, and enhancing the function of effector T cells.⁵⁷ CAR-T cells combined with immune checkpoint inhibitors are also a promising therapeutic approach. Multiple studies have demonstrated that the utilization of immune checkpoint inhibitors in conjunction with CAR-T cells can enhance their cytotoxicity against tumor cells, reverse the depletion of CAR-T cells, and augment their persistence.^9,58,59 Adachi et al.²³ introduced the genes encoding IL-7 and CCL19 receptors into the intracellular domain of CAR, enabling the release of IL-7 and CCL19 upon CAR-T cell activation. This innovative design enhances the durability and infiltration capacity of CAR-T cells within solid tumors. In addition to optimizing the intracellular domain structure of CAR, we can also improve the extracellular domain structure, such as bivalent tandem CAR and dual-signaling CAR, which expands the recognition range of CAR.⁶⁰ CRISPR-Cas9 technology is a rapidly developing gene-editing tool with the advantages of high efficiency and high precision.^61,62 Consequently, integrating CRISPR-Cas9 technology with CAR-T cell therapy represents a promising approach.⁶³ Eyquem et al.²⁵ employed CRISPR-Cas9 technology to target the CAR to TRAC locus, which inhibited the tonic CAR signaling, thereby effectively delaying the failure of CAR-T cells. Furthermore, CRISPR-Cas9 technology can be utilized to disrupt certain genes, such as PD-L1⁶⁴ and SHP-1,⁶⁵ which can improve the tumor-killing effect of CAR-T cells. The integration of CRISPR-Cas9 technology into CAR-T cell therapy presents a novel approach for cancer treatment, with a highly promising outlook.

Overall, after comprehensive analysis, these ten studies mainly focus on the following aspects:

1. The investigation of CAR-T cell therapy in solid tumors (especially brain tumors), including the evaluation of efficacy, safety, and prognosis;

2. Identification of therapeutic targets for solid tumors (we summarized some solid tumor targets for CAR-T cell therapy, as shown in Table S2);

3. Augmentation of CAR-T cell persistence in solid tumors, such as combining immune checkpoint inhibitors;

4. Utilization of CRISPR/CAS9 gene editing technology in CAR-T cells;

5. Enhancement of the anti-tumor efficacy of CAR-T cells through optimization of CAR structure.

The research topics of great concern in this research field mainly include the above five aspects. Each of these aspects represents a significant research topic, encompassing preclinical and clinical experiments involving CAR-T in solid tumors, the identification and utilization of novel targets, the investigation of combined therapeutic approaches, the application of emerging technologies, and the optimization and improvement of CAR design. With the in-depth study of these topics, it is believed that CAR-T cells will play a more and more effective role in solid tumors.

Hotspot evolution, knowledge structure, and emerging topics

The Timeline viewer of keywords can intuitively show the evolution of keywords and the research topics at each stage (Figure 7). In this field, a substantial quantity of keywords emerged at various stages spanning from 2012 to 2023. Based on the abundance of keywords, it has been categorized into three distinct segments, with 2015 and 2020 serving as nodes. The most frequently used keywords appeared before 2015. These keywords are mainly related to the research on CAR-T cells in the treatment of hematological malignancies. A gradual increase in research on CAR-T cells in the treatment of solid tumors began after 2015. Moreover, some high-frequency keywords appeared in 2022–2023, including oncolytic virus, macros, nanoparticles, CAR-NK cells, and tumor-associated macrophages. This represents the latest research direction in this field to some extent.

Keywords can generally reflect the research content of a research. By analyzing the top 20 keywords, we can get some important information. Representative keywords include CAR-T, solid tumor, melanoma, glioblastoma, efficacy, persistence, survival, checkpoint inhibitors, TME, and NK cells. These keywords suggest that a) melanoma and glioblastoma are the most studied solid tumors in this field; b) The curative effect and prognosis of CAR-T cells in the treatment of solid tumors are the focus; c) combined with other therapies to improve the curative effect. Additionally, our research shows that brain tumors (specifically glioblastoma and neuroblastoma) are the most extensively investigated, followed by melanoma and breast cancer.

Keyword clustering revealed five clusters. Cluster 1 primarily focuses on the investigation of CAR-T cells in diverse solid tumors, encompassing efficacy, drug resistance, and associated targets. Cluster 2 primarily centers on elucidating the mechanism of CAR-T cells in solid tumors. Cluster 3 primarily concentrates on the exploration of CAR-T cells in glioblastoma. Cluster 4 primarily pertains to the toxic reactions associated with CAR-T cells. Cluster 5 primarily delves into the research of adoptive cell therapy in melanoma. These five aspects generally reflect some important research topics in this field.

According to the analysis of 17 references with strong citation bursts (Table 6),^28–44 we identified 10 emerging topics related to this field, as follows:

1. Research about CAR-NK cells and CAR-M cells;^28,29

2. Employing CRISPR-Cas9 technology for targeted gene knockout to enhance the tumor-killing ability of CAR-T cells;^30,32

3. The combination of RNA vaccine and CAR-T cells;³³

4. The combination of oncolytic adenovirus and CAR-T cells;⁴³

5. Utilizing the glioma cell-binding capability of chlorotoxin (CLTX) to engineer CLTX-CAR-T cells for glioma therapy;³⁴

6. Employing tandem CAR to enhance the effectiveness of CAR-T cells;⁴⁴

7. Investigation into the resistance mechanisms of CAR-T cells;³⁷

8. The intrinsic mechanisms underlying the binding of CAR to tumor antigens;³⁸

9. Development of a CAR-T cell response model and exploration of factors influencing the efficacy of CAR-T cells in solid tumors;³⁹

10. Pooled Knock-In Sequencing (PoKI-Seq) developed by Roth et al.⁴⁰ can be used for genome modification of cellular immunotherapy.

Through scientific and reasonable analysis, we have obtained ten emerging research topics in this field, which provide possible research directions for researchers in this field. As an extension of CAR-T cell technology, the exploration of CAR-NK cells and CAR-M cells has gained significant attention in current research. CAR-NK cells offer several advantages, such as a diverse range of sources, a lower incidence of CRS and neurotoxicity, and CAR-independent mechanisms for tumor eradication. The advantages of CAR-M cells include a wide range of sources, phagocytosis, greater ability to infiltrate, and better resistance to TME inhibition.^14,66,67 However, the development of CAR-M cell-related technologies is currently less mature compared to CAR-T and CAR-NK cells. The current research on CAR-NK cell therapy and CAR-M cell therapy for solid tumor treatment is still in its nascent stages. In a phase I clinical trial,⁶⁸ researchers developed chimeric antigen receptor (CAR) natural killer (NK) cells targeting natural killer group 2 member D (NKG2D) for the treatment of metastatic colorectal cancer. Two colorectal cancer patients with malignant ascites received multiple intraperitoneal injections of NKG2D-CAR-NK cells. The findings indicated a notable reduction in both ascites volume and cancer cell count within the ascites. Another colorectal cancer patient with liver metastasis received an ultrasound-guided percutaneous injection of the liver combined with an intraperitoneal injection of NKG2D-CAR-NK cells. The results showed that the volume of liver metastasis was reduced from 66.0 mm × 28.5 mm to 46.9 mm × 24.0 mm.⁶⁸ Furthermore, Chen et al.‘s preclinical research demonstrated that HER2-CAR-M cells and CD47-CAR-M cells exhibit targeted phagocytosis toward HER+ or CD47+ ovarian cancer cells, while also bolstering the body’s adaptive immune response and ultimately impeding tumor advancement.⁶⁹

Combining RNA vaccines or oncolytic viruses represents an innovative approach to enhance the effectiveness of CAR-T cells. In a recent phase 1 clinical trial (BNT211–01), it was demonstrated that the combination of CLDN6-CAR-T cells and an amplifying RNA vaccine is a viable option for the treatment of solid tumors, while maintaining manageable safety profiles. Some studies have shown that combining modified oncolytic adenovirus with CAR-T cells can improve the infiltration ability and anti-tumor response of CAR-T cells in solid tumors.^70,71 Moreover, Wang et al.³⁴ constructed CLTX-CAR-T cells to treat glioblastoma, capitalizing on the specific affinity of chlorotoxin (CLTX) toward glioblastoma cells. These cells have the advantages of expanding the killing range of glioblastoma and high safety. Notably, up to now, there is only one study on the relationship between CLTX and CAR-T cells, thus presenting vast opportunities for future exploration and advancement in this field.

The term “Tandem CAR” denotes the sequential connection of two distinct single-chain variable fragments (scFv). Consequently, tandem CAR exhibits the capability to concurrently identify two tumor antigens. In contrast to univalent CAR, tandem CAR broadens the spectrum of recognized tumor antigens and enhances its ability to combat tumor heterogeneity and immune evasion. A considerable number of studies about tandem CAR-T cells can be found on PubMed, with the quantity steadily increasing. This design is highly favored by researchers.

The complexity of the TME in solid tumors surpasses that of hematological malignancies, prompting researchers to suggest the utilization of gene editing technology to overcome TME inhibition.⁷² Roth et al.⁴⁰ have introduced a novel mixed gene knock-in screening approach and devised PoKI-seq sequencing technology to document the single-cell status and gene structure knock-in status. This technology enables efficient high-throughput screening of fragment sequences that have the potential to enhance T cell function. The study further demonstrated that the utilization of TGF-βR2–4-1BB can considerably enhance the efficacy of solid tumor elimination by TCR-T cells, thereby presenting promising prospects for application. Most importantly, this novel technique offers valuable technical assistance for the advancement of novel cellular immunotherapy, including CAR-T cell therapy.

Conclusion

In recent years, the research on CAR-T cells in solid tumors has developed rapidly. Consequently, this study undertook a descriptive analysis in this domain utilizing bibliometric methods. A comprehensive, systematic, and objective examination of articles about this research area was conducted, encompassing various aspects such as publication count, country and institution affiliations, periodical distribution, citation frequency, and highly cited documents. Scientific statistics, explanations, and discussions were subsequently provided. Furthermore, this study also reveals the development trend of this field, alongside identifying five research hotspots and ten emerging topics in this field. These findings may hold significant reference value for researchers specializing in the realm of CAR-T cell therapy. It is important to note that the successful application of CAR-T cell therapy in solid tumors remains a formidable task. Presently, no substantial breakthroughs have been achieved, presenting both a challenge and an opportunity. It is our strong belief that as technology continues to advance, CAR-T cell therapy will emerge as a viable treatment option for patients with solid tumors.

Author contributions

L.M.: Writing-Original draft preparation, manuscript, investigation, and figure preparation. J.Z.: manuscript, investigation, and figure preparation. W.X.: Investigation and figure preparation. Q.Q.: Investigation. G.Z.: Investigation. Q.Y. Investigation. Y.L. Investigation. H.Z.: Methodology, Supervision. C.S.: Methodology, Supervision. W.W.: Conceptualization, Methodology, Supervision.

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/10.1080/21645515.2024.2338984.

Additional information

Funding

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