<?xml version="1.0" encoding="UTF-8"?><!DOCTYPE article PUBLIC "-//NLM//DTD Journal Publishing DTD v2.0 20040830//EN" "journalpublishing.dtd"><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" dtd-version="2.0" xml:lang="en" article-type="reviewer-report"><front><journal-meta><journal-id journal-id-type="nlm-ta">JMIRx Med</journal-id><journal-id journal-id-type="publisher-id">xmed</journal-id><journal-id journal-id-type="index">34</journal-id><journal-title>JMIRx Med</journal-title><abbrev-journal-title>JMIRx Med</abbrev-journal-title><issn pub-type="epub">2563-6316</issn><publisher><publisher-name>JMIR Publications</publisher-name><publisher-loc>Toronto, Canada</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">v6i1e71293</article-id><article-id pub-id-type="doi">10.2196/71293</article-id><article-categories><subj-group subj-group-type="heading"><subject>Peer-Review Report</subject></subj-group></article-categories><title-group><article-title>Peer Review of &#x201C;Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy for Recurrent Glioblastoma: An Augmented Meta-Analysis of Phase 1 Clinical Trials (Preprint)&#x201D;</article-title></title-group><contrib-group><contrib contrib-type="author"><name name-style="western"><surname>Fairhurst</surname><given-names>Vanessa</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name name-style="western"><surname>Mahmoud</surname><given-names>Randa Salah Gomaa</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name name-style="western"><surname>Olatoye</surname><given-names>Toba</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name name-style="western"><surname>Sakilay</surname><given-names>Sylvester</given-names></name></contrib></contrib-group><aff id="aff1"><institution>PREreview</institution><addr-line>-</addr-line><addr-line>Portland</addr-line><addr-line>OR</addr-line><country>United States</country></aff><aff id="aff2"><institution>Faculty of Human Medicine, Zagazig University</institution><addr-line>Zagazig</addr-line><country>Egypt</country></aff><aff id="aff3"><institution>University of Ilorin</institution><addr-line>Ilorin</addr-line><country>Nigeria</country></aff><contrib-group><contrib contrib-type="editor"><name name-style="western"><surname>Schwartz</surname><given-names>Amy</given-names></name></contrib></contrib-group><pub-date pub-type="collection"><year>2025</year></pub-date><pub-date pub-type="epub"><day>24</day><month>1</month><year>2025</year></pub-date><volume>6</volume><elocation-id>e71293</elocation-id><history><date date-type="received"><day>14</day><month>01</month><year>2025</year></date><date date-type="accepted"><day>14</day><month>01</month><year>2025</year></date></history><copyright-statement>&#x00A9; Vanessa Fairhurst, Randa Salah Gomaa Mahmoud, Toba Olatoye, Sylvester Sakilay. Originally published in JMIRx Med (<ext-link ext-link-type="uri" xlink:href="https://med.jmirx.org">https://med.jmirx.org</ext-link>), 24.1.2025. </copyright-statement><copyright-year>2025</copyright-year><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/"><p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">https://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIRx Med, is properly cited. The complete bibliographic information, a link to the original publication on <ext-link ext-link-type="uri" xlink:href="https://med.jmirx.org/">https://med.jmirx.org/</ext-link>, as well as this copyright and license information must be included.</p></license><self-uri xlink:type="simple" xlink:href="https://xmed.jmir.org/2025/1/e71293"/><related-article related-article-type="companion" ext-link-type="doi" xlink:href="10.1101/2024.10.23.24316015" xlink:title="Preprint (medRxiv)" xlink:type="simple">https://www.medrxiv.org/content/10.1101/2024.10.23.24316015v1</related-article><kwd-group><kwd>CAR T-cell therapy</kwd><kwd>cancer</kwd><kwd>glioblastoma</kwd><kwd>brain tumor</kwd><kwd>meta-analysis</kwd><kwd>chimeric antigen receptor</kwd></kwd-group></article-meta></front><body><p><italic>This is a peer-review report for the preprint &#x201C;Safety and Efficacy of Chimeric Antigen Receptor T-cell Therapy for Recurrent Glioblastoma: An Augmented Meta-Analysis of Phase 1 Clinical Trials</italic>.&#x201D;</p><p>This review is the result of a virtual collaborative live review discussion organized and hosted by PREreview and JMIR Publications on Dec 12, 2024. The discussion was joined by 11 people: 3 facilitators, 1 member of the JMIR Publications team, and 7 live review participants including 3 who agreed to be named but did not assist in compiling the final review: Eudora Nwanaforo, Kelechi Elechi, and Murtala Haruna Bawa. The authors of this review have dedicated additional asynchronous time over the course of 2 weeks to help compose this final report using the notes from the live review. We thank all participants who contributed to the discussion and made it possible for us to provide feedback on this preprint.</p><sec id="s2"><title>Summary</title><p>The study [<xref ref-type="bibr" rid="ref1">1</xref>] was designed to address the limitations of previous studies and evaluate the safety and efficacy of chimeric antigen receptor (CAR) T-cell therapy for recurrent glioblastoma. The results of this study are predictive rather than confirmatory. CAR T-cell therapy for glioblastoma was not predicted to significantly improve survival or achieve substantial complete responses. Stable disease rates were modest, while disease progression was notable. Adverse events, especially CAR T-cell therapy&#x2013;related encephalopathy, raise safety concerns. Overall survival was 6.49 months in patients receiving CAR T-cell therapy after augmented analysis, and only 80% of patients exhibited this outcome. It was not statistically different from the median overall survival observed in patients with recurrent glioblastoma undergoing standard treatment, thereby indicating that CAR T-cell therapy, in its current form, does not offer substantially improved survival compared to standard treatments. Further trials and refinements are needed to enhance CAR T-cell therapy&#x2019;s effectiveness and safety in glioblastoma treatment. An interesting fact is that a novel statistical technique (augmented meta-analyses) was used in this study. It was a combination of a cross-sectional (quantitative) and augmented meta-analysis (qualitative).</p></sec><sec id="s3"><title>List of Major Concerns and Feedback</title><sec id="s2-1"><title>Methods</title><sec id="s2-1-1"><title>Augmented Meta-Analysis</title><list list-type="bullet"><list-item><p>This section is limited in its description of the methodology used in the study. It would be helpful to include more information on the machine learning model or language model used to generate the extra cases.</p></list-item><list-item><p>The title and aim specify that the study focuses on recurrent glioblastoma, but this specificity is not reflected in the inclusion criteria. It would be helpful to adjust the inclusion criteria to explicitly state that the study is targeting patients with recurrent glioblastoma. This will align the methodology with the aim as stated.</p></list-item><list-item><p>The inclusion criteria do not specify that patients are in phase 1 clinical trials, where safety is a primary focus. Clearly state in the inclusion criteria that patients are part of phase 1 clinical trials. This will provide context for the study&#x2019;s focus on safety.</p></list-item><list-item><p>There is no reference to the earlier use of augmented meta-analysis in cancer or medical research, nor is it explicitly stated if this is a new application. If augmented meta-analysis has been previously applied, cite relevant references. If this is its first application, explicitly state so and highlight its novelty.</p></list-item></list></sec></sec><sec id="s2-2"><title>Results</title><sec id="s2-2-1"><title>Literature Review and Risk of Bias Assessment Section</title><list list-type="bullet"><list-item><p>It would be helpful to add the details of Figure 1 and Table 1 that explain the details of the cause of exclusion, the results of the Newcastle Ottawa Scale, which study reached the high-quality level, etc.</p></list-item></list></sec></sec><sec id="s2-3"><title>Discussion</title><list list-type="bullet"><list-item><p>It is important to add a comparison between the mean overall survival for patients with glioblastoma who underwent CAR T-cell therapy and the median overall survival observed in patients receiving the standard protocol for recurrent glioblastoma treatment to the Results section, as this comparison is mentioned in the first paragraph of the Discussion section.</p></list-item></list></sec><sec id="s2-4"><title>Reproducibility of the Study</title><list list-type="bullet"><list-item><p>The data presented in the study are beneficial for reproducibility except for the augmented meta-analysis, which is hindered by the lack of clear documentation on the large language model settings.</p></list-item><list-item><p>The details of the augmented meta-analysis are not available. Provide access to the source code or methodological details for augmented meta-analysis, either as supplementary material or a public repository link. Transparency will strengthen the study&#x2019;s reproducibility.</p></list-item></list></sec></sec><sec id="s4"><title>List of Minor Concerns and Feedback</title><sec id="s3-1"><title>Concerns With Techniques/Analyses</title><list list-type="bullet"><list-item><p>Abbreviations like &#x201C;IL-13Ralpha-2,&#x201D; &#x201C;EGFRvIII,&#x201D; &#x201C;HER2,&#x201D; and &#x201C;HephA2&#x201D; are not identified in the Included Study Characteristics section. Expand the abbreviations and provide their full names (eg, &#x201C;Interleukin-13 Receptor Subunit Alpha-2&#x201D;) when first mentioned. This ensures clarity for readers not familiar with the terms.</p></list-item><list-item><p>The last line of the large language model statement on page 16 does not explain how augmented meta-analysis was applied. Elaborate on how augmented meta-analysis was applied, especially in terms of methodology and integration with the study data.</p></list-item></list></sec><sec id="s3-2"><title>Figures and Tables</title><list list-type="bullet"><list-item><p>The screening section in Figure 1 is missing a rectangle to indicate the exclusion of 300 records. Update it using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart to include a rectangle that details the 300 excluded records and ensures the causes of exclusion are clearly stated.</p></list-item><list-item><p>The reasons for exclusion are not detailed in the PRISMA flowchart. Follow PRISMA guidelines to specify the causes of exclusion, such as duplicates, irrelevance, or incomplete data, within the flowchart.</p></list-item><list-item><p>Comments following Figure 1 are not in line with its instructions. Restructure the comments to follow the instructions and present the details of the research study accordingly.</p></list-item></list></sec><sec id="s3-3"><title>Additional Comments</title><list list-type="bullet"><list-item><p>No reference is provided for the trim-and-fill method mentioned in the augmented meta-analysis of overall survival (page 10). Cite a relevant source, such as [<xref ref-type="bibr" rid="ref2">2</xref>] or another appropriate reference.</p></list-item><list-item><p>The Cochrane Handbook (Part 2, Chapter 9) should be referenced in the Statistical Analysis section and its numbered reference cited in the text.</p></list-item><list-item><p>References in the third paragraph of the Introduction mix meta-analyses and clinical trials without clear distinction. Rearrange and clarify the references while ensuring that references to meta-analyses and clinical trials are grouped and contextualized appropriately to avoid confusion.</p></list-item><list-item><p>Repetition of the sentence &#x201C;Egger&#x2019;s test for publication bias could not be performed since the number of included studies in this outcome was less than ten&#x201D; could be avoided by mentioning it once in the Methods section as the total number of the included studies is 8.</p></list-item><list-item><p>In addition, the repetition of the sentence &#x201C;The wide range of the 95% confidence interval was suggestive of data sparsity, so augmented meta-analysis was indicated before making conclusions&#x201D; could be avoided by mentioning it once in the Augmented Meta-Analysis section of the Methods.</p></list-item></list></sec></sec></body><back><ack><p>PREreview and JMIR Publications thank the authors of the preprint for posting their work openly for feedback. We also thank all participants of the live review call for their time and for engaging in the lively discussion that generated this review.</p></ack><fn-group><fn fn-type="conflict"><p>VF was a facilitator of this call and one of the organizers. No other competing interests were declared by the reviewers.</p></fn></fn-group><glossary><title>Abbreviations</title><def-list><def-item><term id="abb1">CAR</term><def><p>chimeric antigen receptor</p></def></def-item><def-item><term id="abb2">PRISMA</term><def><p>Preferred Reporting Items for Systematic Reviews and Meta-Analyses</p></def></def-item></def-list></glossary><ref-list><title>References</title><ref id="ref1"><label>1</label><nlm-citation citation-type="preprint"><person-group person-group-type="author"><name name-style="western"><surname>Azzam</surname><given-names>AY</given-names> </name><name name-style="western"><surname>Morsy</surname><given-names>MM</given-names> </name><name name-style="western"><surname>Azab</surname><given-names>MA</given-names> </name><etal/></person-group><article-title>Safety and efficacy of chimeric antigen receptor T-cell therapy for recurrent glioblastoma: an augmented meta-analysis of phase 1 clinical trials</article-title><source>medRxiv</source><comment>Preprint posted online on  Oct 24, 2024</comment><pub-id pub-id-type="doi">10.1101/2024.10.23.24316015</pub-id></nlm-citation></ref><ref id="ref2"><label>2</label><nlm-citation citation-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Shi</surname><given-names>L</given-names> </name><name name-style="western"><surname>Lin</surname><given-names>L</given-names> </name></person-group><article-title>The trim-and-fill method for publication bias: practical guidelines and recommendations based on a large database of meta-analyses</article-title><source>Medicine (Baltimore)</source><year>2019</year><month>06</month><volume>98</volume><issue>23</issue><fpage>e15987</fpage><pub-id pub-id-type="doi">10.1097/MD.0000000000015987</pub-id><pub-id pub-id-type="medline">31169736</pub-id></nlm-citation></ref></ref-list></back></article>