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Dose–response correlation for CAR-T cells: a systematic review of clinical studies
  1. Anand Rotte1,
  2. Matthew J Frigault2,
  3. Ayub Ansari1,
  4. Brad Gliner1,
  5. Christopher Heery1 and
  6. Bijal Shah3
  1. 1Department of Clinical and Regulatory Affairs, Arcellx Inc, Redwood City, California, USA
  2. 2Department of Cellular Immunotherapy, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
  3. 3Department of Malignant Hematology, Moffitt Cancer Center, Tampa, Florida, USA
  1. Correspondence to Dr Anand Rotte; arotte{at}arcellx.com; Dr Matthew J Frigault; mfrigault{at}partners.org

  • AR and MJF are joint first authors.

Abstract

The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently under clinical development, with most in early stage, during which dose selection is a key goal. The objective of this review is to address the question of dose-dependent effects on response and/or toxicity from available CAR-T cell clinical trial data. For that purpose, systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematological cancers. Studies published in English were considered. Studies in children (age <18 years), solid tumors, bispecific CAR-T cells and CAR-T cell cocktails were excluded. As a result, a total of 74 studies met the inclusion criteria. Thirty-nine studies tested multiple dose levels of CAR-T cells with at least >1 patient at each dose level. Thirteen studies observed dose-related increase in disease response and 23 studies observed dose-related increase in toxicity across a median of three dose levels. Optimal clinical efficacy was seen at doses 50–100 million cells for anti-CD19 CAR-T cells and >100 million cells for anti-BCMA CAR-T cells in majority of studies. The findings suggest, for a given construct, there exists a dose at which a threshold of optimal efficacy occurs. Dose escalation may reveal increasing objective response rates (ORRs) until that threshold is reached. However, when ORR starts to plateau despite increasing dose, further dose escalation is unlikely to result in improved ORR but is likely to result in higher incidence and/or severity of mechanistically related adverse events.

  • Immunotherapy
  • Receptors, Chimeric Antigen
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2022-005678

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    Introduction

    Cancer immunotherapy has made giant strides in the past 10 years with the development of multiple strategies including tumor-specific chimeric antigen receptor (CAR-) T cell therapies, monoclonal antibodies targeting checkpoint blockers and oncolytic viruses.1–6 CAR-T cell therapy demonstrated impressive results in hematological cancers with objective response rates (ORRs) as high as 100% noted in some studies.7 8 To date, six CAR-T cell therapies including axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), tisagenlecleucel (tisa-cel), lisocabtagene maraleucel (liso-cel), idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have been approved by the US Food and Drug Administration (FDA) for different hematological malignancies with wide-ranging doses such as 60–600 million cells for tisa-cel, 50–110 million cells for liso-cel and 2 million cells/kg body weight for axi-cel (table 1). While currently available CAR-T cell therapies showed excellent response rates, limitations such as durability of efficacy, incidence of adverse events, including cytokine release syndrome (CRS) and neurotoxicity, and production-related issues warrant continued advancement of novel CAR-T cell therapies.

    View this table:
    Table 1

    US Food and Drug Administration (FDA)-approved CAR-T cell therapies (current as of February 2022)

    To address the limitations and improve treatment outcomes, several CAR-T cell therapies of autologous and allogeneic origin are currently being developed, with most in early stages of clinical development. Dose selection is a critical determinant of the success of any cancer therapeutic, including cell therapies. Recommendation of subtherapeutic dose for the pivotal study could result in lower efficacy, whereas excessive dose could result in higher incidence and/or greater severity of adverse events. Typically phase 1 dose escalation studies are performed to recommend possible effective dose and maximum tolerated dose (MTD). Unless MTD is reached during the phase 1 study, determination of further dose escalation impact on efficacy and/or the incidence or severity of adverse events may not be possible. Dose selection may be more difficult for therapies like CAR-T cells, which cannot be described by typical principles of clinical pharmacology, such as receptor occupancy and elimination kinetics.

    Currently, initial dose recommendations are made based on preclinical models and empiric data from previous relevant studies with similar constructs in the same cancer type. However, the question of possible increase in efficacy with higher dose continues to remain in clinical development discussions because there is conflicting evidence on CAR-T cell dose–response. Positive correlation between increased response and higher dose levels was reported in some studies,9 10 whereas no correlation was seen and efficacy was similar at all dose levels in other studies.11 This review aimed to perform systematic literature review of CAR-T cell studies in adult patients with hematological malignancies and summarize the findings on dose–efficacy and dose–safety correlations. The main question the review intended to address was if there is a correlation between dose of CAR-T cell therapy and response in patients and if the efficacy increases or decreases in a dose-dependent fashion. Second, the study aimed to understand if the incidence or severity of cytokine release syndrome (CRS) and neurotoxicity was impacted by dose. Finally, the study aimed to document the findings on predictors of response including peak expansion (Cmax), area under the expansion curve (AUC) and tumor burden.

    Methods

    This systematic review followed the guidelines defined by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Statement.12

    Search criteria

    The following search terms were used in the literature search for related articles: “CAR”, “chimeric antigen receptor”, “CAR-T cell”, “acute lymphoblastic leukemia”, “ALL”, “diffuse large B-cell lymphoma”, “DLBCL”, “multiple myeloma” and “MM”. Searches were conducted on PubMed and Embase in August 2021 and November 2021, respectively. A total of seven searches were conducted on each database: (1) “CAR” or “chimeric antigen receptor”; (2) “CAR-T cell” and “acute lymphoblastic leukemia” or “ALL”; (3) “CAR-T cell” and “diffuse large B-cell lymphoma” or “DLBCL”; (4) “CAR-T cell” and “multiple myeloma” or “MM”; (5) “chimeric antigen receptor” and “acute lymphoblastic leukemia”; (6) “chimeric antigen receptor” and “diffuse large B-cell lymphoma”; and (7) “chimeric antigen receptor” and “multiple myeloma”.

    Eligibility

    All clinical prospective and retrospective studies reporting outcomes in adult patients (age ≥18 years) with hematological malignancies including acute lymphoblastic leukemia (ALL), diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM) met the inclusion criteria for consideration. Studies were excluded if they met any of the following exclusion criteria: (1) articles reported in languages other than English; (2) conference presentations and abstracts; (3) studies that did not use lymphodepletion regimen; (4) studies in children; (5) studies in solid tumors; (6) studies using bispecific CAR-T cells; (7) studies using CAR-T cell cocktails; (8) studies using bispecific antibodies; (9) studies using antibody drug conjugates; (10) articles reporting additional outcomes/post hoc analyses of previously published study; (11) preclinical studies; (12) systematic literature review articles; and (13) review articles. Bispecific CAR-T cells, solid tumors and studies in children were excluded from the review because the kinetics, efficacy and safety can be comparatively different.

    Data extraction

    Studies meeting the eligibility criteria were screened based on their title, abstract and full text by two independent reviewers. Reasons for excluding studies were recorded, and included studies were cross checked prior to data extraction such that any discrepancy arising between the two reviewers was resolved through discussion. The following data were extracted from each study’s full text: study details (author name, year of publication and country), patient characteristics (number of patients, cancer subtype, lines of prior therapy and tumor burden), CAR-T cell details (dose and regimen, target antigen, costimulatory domains, gene transfer method, generation of CAR-T cells and persistence of CAR-T cells), efficacy outcomes (overall survival (OS); progression-free survival (PFS); objective response rate (ORR); complete response rate (CRR); onset of response, duration of response (DoR), and markers of response and safety outcomes (CRS and neurotoxicity, onset of CRS/neurotoxicity).

    Studies that reported outcomes from multiple doses of CAR-T cells were identified, and studies in which at least 50 patients received CAR-T therapy were prioritized. Dose was calculated for 70 kg for studies that used body weight-based dose and for 1.6 m2 for studies that used body surface area-based dose to convert to a flat dose value in order to compare the dose across studies.

    Results

    Characteristics of selected studies

    Literature search for clinical articles published between 1 January 2010 and 15 May 2022 identified 2901 papers on CAR-T cells. After removing duplicates and screening for relevant articles based on title, abstract and then full text by two reviewers, 74 articles were selected for systematic review and data extraction (figure 1).13–66 Among the included studies, 19 (26%) studies had at least 50 patients treated, and 55 (74%) studies had <50 patients (online supplemental table S1). Quality of included studies was assessed using the guidelines for non-randomized single-arm studies (online supplemental table S2).67–70 Majority of the studies included patients with ALL (n=30, 40%) or DLBCL (n=21, 28%) or MM (n=17, 23%). In total, 3109 patients with hematological cancers were treated including 927 (30%) DLBCL patients, 1054 (34%) B-ALL patients and 501 (16%) MM patients.

    Supplemental material

    Figure 1
    Figure 1

    Study flow and selection of articles. CAR, chimeric antigen receptor.

    Multiple dose levels of CAR-T cells with >1 patient at each dose level were tested in 39 studies (table 2) including 9 (23%) studies with cohort size of at least 50 patients and 36 (92%) studies with cohort size of at least 10 patients. The TRANSCEND study by Abramson et al11 in patients with large B cell lymphoma was the largest study with 269 patients evaluating three dose levels of treatment. Majority of the multidose studies targeted CD19 (26/39; 67%) and had single intracellular domain (33/39; 85%). Intracellular signaling domain included 4–1-BB in 19 (49%) studies, CD28 in 13 studies (33%), 4–1-BB and CD28 in 2 (5%) studies and CD28 and CD27 or OX40 in 2 (5%) studies (table 2).

    View this table:
    Table 2

    Summary of studies evaluating multiple dose levels

    Factors associated with response and incidence of CRS and neurotoxicity

    Dose

    To evaluate the dose–response association, studies that tested at least two dose levels and had more than one patient per dose level were included in the first step. Determination of CAR-T cell dose varied across studies, and flat dose of fixed number of cells were given in some studies, whereas other studies dosed patients on cells per kilogram (kg) body weight or cells per body surface area. To compare the dose across studies, dose was normalized and converted to flat dose by calculating the dose for 70 kg body weight or for 1.6 m2 for studies that used body weight-based dose and body surface area-based dose, respectively. Out of 39 studies that tested at least two dose levels of CAR-T cells, association between dose administered and ORR/CRR (efficacy) was observed in 13 (33%) studies (table 2). When the studies with cohort size of at least 50 patients were compared (n=9), one study reported clear increase in response at higher doses,10 two studies reported increase in response from DL1 to DL2 but no further increase at DL371 72 and one study observed positive correlation between dose and response in patients who had SD or PD at the time of infusion.73 Intriguingly, the ORR and/or CR rate tended to be slightly better in the lower dose level cohorts in the studies that reported no correlation between dose and disease response (table 2, online supplemental table S3).

    Within the studies that showed association between dose and ORR, the starting dose was comparatively lower (<30 million cells),13 29 30 37 66 72 whereas the studies that showed no association between dose and disease response, the starting dose or DL1 was over 50 million cells.11 74–76 The study by Zhao et al used a lower DL1 (21 million cells for 70 kg) and concluded that there was no association between CAR-T cell dose and response. However, authors discussed that only 20% (n=2/10) of patients in the DL1 group achieved PR or more, which was lower compared with other dose levels in the study. Similarly, DL1 in the Zuma-3 study72 observed a positive dose response between DL1 (35 million cells for 70 kg) and DL2 (70 million cells for 70 kg) but did not see further increase in ORR in DL3 (140 million cells for 70 kg) cohort. While inconclusive, this suggests that very low doses of CAR T cells may not reach the threshold of full clinical activity which, when reached, results in maximal ORR/CR that cannot be improved on with increasing dose. In contrast, DL1 in the ide-cel pivotal study was 150 million cells10 and the ORR as well as CR/sCR rate increased from DL1 to DL2 (300 million cells) and to DL3 (450 million cells) indicating that in cases where optimal clinical activity is not achieved at 100–150 million cells, further increase may increase the ORR.

    To evaluate if there were any possible differences in association due to difference in target antigen or intracellular domains, studies that evaluated multiple doses were separated based on target antigen and on intracellular domains and the dose–response and dose–safety association was evaluated. As illustrated in figure 2, 8/26 (31%) studies targeting CD19 and 5/9 (55%) studies targeting BCMA noted a positive correlation between dose and ORR/CRR. Similar results were seen (figure 2) when studies were categorized based on intracellular signaling domain (single vs dual) and type of intracellular signaling domain (4–1-BB vs CD28). Interestingly, the trends seen when studies were separated based on antigen or signaling domain were in line with the trend seen with entire cohort. Association between dose–response was mainly at doses below the threshold of optimal clinical activity, but when optimal clinical activity was reached, further escalation increased toxicity without increasing ORR.

    Figure 2
    Figure 2

    Response and toxicity association with dose in studies categorized by (A) CAR-T cells targeting CD19, (B) CAR-T cells targeting BCMA, (C) CAR-T cells with single intracellular (IC) domain, (D) CAR-T cells with two IC domains, (E) CAR-T cells with 4–1-BB IC domain and (F) CAR-T cells with CD28 IC domain. Positive association with dose was recorded as yes or no.

    Dose–safety association was less frequently explored or reported compared with dose–response association. Out of the 39 studies that commented on dose–response correlation, 34 (87%) studies either commented on incidence and/or severity of CAR-T related adverse events including CRS and immune cell associated neurotoxicity syndrome (ICANS) or reported the adverse events (AEs) separately at different dose levels. Increased incidence and/or severity of CRS/ICANS was observed in 23 (68%) studies, and 11 (32%) studies noted no association between dose and toxicity (table 2). Out of 11 studies with cohort size over 50 patients, seven (64%) studies observed higher adverse events,10 71 72 75 one (9%) study noted no association with dose77 and three (27%) studies did not comment on dose–safety association.11 76 Top DL varied widely in the studies that showed direct correlation between dose and adverse events with dose administered ranging between 110 million cells and 1000 million cells (table 2 and online supplemental table S3). Among the 11 studies that showed no association between dose and adverse events, split or fractionated dosing was used to mitigate adverse events in four (36%) studies32 35 38 64 and ORR was also low in three (27%) studies.16 44 56

    CAR-T cell expansion (AUC) and peak (Cmax)

    Majority of the studies did not report CAR-T cell pharmacokinetics (PKs) parameters (AUC and Cmax) at individual dose levels. PK data reported in the studies were extracted and listed in online supplemental table S4. Disease response, adverse event incidence and adverse event severity were clearly associated with CAR-T cell expansion (see ‘Findings on association with dose’ column in table 2 and online supplemental table S3). Almost all studies that reported the factors associated with response noted that the disease response and/or CRS incidence or severity correlated directly with AUC or Cmax of CAR-T cells. Even in the studies that did not see a correlation between dose and disease response,11 76 CAR-T cell PK was shown to be directly associated with response and/or safety.

    In contrast, the association between dose and pharmacokinetic parameters was not clear. Majority of the studies (19/39; 49%) that tested multiple doses, either did not report PK or did not report PK separately for each DL. Among the studies that reported granular details of PK, positive correlation between dose and AUC and/or Cmax was observed in eight studies, and no correlation was noted in 11 studies (see ‘Findings on association with dose’ column in table 2 and online supplemental table S3).

    Time to peak expansion and onset of response

    As the CAR-T cell expansion can translate into tumor cell cytotoxicity, data from studies reporting time to peak expansion and onset of response (efficacy/safety events) were extracted (online supplemental table S5; figure 3). Fifty-two (70%) studies reported the time to peak CAR T-cell expansion and/or response including 11 studies with cohort size over 50 patients.10 11 71 72 74–77 However, studies reported the onset times for the entire cohort; granular details at different dose levels were not reported. Interestingly, time to peak expansion in peripheral blood was comparable across all studies (7–14 days) even though doses varied. Similarly, median time to response (1 month), CRS events (1–7 days) and neurotoxicity events (2–12 days) were comparable across all studies. However, it should be noted that median time to response is limited to the first evaluation of response, which typically occurs at 1 month across all studies.

    Figure 3
    Figure 3

    Time to peak expansion (left panels), onset of CRS and ICANS (right panels) in the CAR-T cells studies targeting (A and B) CD19 with 4–1-BB as intracellular signal, (C and D) CD19 with CD28 as intracellular signal and (E and F) BCMA with 4–1-BB as intracellular signal, except ref no. 13 has CD28 as intracellular signal. Markers represent median values, and error bars represent range (min–max) or IQR. Studies that reported only range are represented without markers. Detailed information is included in online supplemental table S5. CAR, chimeric antigen receptor; CRS, cytokine release syndrome.

    Tumor burden

    Twenty-eight (38%) studies reported details of tumor burden at the time of treatment and its correlation with disease response and/or incidence/severity of CRS and neurotoxicity (online supplemental table S6).9–11 42 75 76 78–81 High tumor burden was seen to be associated with lower response rates in majority of the studies (n=15; 54%) and was found to be associated with better response rate only in two (7%) studies.25 80 The association between tumor burden and adverse event incidence or severity was reported in 14 (50%) studies: nine (32%) studies observed that high tumor burden was associated with higher incidence and/or severity of CRS and neurotoxicity, whereas five (18%) studies noted no difference (online supplemental table S6). Interestingly, studies by Turtle et al and Park et al used bone marrow tumor burden-based risk adoptive dosing strategy and noted that the approach reduced the toxicity of treatment.53 76

    Discussion

    Current systematic review aimed to address a critical question in the early clinical development of CAR-T cells. Previous systematic reviews mainly summarized efficacy and/or safety outcomes or biomarkers associated with safety outcomes for a specific CAR-T cell therapy or a specific indication,82–89 but the correlation between dose and related factors and response was not studied. To derive from the combined knowledge of all relevant clinical studies, all CAR-T cells therapies for hematological cancers were analyzed together for correlations and then analyzed separately based on target antigens as well as intracellular domains. The review did not pool the efficacy or safety data across the studies. Instead, outcomes of each study were analyzed individually, and positive correlations or lack of correlations between dose and ORR/CRR, dose and toxicity were noted first, followed by overall assessment of correlation between dose and response (table 2, figure 2). This approach ensured that each study had its own comparative cohorts and thereby accounted for the possible differences in target antigens and CAR-T cell products.

    In response to question of whether there is a dose-related increase in disease response to CAR-T cells, the results show that dose and disease response association was mainly seen when optimal clinical efficacy (defined based on the outcomes from the studies as >70% ORR) was not achieved at lower doses. The studies that did not show association (table 2 and online supplemental table S3) either had a very good overall response rate or had a poor overall response rate indicating that further dose escalation may not result in increased response when the response rates are very high (80%–100%) or very low (0–20%) due to intrinsic product attributes affecting cell expansion kinetics. Our findings also noted a general trend in dose required to achieve optimal clinical efficacy. Majority of anti-CD19 CAR-T cell studies achieved optimal clinical efficacy (>70% ORR) at doses between 50 and 100 million cells (table 2 and online supplemental table S3). Comparatively higher doses (>100 million cells) were needed to achieve optimal clinical efficacy for majority of anti-BCMA CAR-T cell studies (table 2 and online supplemental table S3), but it is to be noted that some anti-BCMA CAR-T cells like cilta-cel achieved optimal clinical efficacy at lower dose (<100 million cells) and did not see further increase in response at doses above 100 million cells.71 The differences in dose required to achieve optimal clinical efficacy between anti-CD19 and anti-BCMA CAR-T cells are possibly due to differences in the target antigen expression on tumor cells or CAR-T cell product attributes. Similarly, the differences in optimal clinical efficacy dose between CAR-T cells targeting same antigen are possibly due to product characteristics such as CAR expression per cell, proportion of CAR+ cells in the final product and viability of CAR+ cells.

    In contrast to dose and disease response association, incidence and/or severity of CAR-T cell-related adverse events including CRS and neurotoxicity was associated with the dose in majority of studies (table 2), possibly because at higher doses, there are increased chances of direct activation of non-target immune cells such as macrophages and innate immune cells through cell–cell interactions before and/or as CAR-T cells interact with their target tumor cells. Interestingly, the onset of CRS was within 7 days in most studies and the time to reach peak expansion was 2 weeks in most studies (online supplemental table S5) supporting the hypothesis that the initiation of CRS was possibly related to CAR-T cell activity before reaching Cmax.

    Tumor burden is another factor that is commonly considered during CAR-T cell treatment and its association with response is debated during the clinical development of CAR-T cells. In response to the question of whether tumor burden is directly or inversely associated with response, the results show that high tumor burden is very likely to be associated with low disease response and with high adverse events. All the studies identified in the review showed an inverse association between tumor burden and disease response (online supplemental table S6) except the study by Wang et al80 which, unlike all other studies, used a comparatively different cut-off (</≥ cohort median) and observed that patients with tumor burden less than median had lower ORR. Intriguingly, peak CAR-T cell expansion (Cmax), a parameter shown to be associated with response was found to be lower in patients with high tumor burden.90 The findings are in line with previous studies that noted that high tumor burden was associated with lower response to immunotherapy. In fact, some of the CAR-T cell studies have even proposed the tumor burden-based risk-adoptive dosing approach46 53 or aggressive treatment with chemotherapy or radiotherapy to shrink the tumors91 prior to CAR-T cell treatment.

    The review was mainly able to achieve the difficult task of consolidating the learnings from different types of CAR-T cell studies performed in heterogenous patient population by evaluating the association between dose and response separately for each study. The findings from our study show that the answer to the question of whether there is a dose–response correlation is possibly not a simple yes or no. Our study identified and listed the trials that saw increased response at higher dose levels and the trials that had similar response at all dose levels and described the common factors seen in both categories. The studies that did not see any association between dose and response either had a very low response rate at all the doses tested indicating that the cell product was not effective or had a very high response rate at all the doses tested indicating that the product was very effective and lowest dose administered was able to achieve maximum possible response. Similarly, in the studies that saw an increase in response with dose increments, lowest dose was apparently not sufficient to achieve optimal effector to target cell ratio (E-T ratio) and drive the response. The findings support the point that CAR-T cell therapy is a living drug that involves in vivo proliferation of cells and in vivo expansion of CAR-T cells is possibly more relevant than the starting dose and also support the point that the effector to target cell ratio (E-T ratio) needs to be considered during determination of the dose as low E-T ratio can result in ineffective response. Finally, the summary of median time to peak expansion, onset of response, onset of CRS and onset of neurotoxicity included in the review support the hypothesis that PKs of CAR-T cells and mechanisms are comparable across all hematological cancers.

    Based on the mechanisms of CAR-T cell activity and the results from the studies included in the review, a sigmoidal dose response curve (figure 4) can be proposed. It includes a threshold dose defined as dose needed to achieve the least effective E-T ratio and the optimal efficacy dose, defined as lowest dose that had most effective E-T ratio and highest efficacy was comparable across majority of the studies irrespective of target antigen and intracellular signaling domain. A positive correlation between dose and ORR is less likely above the optimal efficacy dose, and further increase in dose would likely increase the toxicity of CAR-T cells (figure 4).

    Figure 4
    Figure 4

    Model showing dose–response (A) and dose–toxicity (B) correlation of CAR-T cells. Increments in response can be seen when dose increments are made at lower doses (<50 million cells approximately). Increase in response is associated with increase in frequency of adverse events (CRS and ICANS), but the toxicity is manageable with standard treatment at threshold efficacy. Further increase in dose (>150 million cells approximately) beyond threshold efficacy could only have marginal increase in efficacy but could lead to significant increase in toxicity of CAR-T cells manifested as increased severity of adverse events. CAR, chimeric antigen receptor; CRS, cytokine release syndrome.

    Limitations

    Review is limited by the studies included. All studies were non-randomized, open label, lacked control cohort and the majority had small sample size. Furthermore, majority of the studies did not include independent review committee for selection of subjects (selection bias) and had >20% loss of subjects to follow-up (attrition bias; online supplemental table S2). Studies also did not report granular differences in CAR-T cell expansion, onset of response and persistence between dose levels. Durability of response and its correlation with dose was also not explored within the studies. Finally, the review excluded solid tumors and studies in children, which could limit the application of the findings to adult hematological cancers.

    Conclusion

    In summary, the findings from the systematic literature review suggest that there may be an optimal dose of efficacy in CAR-T cell therapeutics at which maximal clinical effect is achieved and beyond which no additional antitumor effect can be observed. However, increasing the dose beyond the optimal efficacy or increasing the dose when the ORR is relatively high may result in higher incidence and/or severity of adverse events. The findings also show that high tumor burden is likely associated with lower response to CAR-T cell treatment.

    Supplemental material

    Ethics statements

    Patient consent for publication

    Ethics approval

    Not applicable.

    References

    1. ↵
      1. Lemaire V,
      2. Shemesh CS,
      3. Rotte A
      . Pharmacology-based ranking of anti-cancer drugs to guide clinical development of cancer immunotherapy combinations. J Exp Clin Cancer Res 2021;40:311.doi:10.1186/s13046-021-02111-5pmid:http://www.ncbi.nlm.nih.gov/pubmed/34598713
      OpenUrlPubMed
    2. ↵
      1. Townsend MH,
      2. Shrestha G,
      3. Robison RA, et al
      . The expansion of targetable biomarkers for CAR T cell therapy. J Exp Clin Cancer Res 2018;37:163.doi:10.1186/s13046-018-0817-0pmid:http://www.ncbi.nlm.nih.gov/pubmed/30031396
      OpenUrlPubMed
    3. ↵
      1. Larson RC,
      2. Maus MV
      . Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat Rev Cancer 2021;21:145–61.doi:10.1038/s41568-020-00323-zpmid:http://www.ncbi.nlm.nih.gov/pubmed/33483715
      OpenUrlPubMed
    4. ↵
      1. Rotte A,
      2. Sahasranaman S,
      3. Budha N
      . Targeting TIGIT for immunotherapy of cancer: update on clinical development. Biomedicines 2021;9. doi:doi:10.3390/biomedicines9091277. [Epub ahead of print: 21 09 2021].pmid:http://www.ncbi.nlm.nih.gov/pubmed/34572463
    5. ↵
      1. Styczyński J
      . A brief history of CAR-T cells: from laboratory to the bedside. Acta Haematol Pol 2020;51:2–5.doi:10.2478/ahp-2020-0002
      OpenUrlCrossRef
    6. ↵
      1. Shemesh CS,
      2. Hsu JC,
      3. Hosseini I, et al
      . Personalized cancer vaccines: clinical landscape, challenges, and opportunities. Mol Ther 2021;29:555–70.doi:10.1016/j.ymthe.2020.09.038pmid:http://www.ncbi.nlm.nih.gov/pubmed/33038322
      OpenUrlPubMed
    7. ↵
      1. Berdeja JG,
      2. Madduri D,
      3. Usmani SZ, et al
      . Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 2021;398:314–24.doi:10.1016/S0140-6736(21)00933-8pmid:http://www.ncbi.nlm.nih.gov/pubmed/34175021
      OpenUrlPubMed
    8. ↵
      1. CARTITUDE-1
      . Phase 1b/2 Study of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy, in Relapsed/Refractory Multiple Myeloma. In: ASH 62nd annual meeting. Virtual meeting, 2020.
    9. ↵
      1. Neelapu SS,
      2. Locke FL,
      3. Bartlett NL, et al
      . Axicabtagene Ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377:2531–44.doi:10.1056/NEJMoa1707447pmid:http://www.ncbi.nlm.nih.gov/pubmed/29226797
      OpenUrlCrossRefPubMed
    10. ↵
      1. Munshi NC,
      2. Anderson LD,
      3. Shah N, et al
      . Idecabtagene Vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 2021;384:705–16.doi:10.1056/NEJMoa2024850pmid:http://www.ncbi.nlm.nih.gov/pubmed/33626253
      OpenUrlCrossRefPubMed
    11. ↵
      1. Abramson JS,
      2. Palomba ML,
      3. Gordon LI, et al
      . Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 2020;396:839–52.doi:10.1016/S0140-6736(20)31366-0pmid:http://www.ncbi.nlm.nih.gov/pubmed/32888407
      OpenUrlCrossRefPubMed
    12. ↵
      1. Moher D,
      2. Liberati A,
      3. Tetzlaff J, et al
      . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535.doi:10.1136/bmj.b2535pmid:http://www.ncbi.nlm.nih.gov/pubmed/19622551
      OpenUrlFREE Full Text
    13. ↵
      1. Ali SA,
      2. Shi V,
      3. Maric I, et al
      . T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 2016;128:1688–700.doi:10.1182/blood-2016-04-711903pmid:http://www.ncbi.nlm.nih.gov/pubmed/27412889
      OpenUrlAbstract/FREE Full Text
    14. ↵
      1. An F,
      2. Wang H,
      3. Liu Z, et al
      . Influence of patient characteristics on chimeric antigen receptor T cell therapy in B-cell acute lymphoblastic leukemia. Nat Commun 2020;11:5928.doi:10.1038/s41467-020-19774-xpmid:http://www.ncbi.nlm.nih.gov/pubmed/33230103
      OpenUrlPubMed
    15. ↵
      1. Bao F,
      2. Wan W,
      3. He T, et al
      . Autologous CD19-directed chimeric antigen receptor-T cell is an effective and safe treatment to refractory or relapsed diffuse large B-cell lymphoma. Cancer Gene Ther 2019;26:248–55.doi:10.1038/s41417-018-0073-7pmid:http://www.ncbi.nlm.nih.gov/pubmed/30622321
      OpenUrlCrossRefPubMed
    16. ↵
      1. Baumeister SH,
      2. Murad J,
      3. Werner L, et al
      . Phase I trial of autologous CAR T cells targeting NKG2D ligands in patients with AML/MDS and multiple myeloma. Cancer Immunol Res 2019;7:100–12.doi:10.1158/2326-6066.CIR-18-0307pmid:http://www.ncbi.nlm.nih.gov/pubmed/30396908
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Brudno JN,
      2. Lam N,
      3. Vanasse D, et al
      . Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma. Nat Med 2020;26:270–80.doi:10.1038/s41591-019-0737-3pmid:http://www.ncbi.nlm.nih.gov/pubmed/31959992
      OpenUrlCrossRefPubMed
    18. ↵
      1. Cao J,
      2. Wang G,
      3. Cheng H, et al
      . Potent anti-leukemia activities of humanized CD19-targeted chimeric antigen receptor T (CAR-T) cells in patients with relapsed/refractory acute lymphoblastic leukemia. Am J Hematol 2018;93:851–8.doi:10.1002/ajh.25108pmid:http://www.ncbi.nlm.nih.gov/pubmed/29633386
      OpenUrlPubMed
    19. ↵
      1. Casadei B,
      2. Argnani L,
      3. Guadagnuolo S, et al
      . Real world evidence of car T-cell therapies for the treatment of relapsed/refractory B-cell non-Hodgkin lymphoma: a monocentric experience. Cancers 2021;13. doi:doi:10.3390/cancers13194789. [Epub ahead of print: 24 09 2021].pmid:http://www.ncbi.nlm.nih.gov/pubmed/34638273
    20. ↵
      1. Chen W,
      2. Wang Y,
      3. Qi K, et al
      . Efficacy and safety of chimeric antigen receptor T-cell therapy for relapsed/refractory immunoglobulin D multiple myeloma. Transplant Cell Ther 2021;27:273.e1–273.e5.doi:10.1016/j.jtct.2020.12.017pmid:http://www.ncbi.nlm.nih.gov/pubmed/33781540
      OpenUrlPubMed
    21. ↵
      1. Cohen AD,
      2. Garfall AL,
      3. Stadtmauer EA, et al
      . B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest 2019;129:2210–21.doi:10.1172/JCI126397pmid:http://www.ncbi.nlm.nih.gov/pubmed/30896447
      OpenUrlCrossRefPubMed
    22. ↵
      1. Cornell RF,
      2. Bishop MR,
      3. Kumar S, et al
      . A phase 1, multicenter study evaluating the safety and efficacy of KITE-585, an autologous anti-BCMA CAR T-cell therapy, in patients with relapsed/refractory multiple myeloma. Am J Cancer Res 2021;11:3285–93.pmid:http://www.ncbi.nlm.nih.gov/pubmed/34249462
      OpenUrlPubMed
    23. ↵
      1. Cruz CRY,
      2. Micklethwaite KP,
      3. Savoldo B, et al
      . Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 2013;122:2965–73.doi:10.1182/blood-2013-06-506741pmid:http://www.ncbi.nlm.nih.gov/pubmed/24030379
      OpenUrlAbstract/FREE Full Text
    24. ↵
      1. Cui R,
      2. Lyu C,
      3. Li Q, et al
      . Humanized anti-CD19 chimeric antigen receptor-T cell therapy is safe and effective in lymphoma and leukemia patients with chronic and resolved hepatitis B virus infection. Hematol Oncol 2021;39:75–86.doi:10.1002/hon.2807pmid:http://www.ncbi.nlm.nih.gov/pubmed/32949412
      OpenUrlPubMed
    25. ↵
      1. Davila ML,
      2. Riviere I,
      3. Wang X, et al
      . Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 2014;6:224ra25.doi:10.1126/scitranslmed.3008226pmid:http://www.ncbi.nlm.nih.gov/pubmed/24553386
      OpenUrlAbstract/FREE Full Text
    26. ↵
      1. Enblad G,
      2. Karlsson H,
      3. Gammelgård G, et al
      . A phase I/IIa trial using CD19-Targeted third-generation CAR T cells for lymphoma and leukemia. Clin Cancer Res 2018;24:6185–94.doi:10.1158/1078-0432.CCR-18-0426pmid:http://www.ncbi.nlm.nih.gov/pubmed/30097433
      OpenUrlAbstract/FREE Full Text
    27. ↵
      1. Eom H-S,
      2. Choi BK,
      3. Lee Y, et al
      . Phase I clinical trial of 4-1BB-based adoptive T-cell therapy for Epstein-Barr Virus (EBV)-positive tumors. J Immunother 2016;39:140–8.doi:10.1097/CJI.0000000000000113pmid:http://www.ncbi.nlm.nih.gov/pubmed/26938947
      OpenUrlPubMed
    28. ↵
      1. Feng J,
      2. Xu H,
      3. Cinquina A, et al
      . Treatment of aggressive T cell lymphoblastic lymphoma/leukemia using Anti-CD5 CAR T cells. Stem Cell Rev Rep 2021;17:652–61.doi:10.1007/s12015-020-10092-9pmid:http://www.ncbi.nlm.nih.gov/pubmed/33410096
      OpenUrlPubMed
    29. ↵
      1. Frey NV,
      2. Gill S,
      3. Hexner EO, 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;38:2862–71.doi:10.1200/JCO.19.03237pmid:http://www.ncbi.nlm.nih.gov/pubmed/32298202
      OpenUrlCrossRefPubMed
    30. ↵
      1. Frey NV,
      2. Shaw PA,
      3. Hexner EO, et al
      . Optimizing chimeric antigen receptor T-cell therapy for adults with acute lymphoblastic leukemia. J Clin Oncol 2020;38:415–22.doi:10.1200/JCO.19.01892pmid:http://www.ncbi.nlm.nih.gov/pubmed/31815579
      OpenUrlPubMed
    31. ↵
      1. Geyer MB,
      2. Rivière I,
      3. Sénéchal B, et al
      . Autologous CD19-Targeted CAR T cells in patients with residual CLL following initial purine Analog-Based therapy. Mol Ther 2018;26:1896–905.doi:10.1016/j.ymthe.2018.05.018pmid:http://www.ncbi.nlm.nih.gov/pubmed/29910179
      OpenUrlCrossRefPubMed
    32. ↵
      1. Geyer MB,
      2. Rivière I,
      3. Sénéchal B, et al
      . Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL. JCI Insight 2019;5. doi:doi:10.1172/jci.insight.122627. [Epub ahead of print: 02 Apr 2019].pmid:http://www.ncbi.nlm.nih.gov/pubmed/30938714
    33. ↵
      1. Gu R,
      2. Liu F,
      3. Zou D, 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;13:122.doi:10.1186/s13045-020-00953-8pmid:http://www.ncbi.nlm.nih.gov/pubmed/32894185
      OpenUrlPubMed
    34. ↵
      1. Hirayama AV,
      2. Gauthier J,
      3. Hay KA, et al
      . High rate of durable complete remission in follicular lymphoma after CD19 CAR-T cell immunotherapy. Blood 2019;134:636–40.doi:10.1182/blood.2019000905pmid:http://www.ncbi.nlm.nih.gov/pubmed/31648294
      OpenUrlAbstract/FREE Full Text
    35. ↵
      1. Hu Y,
      2. Wu Z,
      3. Luo Y, 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;23:3297–306.doi:10.1158/1078-0432.CCR-16-1799pmid:http://www.ncbi.nlm.nih.gov/pubmed/28039267
      OpenUrlAbstract/FREE Full Text
    36. ↵
      1. Kalos M,
      2. Levine BL,
      3. Porter DL, et al
      . T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011;3:95ra73.doi:10.1126/scitranslmed.3002842pmid:http://www.ncbi.nlm.nih.gov/pubmed/21832238
      OpenUrlAbstract/FREE Full Text
    37. ↵
      1. Kochenderfer JN,
      2. Dudley ME,
      3. Feldman SA, 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;119:2709–20.doi:10.1182/blood-2011-10-384388pmid:http://www.ncbi.nlm.nih.gov/pubmed/22160384
      OpenUrlAbstract/FREE Full Text
    38. ↵
      1. Li C,
      2. Cao W,
      3. Que Y, et al
      . A phase I study of anti-BCMA CAR T cell therapy in relapsed/refractory multiple myeloma and plasma cell leukemia. Clin Transl Med 2021;11:e346.doi:10.1002/ctm2.346pmid:http://www.ncbi.nlm.nih.gov/pubmed/33784005
      OpenUrlCrossRefPubMed
    39. ↵
      1. Magnani CF,
      2. Gaipa G,
      3. Lussana F, et al
      . Sleeping beauty-engineered CAR T cells achieve antileukemic activity without severe toxicities. J Clin Invest 2020;130:6021–33.doi:10.1172/JCI138473pmid:http://www.ncbi.nlm.nih.gov/pubmed/32780725
      OpenUrlCrossRefPubMed
    40. ↵
      1. Pan J,
      2. Niu Q,
      3. Deng B, et al
      . CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia. Leukemia 2019;33:2854–66.doi:10.1038/s41375-019-0488-7pmid:http://www.ncbi.nlm.nih.gov/pubmed/31110217
      OpenUrlPubMed
    41. ↵
      1. Porter DL,
      2. Hwang W-T,
      3. Frey NV, et al
      . Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015;7:303ra139.doi:10.1126/scitranslmed.aac5415pmid:http://www.ncbi.nlm.nih.gov/pubmed/26333935
      OpenUrlAbstract/FREE Full Text
    42. ↵
      1. Raje N,
      2. Berdeja J,
      3. Lin Y, et al
      . Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med 2019;380:1726–37.doi:10.1056/NEJMoa1817226pmid:http://www.ncbi.nlm.nih.gov/pubmed/31042825
      OpenUrlCrossRefPubMed
    43. ↵
      1. Ramos CA,
      2. Grover NS,
      3. Beaven AW, et al
      . Anti-CD30 CAR-T cell therapy in relapsed and refractory Hodgkin lymphoma. J Clin Oncol 2020;38:3794–804.doi:10.1200/JCO.20.01342pmid:http://www.ncbi.nlm.nih.gov/pubmed/32701411
      OpenUrlCrossRefPubMed
    44. ↵
      1. Ramos CA,
      2. Savoldo B,
      3. Torrano V, et al
      . Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Invest 2016;126:2588–96.doi:10.1172/JCI86000pmid:http://www.ncbi.nlm.nih.gov/pubmed/27270177
      OpenUrlPubMed
    45. ↵
      1. Ritchie DS,
      2. Neeson PJ,
      3. Khot A, et al
      . Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther 2013;21:2122–9.doi:10.1038/mt.2013.154pmid:http://www.ncbi.nlm.nih.gov/pubmed/23831595
      OpenUrlCrossRefPubMed
    46. ↵
      1. Roddie C,
      2. Dias J,
      3. O'Reilly MA, et al
      . Durable responses and low toxicity after fast off-rate CD19 chimeric antigen receptor-T therapy in adults with relapsed or refractory B-cell acute lymphoblastic leukemia. J Clin Oncol 2021;39:3352–63.doi:10.1200/JCO.21.00917pmid:http://www.ncbi.nlm.nih.gov/pubmed/34464155
      OpenUrlCrossRefPubMed
    47. ↵
      1. Rossi J,
      2. Paczkowski P,
      3. Shen Y-W, et al
      . Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL. Blood 2018;132:804–14.doi:10.1182/blood-2018-01-828343pmid:http://www.ncbi.nlm.nih.gov/pubmed/29895668
      OpenUrlAbstract/FREE Full Text
    48. ↵
      1. Sauter CS,
      2. Senechal B,
      3. Rivière I, et al
      . CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma. Blood 2019;134:626–35.doi:10.1182/blood.2018883421pmid:http://www.ncbi.nlm.nih.gov/pubmed/31262783
      OpenUrlAbstract/FREE Full Text
    49. ↵
      1. Schuster SJ,
      2. Svoboda J,
      3. Chong EA, et al
      . Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 2017;377:2545–54.doi:10.1056/NEJMoa1708566pmid:http://www.ncbi.nlm.nih.gov/pubmed/29226764
      OpenUrlCrossRefPubMed
    50. ↵
      1. Shao M,
      2. Yu Q,
      3. Teng X, et al
      . CRS-related coagulopathy in BCMA targeted CAR-T therapy: a retrospective analysis in a phase I/II clinical trial. Bone Marrow Transplant 2021;56:1642–50.doi:10.1038/s41409-021-01226-9pmid:http://www.ncbi.nlm.nih.gov/pubmed/33608658
      OpenUrlPubMed
    51. ↵
      1. Summers C,
      2. Wu QV,
      3. Annesley C, et al
      . Hematopoietic cell transplantation after CD19 chimeric antigen receptor T cell-induced acute lymphoblastic lymphoma remission confers a Leukemia-Free survival advantage. Transplant Cell Ther 2022;28:21–9.doi:10.1016/j.jtct.2021.10.003pmid:http://www.ncbi.nlm.nih.gov/pubmed/34644605
      OpenUrlCrossRefPubMed
    52. ↵
      1. Tu S,
      2. Huang R,
      3. Guo Z, et al
      . Shortening the ex vivo culture of CD19-specific CAR T-cells retains potent efficacy against acute lymphoblastic leukemia without CAR T-cell-related encephalopathy syndrome or severe cytokine release syndrome. Am J Hematol 2019;94:E322–5.doi:10.1002/ajh.25630pmid:http://www.ncbi.nlm.nih.gov/pubmed/31489688
      OpenUrlPubMed
    53. ↵
      1. Turtle CJ,
      2. Hanafi L-A,
      3. Berger C, et al
      . CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 2016;126:2123–38.doi:10.1172/JCI85309pmid:http://www.ncbi.nlm.nih.gov/pubmed/27111235
      OpenUrlCrossRefPubMed
    54. ↵
      1. Turtle CJ,
      2. Hanafi L-A,
      3. Berger C, 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;8:355ra116.doi:10.1126/scitranslmed.aaf8621pmid:http://www.ncbi.nlm.nih.gov/pubmed/27605551
      OpenUrlAbstract/FREE Full Text
    55. ↵
      1. Turtle CJ,
      2. Hay KA,
      3. Hanafi L-A, 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;35:3010–20.doi:10.1200/JCO.2017.72.8519pmid:http://www.ncbi.nlm.nih.gov/pubmed/28715249
      OpenUrlCrossRefPubMed
    56. ↵
      1. Wang C-M,
      2. Wu Z-Q,
      3. Wang Y, et al
      . Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory Hodgkin lymphoma: an open-label phase I trial. Clin Cancer Res 2017;23:1156–66.doi:10.1158/1078-0432.CCR-16-1365pmid:http://www.ncbi.nlm.nih.gov/pubmed/27582488
      OpenUrlAbstract/FREE Full Text
    57. ↵
      1. Wang D,
      2. Wang J,
      3. Hu G, et al
      . A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. Blood 2021;137:2890–901.doi:10.1182/blood.2020008936pmid:http://www.ncbi.nlm.nih.gov/pubmed/33512480
      OpenUrlCrossRefPubMed
    58. ↵
      1. Wang J,
      2. Mou N,
      3. Yang Z, et al
      . Efficacy and safety of humanized anti-CD19-CAR-T therapy following intensive lymphodepleting chemotherapy for refractory/relapsed B acute lymphoblastic leukaemia. Br J Haematol 2020;191:212–22.doi:10.1111/bjh.16623pmid:http://www.ncbi.nlm.nih.gov/pubmed/32232846
      OpenUrlPubMed
    59. ↵
      1. Wang X,
      2. Popplewell LL,
      3. Wagner JR, et al
      . Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. Blood 2016;127:2980–90.doi:10.1182/blood-2015-12-686725pmid:http://www.ncbi.nlm.nih.gov/pubmed/27118452
      OpenUrlAbstract/FREE Full Text
    60. ↵
      1. Weng J,
      2. Lai P,
      3. Qin L, et al
      . A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia. J Hematol Oncol 2018;11:25.doi:10.1186/s13045-018-0572-xpmid:http://www.ncbi.nlm.nih.gov/pubmed/29458388
      OpenUrlCrossRefPubMed
    61. ↵
      1. Wudhikarn K,
      2. Flynn JR,
      3. Rivière I, et al
      . Interventions and outcomes of adult patients with B-ALL progressing after CD19 chimeric antigen receptor T-cell therapy. Blood 2021;138:531–43.doi:10.1182/blood.2020009515pmid:http://www.ncbi.nlm.nih.gov/pubmed/33851211
      OpenUrlPubMed
    62. ↵
      1. Xu J,
      2. Chen L-J,
      3. Yang S-S, et al
      . Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci U S A 2019;116:9543–51.doi:10.1073/pnas.1819745116pmid:http://www.ncbi.nlm.nih.gov/pubmed/30988175
      OpenUrlAbstract/FREE Full Text
    63. ↵
      1. Yan Z-X,
      2. Li L,
      3. Wang W, et al
      . Clinical efficacy and tumor microenvironment influence in a dose-escalation study of anti-CD19 chimeric antigen receptor T cells in refractory B-cell non-Hodgkin's lymphoma. Clin Cancer Res 2019;25:6995–7003.doi:10.1158/1078-0432.CCR-19-0101pmid:http://www.ncbi.nlm.nih.gov/pubmed/31444250
      OpenUrlAbstract/FREE Full Text
    64. ↵
      1. Ying Z,
      2. Huang XF,
      3. Xiang X, et al
      . A safe and potent anti-CD19 CAR T cell therapy. Nat Med 2019;25:947–53.doi:10.1038/s41591-019-0421-7pmid:http://www.ncbi.nlm.nih.gov/pubmed/31011207
      OpenUrlCrossRefPubMed
    65. ↵
      1. Zhang Q,
      2. Hu H,
      3. Chen S-Y, et al
      . Transcriptome and regulatory network analyses of CD19-CAR-T immunotherapy for B-ALL. Genomics Proteomics Bioinformatics 2019;17:190–200.doi:10.1016/j.gpb.2018.12.008pmid:http://www.ncbi.nlm.nih.gov/pubmed/31201998
      OpenUrlPubMed
    66. ↵
      1. Zhou X,
      2. Tu S,
      3. Wang C, 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.doi:10.3389/fimmu.2020.564099pmid:http://www.ncbi.nlm.nih.gov/pubmed/33329526
      OpenUrlCrossRefPubMed
    67. ↵
      1. Meader N,
      2. King K,
      3. Llewellyn A, et al
      . A checklist designed to aid consistency and reproducibility of grade assessments: development and pilot validation. Syst Rev 2014;3:82.doi:10.1186/2046-4053-3-82pmid:http://www.ncbi.nlm.nih.gov/pubmed/25056145
      OpenUrlCrossRefPubMed
    68. ↵
      1. Guyatt GH,
      2. Oxman AD,
      3. Kunz R, et al
      . GRADE guidelines 6. Rating the quality of evidence--imprecision. J Clin Epidemiol 2011;64:1283–93.doi:10.1016/j.jclinepi.2011.01.012pmid:http://www.ncbi.nlm.nih.gov/pubmed/21839614
      OpenUrlCrossRefPubMed
    69. ↵
      1. Guyatt GH,
      2. Oxman AD,
      3. Kunz R, et al
      . GRADE guidelines: 8. Rating the quality of evidence--indirectness. J Clin Epidemiol 2011;64:1303–10.doi:10.1016/j.jclinepi.2011.04.014pmid:http://www.ncbi.nlm.nih.gov/pubmed/21802903
      OpenUrlCrossRefPubMed
    70. ↵
      1. Guyatt GH,
      2. Oxman AD,
      3. Vist G, et al
      . GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). J Clin Epidemiol 2011;64:407–15.doi:10.1016/j.jclinepi.2010.07.017pmid:http://www.ncbi.nlm.nih.gov/pubmed/21247734
      OpenUrlCrossRefPubMedWeb of Science
    71. ↵
      1. Zhao W-H,
      2. Liu J,
      3. Wang B-Y, et al
      . A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J Hematol Oncol 2018;11:141.doi:10.1186/s13045-018-0681-6pmid:http://www.ncbi.nlm.nih.gov/pubmed/30572922
      OpenUrlCrossRefPubMed
    72. ↵
      1. Shah BD,
      2. Bishop MR,
      3. Oluwole OO, et al
      . KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results. Blood 2021;138:11–22.doi:10.1182/blood.2020009098pmid:http://www.ncbi.nlm.nih.gov/pubmed/33827116
      OpenUrlCrossRefPubMed
    73. ↵
      1. Bishop MR,
      2. Dickinson M,
      3. Purtill D, et al
      . Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med 2022;386:629–39.doi:10.1056/NEJMoa2116596pmid:http://www.ncbi.nlm.nih.gov/pubmed/34904798
      OpenUrlCrossRefPubMed
    74. ↵
      1. Fowler NH,
      2. Dickinson M,
      3. Dreyling M, et al
      . Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med 2022;28:325–32.doi:10.1038/s41591-021-01622-0pmid:http://www.ncbi.nlm.nih.gov/pubmed/34921238
      OpenUrlCrossRefPubMed
    75. ↵
      1. Ying Z,
      2. Yang H,
      3. Guo Y, 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;10:999–1011.doi:10.1002/cam4.3686pmid:http://www.ncbi.nlm.nih.gov/pubmed/33382529
      OpenUrlPubMed
    76. ↵
      1. Park JH,
      2. Rivière I,
      3. Gonen M, et al
      . Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 2018;378:449–59.doi:10.1056/NEJMoa1709919pmid:http://www.ncbi.nlm.nih.gov/pubmed/29385376
      OpenUrlCrossRefPubMed
    77. ↵
      1. Zhang X,
      2. Yang J,
      3. Li J, et al
      . Factors associated with treatment response to CD19 CAR-T therapy among a large cohort of B cell acute lymphoblastic leukemia. Cancer Immunol Immunother 2022;71:689–703.doi:10.1007/s00262-021-03009-zpmid:http://www.ncbi.nlm.nih.gov/pubmed/34365516
      OpenUrlPubMed
    78. ↵
      1. Schuster SJ,
      2. Bishop MR,
      3. Tam CS, et al
      . Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 2019;380:45–56.doi:10.1056/NEJMoa1804980pmid:http://www.ncbi.nlm.nih.gov/pubmed/30501490
      OpenUrlCrossRefPubMed
    79. ↵
      1. Sesques P,
      2. Ferrant E,
      3. Safar V, 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;95:1324–33.doi:10.1002/ajh.25951pmid:http://www.ncbi.nlm.nih.gov/pubmed/32744738
      OpenUrlPubMed
    80. ↵
      1. Wang M,
      2. Munoz J,
      3. Goy A, et al
      . KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2020;382:1331–42.doi:10.1056/NEJMoa1914347pmid:http://www.ncbi.nlm.nih.gov/pubmed/32242358
      OpenUrlCrossRefPubMed
    81. ↵
      1. Jiang H,
      2. Liu L,
      3. Guo T, et al
      . Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy. Ann Hematol 2019;98:1721–32.doi:10.1007/s00277-019-03685-zpmid:http://www.ncbi.nlm.nih.gov/pubmed/31055613
      OpenUrlCrossRefPubMed
    82. ↵
      1. Grigor EJM,
      2. Fergusson D,
      3. Kekre N, et al
      . Risks and benefits of chimeric antigen receptor T-cell (CAR-T) therapy in cancer: a systematic review and meta-analysis. Transfus Med Rev 2019;33:98–110.doi:10.1016/j.tmrv.2019.01.005
      OpenUrlPubMed
    83. ↵
      1. Pettitt D,
      2. Arshad Z,
      3. Smith J, et al
      . Car-T cells: a systematic review and mixed methods analysis of the clinical trial landscape. Molecular Therapy 2018;26:342–53.doi:10.1016/j.ymthe.2017.10.019
      OpenUrlCrossRefPubMed
    84. ↵
      1. Dolladille C,
      2. Ederhy S,
      3. Ezine E, et al
      . Chimeric antigen receptor T ‐cells safety: A pharmacovigilance and meta‐analysis study. Am J Hematol 2021;96:1101–11.doi:10.1002/ajh.26259
      OpenUrl
    85. ↵
      1. Yu W-L,
      2. Hua Z-C
      . Chimeric antigen receptor T-cell (CAR T) therapy for hematologic and solid malignancies: efficacy and safety-a systematic review with meta-analysis. Cancers 2019;11. doi:doi:10.3390/cancers11010047. [Epub ahead of print: 07 01 2019].pmid:http://www.ncbi.nlm.nih.gov/pubmed/30621018
    86. ↵
      1. Lei W,
      2. Xie M,
      3. Jiang Q, et al
      . Treatment-related adverse events of chimeric antigen receptor T-cell (CAR T) in clinical trials: a systematic review and meta-analysis. Cancers 2021;13:3912.doi:10.3390/cancers13153912
    87. ↵
      1. Wu X,
      2. Zhang X,
      3. Xun R, et al
      . Efficacy and safety of Axicabtagene Ciloleucel and Tisagenlecleucel administration in lymphoma patients with secondary CNS involvement: a systematic review. Front Immunol 2021;12:693200.doi:10.3389/fimmu.2021.693200
    88. ↵
      1. Anwer F,
      2. Shaukat A-A,
      3. Zahid U, et al
      . Donor origin CAR T cells: graft versus malignancy effect without GVHD, a systematic review. Immunotherapy 2017;9:123–30.doi:10.2217/imt-2016-0127
      OpenUrl
    89. ↵
      1. Sun Z,
      2. Xun R,
      3. Liu M, et al
      . The association between glucocorticoid administration and the risk of impaired efficacy of Axicabtagene Ciloleucel treatment: a systematic review. Front Immunol 2021;12:646450.doi:10.3389/fimmu.2021.646450
    90. ↵
      1. Shah BD,
      2. Ghobadi A,
      3. Oluwole OO, et al
      . KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet 2021;398:491–502.doi:10.1016/S0140-6736(21)01222-8pmid:http://www.ncbi.nlm.nih.gov/pubmed/34097852
      OpenUrlCrossRefPubMed
    91. ↵
      1. Qu C,
      2. Ping N,
      3. Kang L, et al
      . Radiation priming chimeric antigen receptor T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma with high tumor burden. J Immunother 2020;43:32–7.doi:10.1097/CJI.0000000000000284
      OpenUrl
      1. Frigault MJ,
      2. Bishop MR,
      3. Rosenblatt J, et al
      . Phase 1 study of CART-ddBCMA for the treatment of subjects with relapsed and refractory multiple myeloma. Blood Adv 2022. doi:doi:10.1182/bloodadvances.2022007210. [Epub ahead of print: 25 Apr 2022].pmid:http://www.ncbi.nlm.nih.gov/pubmed/35468618

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    Footnotes

    • Twitter @AnandRotte, @MJFzeta, @ChrisHeery

    • Contributors AR was responsible for conceptualization, design, literature search, data extraction, interpretation and drafting of the first manuscript draft. AA was responsible for literature search and data extraction. BG contributed to the concept, study design, interpretation and review of the manuscript. CH, MJF and BS were responsible for concept of the study, design, interpretation of results, reviewing and revising the manuscript draft.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests AR, CH and BG are employees of Arcellx and hold stocks in the company. AA is a consultant to Arcellx. BS reports honoraria from Pharmacyclics, Janssen, Acrotech, Spectrum, BeiGene and Gilead Sciences; a consultancy or advisory role for Adaptive Biotechnologies, Bristol Myers Squibb/Celgene, Novartis, Pfizer, Amgen, Precision Biosciences and Kite, a Gilead Company; research funding from Incyte, Jazz Pharmaceuticals, Gilead Sciences and Kite; and travel support from Celgene, Novartis, Pfizer, Janssen, Seattle Genetics, Stemline Therapeutics and Kite. MJF reports a consultancy role for Celgene, Novartis, Arcellx and Gilead/Kite; research funding from Novartis and Gilead/Kite.

    • Provenance and peer review Commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.