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CD19 CAR T cells for B cell malignancies: a systematic review and meta-analysis focused on clinical impacts of CAR structural domains, manufacturing conditions, cellular product, doses, patient’s age, and tumor types

BMC Cancer volume 24, Article number: 1037 (2024) Cite this article

Abstract

CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies. However, long-term disease-free survival is still a challenge to overcome. Here, we evaluated the influence of different hinge, transmembrane (TM), and costimulatory CAR domains, as well as manufacturing conditions, cellular product type, doses, patient’s age, and tumor types on the clinical outcomes of patients with B cell cancers treated with CD19 CAR T cells. The primary outcome was defined as the best complete response (BCR), and the secondary outcomes were the best objective response (BOR) and 12-month overall survival (OS). The covariates considered were the type of hinge, TM, and costimulatory domains in the CAR, CAR T cell manufacturing conditions, cell population transduced with the CAR, the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. Fifty-six studies (3493 patients) were included in the systematic review and 46 (3421 patients) in the meta-analysis. The overall BCR rate was 56%, with 60% OS and 75% BOR. Younger patients displayed remarkably higher BCR prevalence without differences in OS. The presence of CD28 in the CAR’s hinge, TM, and costimulatory domains improved all outcomes evaluated. Doses from one to 4.9 million cells/kg resulted in better clinical outcomes. Our data also suggest that regardless of whether patients have had high objective responses, they might have survival benefits from CD19 CAR T therapy. This meta-analysis is a critical hypothesis-generating instrument, capturing effects in the CD19 CAR T cells literature lacking randomized clinical trials and large observational studies.

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Introduction

Chimeric antigen receptors (CARs) are artificial cell membrane receptors responsible for immune cell activation. They are constituted by an extracellular binding domain selected against an antigen, usually in the form of a single-chain variable fragment (scFv), a hinge sequence, and a transmembrane domain fused to intracellular costimulatory and stimulatory signaling domains. First-generation CARs had only one CD3ζ chain in the intracellular domain for T cell activation. Second- and third-generation CARs harbor one and two additional intracellular costimulatory domains, respectively, eliciting complete T cell activation. Fourth-generation CARs are based on second or third-generation CARs designed in a vector able to induce the expression of additional transgenic products, constitutively or by induction, such as cytokines or monoclonal antibodies. The CAR expression has been vastly explored in T cells (CAR T cells), and is evolving in other immune cell types, such as NK cells, dendritic cells, and macrophages, ushering in a new era for the treatment of cancer and other diseases [1, 2]. In clinical trials, the main domains constituting the hinge part of a CAR are CD28, CD8 alpha, IgG4, or IgG1, while for the transmembrane domain (TM), CD28 or CD8 alpha are the most applied. The costimulatory domains more extensively applied in the clinical setting are CD28 and 4-1BB. CD28 incorporation into the costimulatory domain of CD19 CAR elicits tumor eradication, glycolysis, effector memory maturation, and T cell exhaustion, whereas 4-1BB signaling induces in vivo T cell persistence, mitochondrial biogenesis, and reprogramming towards a central memory T cell phenotype [3]. Regardless of a few small studies that explored the clinical impact of using different costimulatory domains in the CAR, there is a lack of information about the influence of different hinge or TM domains on the clinical outcomes of patients treated with CAR T cells.

One of the current most effective CAR T cell therapies targets CD19, an antigen expressed by B cells in all stages of development until differentiation in plasmocytes, including B cell malignancies, such as Hodgkin (HL) and non-Hodgkin lymphoma (NHL), acute (ALL) or chronic lymphocytic leukemia (CLL) [4]. All tumor types treated with this therapy had a high initial complete response (CR) rate, but long-term disease-free survival can still be improved [4]The therapeutic success of CAR T cells is sometimes discrepant as it is shaped by several factors, boosting the conduction of a comparative analysis to address the global impact of in vivo and ex vivo conditions that influence CD19 CAR T cell performance in clinical trials.

Here, we analyzed the rates of the primary outcome – defined as best complete response (BCR) – and secondary outcomes defined as 12-month overall survival (OS) and best objective response (BOR) of CD19-positive leukemia or lymphoma patients treated with CD19 CAR T cells containing different hinge, transmembrane (TMD), and costimulatory domains. We have also analyzed the impact of different parameters related to CAR T cell manufacturing conditions, such as the type of interleukin used for CAR T cell expansion, CAR T cells activation method, and cell population transduced with the CAR. We have also evaluated the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. This meta-analysis will be helpful as a hypothesis-generating instrument as it tries to capture effects in the literature that is still recent, lacking randomized clinical trials and large observational studies.

Methods

Search strategy

We accomplished a systematic review and meta-analysis according to the PRISMA statement [5, 6], registered on PROSPERO (CRD42022360268). The main study question is the rate of BCR in patients undergoing treatment for B cell malignancies according to the CD19 CAR T cells hinge, transmembrane, and costimulatory domains. The MEDLINE/PubMed database was searched from the inception until August 2021, using the following keywords: “receptors, chimeric antigen“[MeSH Terms] OR (“receptors“[All Fields] AND “chimeric“[All Fields] AND “antigen“[All Fields]) OR “chimeric antigen receptors“[All Fields] OR (“chimeric“[All Fields] AND “antigen“[All Fields] AND “receptor“[All Fields]) OR “chimeric antigen receptor“[All Fields]) AND “CD19“[All Fields].

Study eligibility criteria

The inclusion criteria were patients with CD19-positive leukemia or lymphoma treated with second or third-generation CD19 CAR T cells. Only studies with original data and in English were included. Grey literature and reference lists from included studies were also considered.

The exclusion criteria were studies with (a) no primary outcome reported, (b) dual CAR, (c) other CAR cells types, such as CAR macrophages, (d) combinations with CAR T cells targeting other molecules or with other targeted or non-targeted therapies, such as hematopoietic stem cell transplant, (e) patients with multiple myeloma and other non-hematological tumors, (f) case series, (g) studies such as meta-analyses, reviews, case reports, protocols, books, letters to the editor, comments or specialists’ opinions, abstracts, and (h) pre-clinical studies. Studies ≤ 10 patients were included in the evidence summary but were excluded from the meta-analysis due to statistical constraints.

Data extraction

Data extracted comprised the rate of successful outcomes versus the sample included in the study, and BCR was defined as the primary outcome. The secondary outcomes were OS and BOR. For the meta-analysis, categorical covariates were the types of hinge, TM, and costimulatory (costimulation) domains in the CAR, CAR T cell manufacturing conditions, such as the interleukin used for CAR T cell expansion, CAR T cells activation method, and cell population transduced with the CAR – PBMCs or other specific subsets – (CAR T cell type), as well as the CD19 CAR type (CAR name), and tumor type. Numerical covariates were patient age, number of CAR T cells injected/Kg, and the number of CAR T cells infusions.

Two independent investigators (ERS and NSPC) screened titles and abstracts with ties resolved by a third person (VAP). Three authors (NSPC, VAP, GCPS) independently performed the full-text review and extracted the data, and ERS resolved disagreements.

Data syntheses

The data was presented in a summary of evidence and synthesized as forest plots, with studies ordered by publication year. All methodological details of the meta-analysis were included in the Supplementary Methods.

Risk of bias assessment

Risk of bias assessment adopted the Modified Institute of Health Economics Tool for bias analysis [7] and was performed independently by three authors (NSPC, VAP, GCPS).

Statistical analysis

Statistical analysis was performed with RStudio version 1.1.383 (The R Foundation for Statistical Computing, Vienna, Austria), using meta and metafor packages [8, 9].

Results

Fifty-six studies were included in the systematic review with a total of 3493 patients, 2904 treated with CAR T, and 2809 patients analyzed for rate estimation of BCR. Of these patients, 1440 presented a CR, and 1587 had an objective response (OR). We have also evaluated 12 months-OS, having 42 studies with a total of 2992 patients included, 2479 patients treated with CAR T, and 2393 patients analyzed, of whom 1567 were alive at 12 months.

A total of 46 studies with more than or equal to 10 patients were included in the meta-analysis involving 3421 patients, of whom 2837 were treated with CAR T and 2746 patients analyzed for rate estimation of the primary outcome BCR, being 1251 patients presenting CR and 1571 presenting OR, one of the secondary outcomes evaluated. For the other secondary outcome assessed, OS, we had 37 studies with 2949 patients, 2439 patients treated with CAR T, and 2356 patients analyzed for OS, of whom 1547 were alive at 12 months. The PRISM flow diagram is present in Fig. 1, and the summary of evidence in Table 1.

Fig. 1
figure 1

Flow chart for eligibility assessment according to PRISMA guidelines. Based on model reference(Page et al., 2021a). For more information, visit: http://www.prisma-statement.org/

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Table 1 Evidence summary
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Meta-analysis

General clinical responses of CD19 CAR T therapy

The general proportion of BCR was 56% (95%CI: 49 – 63%), the I2 was 81%, and the τ2 was 0.7911 indicating a large between-study variance (Fig. 2). However, it equals or exceeds 50% in 28 of 46 studies (Fig. 2). Table 2 summarizes meta-analysis data for primary outcome BCR (also presented in full version with references as Suppl. Table 1). The bias assessment is presented in Fig. 3.

Fig. 2
figure 2

The Forest Plot represents the overall rate of the primary outcome Best Complete Response (BCR) of patients treated with CD19 CAR T therapy based on the studies included in the meta-analysis

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Table 2 Best complete response subgroup analysis
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Fig. 3
figure 3

Funnel, Baujat, and Radial plots showing the heterogeneity observed for the primary outcome Best Complete Response (BCR) of patients treated with CD19 CAR T therapy based on the studies included in the meta-analysis

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The general proportion of OS was 60% (95%CI: 53 – 67%), the I2 was 87%, and the τ2 was 0.5642 (Suppl. Figure 1 and Suppl. Table 2) indicating a moderate between study variance. The overall rate of BOR with CD19 CAR T therapy was 75% (95% CI: 68 – 82%, I2 = 78%) with a very high between-study variance (τ2 = 1.2262) and rates equal to or above 50% in 40 of 46 studies (Suppl. Figure 2 and Suppl. Table 3). Together, these data indicate substantial heterogeneity. The bias assessment for OS and BOR are also presented in Suppl. Figure 3. All the other forest plots are presented as Suppl. Figure 4 to 39.

Sensitivity -analysis

Age

Patients under 18 years old had a 79% BCR (95%CI: 65-89%, I2:64%), 62% OS (95%CI: 41-80%, I2:73%) and 84% BOR (95%CI: 75-90%, I2:31%) (Suppl Figs. 4, 5 and 6, respectively). Patients above 18 years old presented a 51% BCR (95%CI: 43 − 57%, I2:82%), 60% OS (95%CI: 52- 67%, I2:88%) and 73% BOR (95%CI: 64-81%, I2:79%) (Suppl Figs. 4, 5 and 6, respectively).

CD19 CAR T cells manufacturing conditions

Considering interleukin used for CAR T cell expansion, when IL-2 was used we found 58% BCR (95%CI: 50-66%, I2:76%), 56% OS (95%CI: 45-66%, I2:86%) and 79% BOR (95%CI: 68-87%, I2:70%) (Suppl Figs. 7, 8 and 9, respectively). When other interleukins were applied, we had a 54% BCR (95%CI: 43-65%, I2:72%), 63% OS (95%CI: 50-75%, I2:91%), and 73% BOR (95%CI: 64-80%, I2:71) (Suppl Figs. 7, 8 and 9, respectively).

The BCR (Suppl Fig. 10), OS (Suppl Fig. 11), and BOR (Suppl Fig. 12) proportions were similar for activation and expansion of CAR T cells with anti-CD3/CD28 beads or anti-CD3 mAb. Considering the cell population transduced with the CAR, we have found similar BCR (Suppl Fig. 13) and BOR (Suppl Fig. 14) rates when using full PBMCs or CD4/CD8 1:1, CD8 only, or other specific subsets. OS rate was higher when using full PBMCs (61%; 95%CI: 53–73%, I2: 86%) compared to 55% for CD4/CD8 1:1, CD8 only, or other specific subsets (55%; 95%CI: 35–73%, I2: 86%) (Suppl Fig. 15).

Number of T cells injected into the patients/Kg

Patients treated with doses between 1 and 4.9 million cells/ kg per injection had BCR rates of 63% (95%CI: 55-71%, I2:77%), 60% OS (95%CI: 50-69%, I2:85%), and 83% BOR (95%CI: 76-88%, I2:74%) (Suppl Figs. 16, 17 and 18, respectively). The 5 to 99 million cells/kg group had only three studies and was not considered for comparison (71% BCR; 95%CI: 25-95%, I2:62%; 58% OS; 95%CI: 21-88%, I2:66%, and 83% BOR, 95%CI:29–98%, I2: 64) (Suppl Figs. 16, 17 and 18, respectively). Doses superior to 100 million cells/kg showed lower BCR (36%; 95%CI: 28–46%, I2:38%), OS (56%, 95%CI: 25–83%, I2:94%) and BOR rates (64%, 95%CI: 32-87%, I2:69%) (Suppl Figs. 16, 17 and 18, respectively).

Number of CAR T cell infusions in the patients

The proportions for a single cell injection were 55% for BCR (95%CI:48-62%, I2: 81%), 61% for OS (95%CI:52-69%, I2: 88%) and 78% for BOR (95%CI:69-85%, I2: 77%) (Suppl Figs. 19, 20 and 21, respectively). For two infusions, the number of studies was meager (65% BCR; 95%CI: 0-100, I2: 97%; 70% OS, 95%CI:55-82%, I2: not applicable) (Suppl Figs. 19, 20 and 21, respectively). Studies with three or more infusions showed a 50% BCR rate (50%; 95%CI: 25–74%, I2: 74%) and 72% BOR (95%CI: 40–91%, I2: 81%) (Suppl Fig. 19, and 21, respectively). For OS, the number of studies was also meager (58% OS, 95%CI: 29–83%, I2: 66%) (Suppl Fig. 20).

CD19 CAR T cell products

For Axicabtagene ciloleucel (Axi-cel), we have found a 62% BCR (95%CI: 56–67%, I2: 52%), 68% OS (95%CI: 59–77%%, I2: 80%) and 86% BOR rates (95%CI: 78–91%, I2: 46%) (Suppl Figs. 22, 23 and 24, respectively). Tisagenlecleucel (Tisa-cel) showed 53% BCR (95%CI:38–67%, I2: 66%), 61% OS (95%CI:42–76%, I2: 92%) and 70% BOR rates (95%CI:59–79%, I2: 55%) (Suppl Figs. 22, 23 and 24, respectively). Other CD19 CAR T products more recently tested had a 60% BCR (95%CI:40–78%, I2:82%), 57% OS (95%CI:52–62%, I2:40%), and 67% BOR rates (95%CI:44–86%, I2:80%) (Suppl Figs. 22, 23 and 24, respectively).

CAR hinge domain

When CD28 was used to construct the CAR hinge domain, we had a 60% BCR (95%CI:55–66%, I2: 52%), 65% OS (95%CI:55–74%, I2: 81%) and 83% BOR rates (95%CI:73–90%, I2: 66%) (Suppl Figs. 25, 26 and 27, respectively). For CD8, we observed 56% BCR (95%CI:42–70%, I2: 75%), 59% OS (95%CI:46–71%, I2: 89%), and 71% BOR (95%CI:58–82%, I2: 66%) (Suppl Figs. 25, 26 and 27, respectively). IgG4 resulted in 50% BCR (95%CI:35–66%, I2: 85%), 50% OS (95%CI:32–59%, I2: 84%) and 71% BOR (95%CI: 54–83%, I2: 79%) (Suppl Figs. 25, 26 and 27, respectively).

CAR transmembrane domain

When the CD28 transmembrane domain was used to build the CAR, we found a 58% BCR (95%CI:48–67%, I2: 80%), 61% OS (95%CI:51–70%, I2: 85%) and 79% BOR (95%CI:69–86%, I2: 80%) (Suppl Figs. 28, 29 and 30, respectively). CD8 alpha in the transmembrane resulted in 54% BCR (95%CI:40–68%, I2: 73%), 59% OS (95%CI:45–72%, I2: 90%) and 70% BOR (95%CI:55–82%, I2: 67%) (Suppl Figs. 28, 29 and 30, respectively).

CAR costimulatory domain

The CD28 costimulatory domain in the CAR resulted in 60% BCR (95%CI:54–66%, I2: 55%), 66% OS (95%CI:57–74%, I2: 79%) and 85% BOR rates (95%CI:78–91%, I2: 45%), while for 4-1BB we had 56% BCR (95%CI:44–67%, I2: 82%), 56% OS (95%CI:45–66%, I2: 89%) and 71% BOR (95%CI:61–79%, I2: 76%) (Suppl Figs. 31, 32 and 33, respectively).

Tumor type

Patients with ALL achieved 73% BCR (95%CI:60–83%, I2: 77%), 57% OS (95%CI:45–68%%, I2: 67%), and 80% BOR (95%CI:66–89%, I2: 64%) %) (Suppl Figs. 34, 35 and 36, respectively), while for NHL, the general BCR was 51% (95%CI:45–57%, I2: 75%), 59% OS (95%CI:46–72%, I2: 92%) and 71% BOR (95%CI:63–78%, I2: 74%) (Suppl Figs. 34, 35 and 36, respectively).

Meta-regression

The meta-regression showed that the group aged above 18 presented a low but significant amount of heterogeneity explained by this variable (H2 = 7.5535) and that the moderator is inversely related to BCR, suggesting that the effect size favors the younger patient (estimate= -1.3211; p = 0.005). Also, costimulation based on CD28 and third-generation CD28/4-1BB presents a small amount of heterogeneity explained (H2 = 9.1079), but both were statistically significant moderators (p = 0.0391 and p = 0.0493, respectively). For BOR, the attributable heterogeneity for costimulatory domains was H2 = 7.5535, and CD28 and 4-1BB were significant for this observation (p = 0.0047 and p = 0.0355). The attributable heterogeneity for the CAR T cell product was small (H2 = 7.4956); however, there was an inverse effect for Tisa-cel and JCAR014 as moderators (p = 0.0336 and p = 0.0097). Finally, for OS, the attributable heterogeneity for the CAR T cell product was H2 = 6.0343, and only the treatment with JCAR014 presented an inverse and statistically significant moderator effect (p = 0.0215).

Risk of bias assessment

A predominant low risk of bias was assessed for the primary and the secondary outcomes, presented in Suppl. Figures 37, 38, and 39, respectively.

Discussion

The pooled 56%BCR found for all CD19 CAR T therapies evaluated herein, with a 60% OS and 75% BOR, corroborates the results found in most CD19 CAR T clinical trials [66]. However, among the studies included in this meta-analysis, there are also some outliers, such as one published by Ramos et al. (2016), showing only 13% BCR and 19% BOR (N = 16 patients, no OS reported), that can be explained by the employment of a first-generation CAR, which usually fails to reach effective antitumor responses [67, 68].For comparison, a meta-analysis focused on DLBCL conducted in 2022 by Ying and collaborators showed a similar pooled 63% OS rate and 74% BOR, diverging only by an expressively lower 48% BCR [69].Additionally, another meta-analysis published in 2021 by Aamir et al., focused on ALL patients, reported an 82% BCR rate. Neither OS nor BOR were reported in this study for comparison [70]. The difference in pooled BCR from these two studies compared with ours can be explained, at least in part, by the mixed tumor types included in our study, such as ALL, CLL, and other NHL subtypes. When we compared ALL and NHL in our sensitivity analysis for tumor type, the most expressive differences between them were also found for BCR (73 versus 51%), followed by BOR (80 versus 71%) rates, while both tumors resulted in similar OS rates (59 versus 57%). Our data also suggest that regardless of whether patients have had high objective responses or not, they might have survival benefits from CD19 CAR T therapy.

Among the CAR T manufacturing conditions evaluated herein, the cell populations chosen to build the CAR product and the cytokine used for T cell expansion promoted the most relevant differences for the clinical outcomes analyzed, mainly for OS. PBMCs had higher OS but similar BOR and BCR rates compared to CD4/CD8 1:1 clustered with CD8 and other specific subsets for analysis. The clustering of CD4/CD8 1:1, CD8 alone, or others might have influenced the results obtained since there is pre-clinical and clinical evidence that CD4:CD8 1:1 seems to outperform other populations. However, we decided to cluster these groups due to the small number of clinical studies available to evaluate each one of these cell populations separately. ILs different from IL-2 used for CD19 CAR T cell manufacturing showed higher OS rates despite similar BCR and lower BOR, evidencing the necessity of running clinical trials using different cytokines for CAR T cell expansion to evaluate their impacts on clinical responses. The CAR T cell activation and expansion methods were equivalent for all outcomes evaluated.

Considering the covariate age, patients under 18 had notably higher BCR and BOR rates but similar OS compared to older patients. CD19 CAR T cell therapy is known to induce a high clinical response rate in children and young adults, especially with B-ALL, but relapses are still a current issue [62], explaining, at least in part, the similar OS despite the higher BCR rates found in younger patients.

Regarding the CAR T cell dose effect, higher BCR, BOR, and OS rates were found for patients treated with doses between 1 and 4.9 million cells/kg compared to those with doses greater than 100 million cells/kg. The dose-effect might be biased considering the higher BCR and BOR rates found for younger patients, usually treated with lower CAR T cell doses. Nevertheless, the age bias can be ruled out for the higher OS rates observed for lower CAR T doses since OS was not affected by age. When the number of CAR T infusions was evaluated, we noted that three or more infusions presented lower rates for the evaluated outcomes. This result is critical because higher CAR T doses with repeated infusions are known to enhance toxicity [71, 72] despite the evident increased manufacturing cost. These results might affect the design of future comparative CD19 CAR T cells-based clinical trials, which can be focused on testing different dose scales up to 100 million cells/kg, limiting the administration to one or two infusions.

The comparison of different molecules used to build the structural CD19-directed CAR hinge (CD8, CD28, or IgG4), transmembrane (CD8 or CD28), and costimulatory domains (CD28 or 4-1BB) showed that the presence of CD28 in these three domains revealed higher rates for all the clinical outcomes evaluated. It might be possible that the different CAR domains act synergistically since they are part of the same functional full costimulatory molecule in human immune cells. However, we cannot affirm or discard this hypothesis based on our data. Particularly considering OS, the most relevant rate difference was found when CD28 was in the CAR’s hinge and costimulatory regions. For BCR, the rate differences between CD28 and other molecules tested were less relevant. A CAR hinge and transmembrane-based comparison with clinical data has never been performed before in the literature, and our meta-analysis gives us some evidence that must be further investigated in future studies to clarify the possibility of synergism combining different/ equal domains. For the costimulatory domains, data recently published in a meta-analysis focused on patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells corroborated our findings, showing higher BCR and BOR rates of CD28 (57% BCR and 81% BOR) compared to 4-1BB (42% BCR and 70% BOR). However, they found a non-significant statistical difference between CD28 and 4-1BB considering the 12-month OS rate for DLBCL patients [69].In the same study, the CD28-based Axi-cel had higher rates for all outcomes evaluated compared with the 4-1BB Tisa-cel CAR T for the treatment of DLBCL patients, with a BCR rate of 57% versus 36%, OS rate of 65% versus 49%, and BOR rate of 82% versus 58%, respectively [69]A clinical trial comparing CD19 CAR-T containing either CD28 or 4-1BB was performed to treat ten ALL patients, five treated with each type of construction in a dose of 0.62 × 106 CAR T cells/kg. This study showed similar responses for both treatments, with the CD28 group resulting in 3 CR, 1 PR, and one no response (NR), and the 4-1BB with 3 CR, 0 PR, and 2 NR. Despite the superior number of NR patients in the 4-1BB group, this group had a unique patient with an ongoing anti-tumor response evaluated five months after treatment [73].This clinical trial was not conclusive due to the limited number of patients. Still considering the costimulatory domain of the CAR, Cappel and Kochenderfer recently reviewed and compared CAR T cell clinical studies based on different targets and having CD28 or 4-1BB as costimulatory domains, including but not limiting CD19 as a target. This general review showed that the available data from clinical trials do not demonstrate a clear advantage of either CD28-costimulated or 4-1BB-costimulated CARs for treating B cell lymphomas or B-ALL, pointing out that more extensive studies and comparative clinical trials must be performed to allow a conclusion about the performance of the different costimulatory domains against B-cell malignancies [74].

This study is the pioneer in evaluating the impact of the hinge and TMD CAR domains in addition to costimulatory domains in CD19 CAR T cell’s clinical response for B cell leukemia and lymphoma, which is an essential unanswered question in the field. In summary, several covariates analyzed might have a positive impact on all the evaluated clinical outcomes BCR, OS, and BOR of patients treated with CD19 CAR T cell therapies, such as age inferior to 18 years old, injection of 1 to 4.9 million CAR T cells per kg, with one CAR T cell infusion – without discard a potential efficiency using two doses – and CD28 constituting the hinge, transmembrane, and costimulatory domains of the CAR, as in Axi-cel product, and must be better explored in future comparative clinical trials.

The lack of randomized trials or large observational studies on CAR T cells justifies the implementation of this meta-analysis, which intends to provide insights on the ongoing procedures for further research, raising questions and spotting potential aspects of interest in the current approaches. Due to the unavoidable heterogeneity observed, the results of this meta-analysis are not deemed for clinical decision-making but to improve the understanding of this complex and multifaceted treatment instead. The extrapolation and generalization of the results obtained in this meta-analysis should be made with caution since it may be biased by the different study designs and characteristics considering CAR structures, CAR T cell manufacture conditions, doses, tumor type, autologous cells isolated from each individual heavily pretreated, and other variables.

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Abbreviations

ALL:

Acute lymphocytic leukemia

BCR:

Best complete response

BOR:

Best objective response

CAR:

Chimeric antigen receptors

CLL:

Chronic lymphocytic leukemia

CR:

Complete response

DLBCL:

Diffuse large B-cell lymphoma

HL:

Hodgkin lymphoma

NHL:

Non-Hodgkin lymphoma

OS:

Overall survival

OR:

Objective response

PBMC:

Peripheral blood mononuclear cells

scFv:

Single-chain variable fragment

TMD:

Transmembrane domains

References

  1. Dana H, Chalbatani GM, Jalali SA, Mirzaei HR, Grupp SA, Suarez ER, Raposo C, Webster TJ. CAR-T cells: early successes in blood cancer and challenges in solid tumors. Acta Pharm Sin B. 2021;11(5):1129–47.

    Article  CAS  PubMed  Google Scholar 

  2. Mantovani A, Allavena P, Marchesi F, Garlanda C. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov. 2022;21(11):799–820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kawalekar OU, O’Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr., Patel PR, Guedan S, Scholler J, Keith B, et al. Distinct signaling of Coreceptors regulates specific metabolism pathways and impacts Memory Development in CAR T cells. Immunity. 2016;44(2):380–90.

    Article  CAS  PubMed  Google Scholar 

  4. Mohty M, Gautier J, Malard F, Aljurf M, Bazarbachi A, Chabannon C, Kharfan-Dabaja MA, Savani BN, Huang H, Kenderian S, et al. CD19 chimeric antigen receptor-T cells in B-cell leukemia and lymphoma: current status and perspectives. Leukemia. 2019;33(12):2767–78.

    Article  PubMed  Google Scholar 

  5. Page MJ, Moher D, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ. 2021;372:n160.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. J Clin Epidemiol. 2021;134:178–89.

    Article  PubMed  Google Scholar 

  7. Grigor EJM, Fergusson DA, Haggar F, Kekre N, Atkins H, Shorr R, Holt RA, Hutton B, Ramsay T, Seftel M, et al. Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in patients with haematological and solid malignancies: protocol for a systematic review and meta-analysis. BMJ Open. 2017;7(12):e019321.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Balduzzi S, Rucker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health. 2019;22(4):153–60.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36:1–48.

    Article  Google Scholar 

  10. Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, Taylor C, Yeh R, Bartido S, Borquez-Ojeda O, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118(18):4817–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119(12):2709–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra138.

    Article  Google Scholar 

  14. Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540–9.

    Article  CAS  PubMed  Google Scholar 

  15. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385(9967):517–28.

    Article  CAS  PubMed  Google Scholar 

  16. Bhoj VG, Arhontoulis D, Wertheim G, Capobianchi J, Callahan CA, Ellebrecht CT, Obstfeld AE, Lacey SF, Melenhorst JJ, Nazimuddin F, et al. Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood. 2016;128(3):360–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, Jena B, Dawson MJ, Kumaresan PR, Su S, et al. Phase I trials using sleeping beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016;126(9):3363–76.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ramos CA, Savoldo B, Torrano V, Ballard B, Zhang H, Dakhova O, Liu E, Carrum G, Kamble RT, Gee AP, et al. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Invest. 2016;126(7):2588–96.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, Hawkins R, Chaney C, Cherian S, Chen X, et al. Immunotherapy of non-hodgkin’s lymphoma with a defined ratio of CD8 + and CD4 + CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8(355):355ra116.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, Bleakley M, Brown C, Mgebroff S, Kelly-Spratt KS, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129(25):3322–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hu Y, Wu Z, Luo Y, Shi J, Yu J, Pu C, Liang Z, Wei G, Cui Q, Sun J, et al. Potent anti-leukemia activities of Chimeric Antigen Receptor-Modified T Cells against CD19 in Chinese patients with Relapsed/Refractory Acute lymphocytic leukemia. Clin Cancer Res. 2017;23(13):3297–306.

    Article  CAS  PubMed  Google Scholar 

  22. Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, Ghobadi A, Budde LE, Bot A, Rossi JM. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25(1):285–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory large B-Cell lymphoma. N Engl J Med. 2017;377(26):2531–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D, et al. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017;377(26):2545–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Turtle CJ, Hay KA, Hanafi LA, Li D, Cherian S, Chen X, Wood B, Lozanski A, Byrd JC, Heimfeld S, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-Specific chimeric Antigen receptor-modified T cells after failure of Ibrutinib. J Clin Oncol. 2017;35(26):3010–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Enblad G, Karlsson H, Gammelgård G, Wenthe J, Lövgren T, Amini RM, Wikstrom KI, Essand M, Savoldo B, Hallböök H, et al. A phase I/IIa trial using CD19-Targeted third-generation CAR T cells for Lymphoma and Leukemia. Clin Cancer Res. 2018;24(24):6185–94.

    Article  CAS  PubMed  Google Scholar 

  27. Geyer MB, Riviere I, Senechal B, Wang X, Wang Y, Purdon TJ, Hsu M, Devlin SM, Halton E, Lamanna N, et al. Autologous CD19-Targeted CAR T cells in patients with residual CLL following initial Purine Analog-based therapy. Mol Ther. 2018;26(8):1896–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jacoby E, Bielorai B, Avigdor A, Itzhaki O, Hutt D, Nussboim V, Meir A, Kubi A, Levy M, Zikich D, et al. Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. Am J Hematol. 2018;93(12):1485–92.

    Article  CAS  PubMed  Google Scholar 

  29. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, et al. Tisagenlecleucel in Children and Young adults with B-Cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, et al. Long-term follow-up of CD19 CAR therapy in Acute Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):449–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rossi J, Paczkowski P, Shen YW, Morse K, Flynn B, Kaiser A, Ng C, Gallatin K, Cain T, Fan R, et al. Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL. Blood. 2018;132(8):804–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Svoboda J, Rheingold SR, Gill SI, Grupp SA, Lacey SF, Kulikovskaya I, Suhoski MM, Melenhorst JJ, Loudon B, Mato AR, et al. Nonviral RNA chimeric antigen receptor-modified T cells in patients with Hodgkin lymphoma. Blood. 2018;132(10):1022–6.

    Article  CAS  PubMed  Google Scholar 

  33. Weng J, Lai P, Qin L, Lai Y, Jiang Z, Luo C, Huang X, Wu S, Shao D, Deng C, et al. A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia. J Hematol Oncol. 2018;11(1):25.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Curran KJ, Margossian SP, Kernan NA, Silverman LB, Williams DA, Shukla N, Kobos R, Forlenza CJ, Steinherz P, Prockop S, et al. Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL. Blood. 2019;134(26):2361–8.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ghorashian S, Kramer AM, Onuoha S, Wright G, Bartram J, Richardson R, Albon SJ, Casanovas-Company J, Castro F, Popova B, et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat Med. 2019;25(9):1408–14.

    Article  CAS  PubMed  Google Scholar 

  36. Hay KA, Gauthier J, Hirayama AV, Voutsinas JM, Wu Q, Li D, Gooley TA, Cherian S, Chen X, Pender BS, et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood. 2019;133(15):1652–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Gooley T, Li D, Cherian S, Chen X, Pender BS, et al. The response to lymphodepletion impacts PFS in patients with aggressive non-hodgkin lymphoma treated with CD19 CAR T cells. Blood. 2019;133(17):1876–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hirayama AV, Gauthier J, Hay KA, Voutsinas JM, Wu Q, Pender BS, Hawkins RM, Vakil A, Steinmetz RN, Riddell SR, et al. High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy. Blood. 2019;134(7):636–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, et al. 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;20(1):31–42.

    Article  CAS  PubMed  Google Scholar 

  40. Ma F, Ho JY, Du H, Xuan F, Wu X, Wang Q, Wang L, Liu Y, Ba M, Wang Y, et al. Evidence of long-lasting anti-CD19 activity of engrafted CD19 chimeric antigen receptor-modified T cells in a phase I study targeting pediatrics with acute lymphoblastic leukemia. Hematol Oncol. 2019;37(5):601–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jäger U, Jaglowski S, Andreadis C, Westin JR, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-Cell lymphoma. N Engl J Med. 2019;380(1):45–56.

    Article  CAS  PubMed  Google Scholar 

  42. Ying Z, Huang XF, Xiang X, Liu Y, Kang X, Song Y, Guo X, Liu H, Ding N, Zhang T. A safe and potent anti-CD19 CAR T cell therapy. Nat Med. 2019;25(6):947–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang Q, Hu H, Chen SY, Liu CJ, Hu FF, Yu J, Wu Y, Guo AY. Transcriptome and Regulatory Network Analyses of CD19-CAR-T immunotherapy for B-ALL. Genomics Proteom Bioinf. 2019;17(2):190–200.

    Article  CAS  Google Scholar 

  44. Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, Mehta A, Purev E, Maloney DG, Andreadis C, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839–52.

    Article  PubMed  Google Scholar 

  45. An F, Wang H, Liu Z, Wu F, Zhang J, Tao Q, Li Y, Shen Y, Ruan Y, Zhang Q, et al. Influence of patient characteristics on chimeric antigen receptor T cell therapy in B-cell acute lymphoblastic leukemia. Nat Commun. 2020;11(1):5928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Benjamin R, Graham C, Yallop D, Jozwik A, Mirci-Danicar OC, Lucchini G, Pinner D, Jain N, Kantarjian H, Boissel N, et al. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. Lancet. 2020;396(10266):1885–94.

    Article  CAS  PubMed  Google Scholar 

  47. Cappell KM, Sherry RM, Yang JC, Goff SL, Vanasse DA, McIntyre L, Rosenberg SA, Kochenderfer JN. Long-term Follow-Up of Anti-CD19 chimeric Antigen receptor T-Cell therapy. J Clin Oncol. 2020;38(32):3805–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chen YH, Zhang X, Cheng YF, Chen H, Mo XD, Yan CH, Chen Y, Han W, Sun YQ, Wang Y, et al. Long-term follow-up of CD19 chimeric antigen receptor T-cell therapy for relapsed/refractory acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation. Cytotherapy. 2020;22(12):755–61.

    Article  PubMed  Google Scholar 

  49. Frey NV, Gill S, Hexner EO, Schuster S, Nasta S, Loren A, Svoboda J, Stadtmauer E, Landsburg DJ, Mato A, et al. Long-term outcomes from a randomized dose optimization study of Chimeric Antigen Receptor Modified T Cells in relapsed chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2862–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gu R, Liu F, Zou D, Xu Y, Lu Y, Liu B, Liu W, Chen X, Liu K, Guo Y, et al. Efficacy and safety of CD19 CAR T constructed with a new anti-CD19 chimeric antigen receptor in relapsed or refractory acute lymphoblastic leukemia. J Hematol Oncol. 2020;13(1):122.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Jacobson CA, Hunter BD, Redd R, Rodig SJ, Chen PH, Wright K, Lipschitz M, Ritz J, Kamihara Y, Armand P, et al. Axicabtagene Ciloleucel in the Non-trial setting: outcomes and correlates of response, resistance, and toxicity. J Clin Oncol. 2020;38(27):3095–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, Nassif Kerbauy L, Overman B, Thall P, Kaplan M, et al. Use of CAR-Transduced Natural Killer cells in CD19-Positive lymphoid tumors. N Engl J Med. 2020;382(6):545–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nastoupil LJ, Jain MD, Feng L, Spiegel JY, Ghobadi A, Lin Y, Dahiya S, Lunning M, Lekakis L, Reagan P, et al. Standard-of-care Axicabtagene Ciloleucel for relapsed or refractory large B-Cell lymphoma: results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2020;38(27):3119–28.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Pasquini MC, Hu ZH, Curran K, Laetsch T, Locke F, Rouce R, Pulsipher MA, Phillips CL, Keating A, Frigault MJ, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-hodgkin lymphoma. Blood Adv. 2020;4(21):5414–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sesques P, Ferrant E, Safar V, Wallet F, Tordo J, Dhomps A, Karlin L, Brisou G, Vercasson M, Hospital-Gustem C, et al. Commercial anti-CD19 CAR T cell therapy for patients with relapsed/refractory aggressive B cell lymphoma in a European center. Am J Hematol. 2020;95(11):1324–33.

    Article  CAS  PubMed  Google Scholar 

  56. Wang W, Jiang J, Wu C. CAR-NK for tumor immunotherapy: clinical transformation and future prospects. Cancer Lett. 2020;472:175–80.

    Article  CAS  PubMed  Google Scholar 

  57. Zhou X, Tu S, Wang C, Huang R, Deng L, Song C, Yue C, He Y, Yang J, Liang Z, et al. Phase I Trial of Fourth-Generation Anti-CD19 Chimeric Antigen Receptor T Cells against Relapsed or refractory B cell Non-hodgkin Lymphomas. Front Immunol. 2020;11:564099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Baird JH, Epstein DJ, Tamaresis JS, Ehlinger Z, Spiegel JY, Craig J, Claire GK, Frank MJ, Muffly L, Shiraz P, et al. Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma. Blood Adv. 2021;5(1):143–55.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Gauthier J, Bezerra ED, Hirayama AV, Fiorenza S, Sheih A, Chou CK, Kimble EL, Pender BS, Hawkins RM, Vakil A, et al. Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies. Blood. 2021;137(3):323–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Iacoboni G, Villacampa G, Martinez-Cibrian N, Bailén R, Lopez Corral L, Sanchez JM, Guerreiro M, Caballero AC, Mussetti A, Sancho JM, et al. Real-world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B-cell lymphoma. Cancer Med. 2021;10(10):3214–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mian A, Wei W, Winter AM, Khouri J, Jagadeesh D, Anwer F, Gerds AT, Dean RM, Sobecks R, Pohlman B, et al. Outcomes and factors impacting use of axicabtagene ciloleucel in patients with relapsed or refractory large B-cell lymphoma: results from an intention-to-treat analysis. Leuk Lymphoma. 2021;62(6):1344–52.

    Article  CAS  PubMed  Google Scholar 

  62. Shah BD, Bishop MR, Oluwole OO, Logan AC, Baer MR, Donnellan WB, O’Dwyer KM, Holmes H, Arellano ML, Ghobadi A, et al. KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results. Blood. 2021;138(1):11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tan Y, Pan J, Deng B, Ling Z, Song W, Xu J, Duan J, Wang Z, Yu X, Chang AH, et al. Toxicity and effectiveness of CD19 CAR T therapy in children with high-burden central nervous system refractory B-ALL. Cancer Immunol Immunother. 2021;70(7):1979–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang S, Wang X, Ye C, Cheng H, Shi M, Chen W, Qi K, Wang G, Wu Q, Zeng L, et al. Humanized CD19-targeted chimeric antigen receptor T (CAR-T) cells for relapsed/refractory pediatric acute lymphoblastic leukemia. Am J Hematol. 2021;96(5):E162–5.

    Article  CAS  PubMed  Google Scholar 

  65. Ying Z, Yang H, Guo Y, Li W, Zou D, Zhou D, Wang Z, Zhang M, Wu J, Liu H, et al. Relmacabtagene autoleucel (relma-cel) CD19 CAR-T therapy for adults with heavily pretreated relapsed/refractory large B-cell lymphoma in China. Cancer Med. 2021;10(3):999–1011.

    Article  CAS  PubMed  Google Scholar 

  66. Ying Z, Huang XF, Xiang X, Liu Y, Kang X, Song Y, Guo X, Liu H, Ding N, Zhang T, et al. A safe and potent anti-CD19 CAR T cell therapy. Nat Med. 2019;25(6):947–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Dai H, Wang Y, Lu X, Han W. Chimeric Antigen receptors modified T-Cells for Cancer Therapy. J Natl Cancer Inst 2016, 108(7).

  68. Ramos CA, Savoldo B, Torrano V, Ballard B, Zhang H, Dakhova O, Liu E, Carrum G, Kamble RT, Gee AP. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Investig. 2016;126(7):2588–96.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Ying Z, Song Y, Zhu J. Effectiveness and safety of Anti-CD19 chimeric Antigen Receptor-T cell immunotherapy in patients with Relapsed/Refractory large B-Cell lymphoma: a systematic review and Meta-analysis. Front Pharmacol. 2022;13:834113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Aamir S, Anwar MY, Khalid F, Khan SI, Ali MA, Khattak ZE. Systematic review and Meta-analysis of CD19-Specific CAR-T cell therapy in Relapsed/Refractory Acute Lymphoblastic Leukemia in the Pediatric and Young Adult Population: Safety and Efficacy outcomes. Clin Lymphoma Myeloma Leuk. 2021;21(4):e334–47.

    Article  CAS  PubMed  Google Scholar 

  71. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127(26):3321–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Campos NSP, Souza BS, Silva G, Porto VA, Chalbatani GM, Lagreca G, Janji B, Suarez ER. Carbonic anhydrase IX: a renewed target for Cancer Immunotherapy. Cancers (Basel) 2022, 14(6).

  73. Li S, Zhang J, Wang M, Fu G, Li Y, Pei L, Xiong Z, Qin D, Zhang R, Tian X, et al. Treatment of acute lymphoblastic leukaemia with the second generation of CD19 CAR-T containing either CD28 or 4-1BB. Br J Haematol. 2018;181(3):360–71.

    Article  CAS  PubMed  Google Scholar 

  74. Cappell KM, Kochenderfer JN. A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains. Nat Rev Clin Oncol. 2021;18(11):715–27.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors sincerely thank all authors of all studies included in this meta-analysis.

Funding

N.S.P.C had a Brazilian National Council for Scientific and Technological Development (CNPq) scholarship (143179/2021-7; 140514/2022-8). V.A.P was supported by a Federal University of ABC institutional scholarship (PIC- UFABC). E.R.S had a grant from Sao Paulo Research Foundation/Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Brazil, number 2018/17656-0 and 2023/03631-3.

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  1. Centro Universitário FMABC, Santo André, 09060-870, SP, Brazil

    Erik Montagna

  2. Center for Natural and Human Sciences, Federal University of ABC, Santo Andre, 09210-580, SP, Brazil

    Najla Santos Pacheco de Campos, Victoria Alves Porto, Giselle Correia Próspero da Silva & Eloah Rabello Suarez

  3. Graduate Program in Medicine - Hematology and Oncology, Federal University of São Paulo, São Paulo, 04023-062, SP, Brazil

    Najla Santos Pacheco de Campos & Eloah Rabello Suarez

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E.M. performed the statistical analysis, manuscript writing and revision; N.S.P.C performed a literature search, provided data extraction, data clarifications and revised the manuscript; V.A.P and G.C.P.S provided data extraction and revised the manuscript; E.R.S. conceived the study, performed literature search, article selection, and manuscript writing and revision.

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Montagna, E., de Campos, N.S.P., Porto, V.A. et al. CD19 CAR T cells for B cell malignancies: a systematic review and meta-analysis focused on clinical impacts of CAR structural domains, manufacturing conditions, cellular product, doses, patient’s age, and tumor types. BMC Cancer 24, 1037 (2024). https://doi.org/10.1186/s12885-024-12651-6

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BMC Cancer

ISSN: 1471-2407

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