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<label for="email-to" class="action-panel-label required-field-asterisk">
To:
</label>
<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required>
</div>
<div class="action-panel-control-wrap">
<label for="email-from" class="action-panel-label">
From:
</label>
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="UBGEKqn1XD76yBIFt467v5sijOtL8bKkboqJngQnxeUAs2Ov6nJ9ZdYWRSbX1MiE">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="UBGEKqn1XD76yBIFt467v5sijOtL8bKkboqJngQnxeUAs2Ov6nJ9ZdYWRSbX1MiE">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="UBGEKqn1XD76yBIFt467v5sijOtL8bKkboqJngQnxeUAs2Ov6nJ9ZdYWRSbX1MiE">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="UBGEKqn1XD76yBIFt467v5sijOtL8bKkboqJngQnxeUAs2Ov6nJ9ZdYWRSbX1MiE">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="UBGEKqn1XD76yBIFt467v5sijOtL8bKkboqJngQnxeUAs2Ov6nJ9ZdYWRSbX1MiE">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="32939032">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://doi.org/10.1038/s41423-020-0515-7"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3094&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=32939032&amp;db=pubmed&amp;nlmid=101242872"
title="See full text options at Nature Publishing Group"
data-ga-category="full_text"
data-ga-action="Nature Publishing Group"
data-ga-label="32939032"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--www.nature.com-static-images-logos-nature-portfolio-120.png" alt="Nature Publishing Group full text link"><span class="text">
Nature Publishing Group
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/32939032/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=32939032&amp;db=pubmed&amp;nlmid=101242872"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="32939032"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/32939032/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/32939032/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="32939032" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F32939032%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="UBGEKqn1XD76yBIFt467v5sijOtL8bKkboqJngQnxeUAs2Ov6nJ9ZdYWRSbX1MiE"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
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<h1 class="heading-title">
Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer
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</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China. tyzwu@jnu.edu.cn." href="#full-view-affiliation-11" ref="linksrc=author_aff">
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</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China. zhinan.yin@yale.edu." href="#full-view-affiliation-13" ref="linksrc=author_aff">
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Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer
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<span class="authors-list-item "><span class="full-name">Yan Xu</span><span class="citation-separator">&nbsp;et al.</span></span>
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1
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Zhuhai Precision Medical Center, Zhuhai People&#x27;s Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519000, Guangdong, PR China." href="#short-view-affiliation-2" ref="linksrc=author_aff">
2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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4
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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3
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Tongji Chibi Hospital, Tongji Medical College, Huazhong University of Science and Technology, Chibi, Hubei, PR China." href="#short-view-affiliation-5" ref="linksrc=author_aff">
5
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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6
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China." href="#short-view-affiliation-3" ref="linksrc=author_aff">
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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9
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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3
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Fuda Cancer Hospital, Faculty of Medical Science, Jinan University, Guangzhou, 510665, Guangdong, PR China." href="#short-view-affiliation-7" ref="linksrc=author_aff">
7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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4
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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10
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China. tyzwu@jnu.edu.cn." href="#short-view-affiliation-11" ref="linksrc=author_aff">
11
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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12
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China. zhinan.yin@yale.edu." href="#short-view-affiliation-13" ref="linksrc=author_aff">
13
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<div class="affiliations">
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Affiliations
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<li data-affiliation-id="short-view-affiliation-1"
id="short-view-affiliation-1"
><sup class="key">1</sup> The First Affiliated Hospital, Faculty of Medical Science, Jinan University, Guangzhou, 510632, Guangdong, PR China.</li>
<li data-affiliation-id="short-view-affiliation-2"
id="short-view-affiliation-2"
><sup class="key">2</sup> Zhuhai Precision Medical Center, Zhuhai People&#x27;s Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519000, Guangdong, PR China.</li>
<li data-affiliation-id="short-view-affiliation-3"
id="short-view-affiliation-3"
><sup class="key">3</sup> The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China.</li>
<li data-affiliation-id="short-view-affiliation-4"
id="short-view-affiliation-4"
><sup class="key">4</sup> Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, PR China.</li>
<li data-affiliation-id="short-view-affiliation-5"
id="short-view-affiliation-5"
><sup class="key">5</sup> Tongji Chibi Hospital, Tongji Medical College, Huazhong University of Science and Technology, Chibi, Hubei, PR China.</li>
<li data-affiliation-id="short-view-affiliation-6"
id="short-view-affiliation-6"
><sup class="key">6</sup> Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany.</li>
<li data-affiliation-id="short-view-affiliation-7"
id="short-view-affiliation-7"
><sup class="key">7</sup> Fuda Cancer Hospital, Faculty of Medical Science, Jinan University, Guangzhou, 510665, Guangdong, PR China.</li>
<li data-affiliation-id="short-view-affiliation-8"
id="short-view-affiliation-8"
><sup class="key">8</sup> Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, PR China.</li>
<li data-affiliation-id="short-view-affiliation-9"
id="short-view-affiliation-9"
><sup class="key">9</sup> Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany. dietrich.kabelitz@uksh.de.</li>
<li data-affiliation-id="short-view-affiliation-10"
id="short-view-affiliation-10"
><sup class="key">10</sup> Zhuhai Precision Medical Center, Zhuhai People&#x27;s Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519000, Guangdong, PR China. tyzwu@jnu.edu.cn.</li>
<li data-affiliation-id="short-view-affiliation-11"
id="short-view-affiliation-11"
><sup class="key">11</sup> The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China. tyzwu@jnu.edu.cn.</li>
<li data-affiliation-id="short-view-affiliation-12"
id="short-view-affiliation-12"
><sup class="key">12</sup> Zhuhai Precision Medical Center, Zhuhai People&#x27;s Hospital (Zhuhai Hospital Affiliated with Jinan University), Jinan University, Zhuhai, 519000, Guangdong, PR China. zhinan.yin@yale.edu.</li>
<li data-affiliation-id="short-view-affiliation-13"
id="short-view-affiliation-13"
><sup class="key">13</sup> The Biomedical Translational Research Institute, Jinan University, Guangzhou, 510632, Guangdong, PR China. zhinan.yin@yale.edu.</li>
</ul>
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<div class="equal-contrib-block">
<div class="equal-contrib-explanation" id="short-view-equal-contrib-explanation"><sup class="key">#</sup> Contributed equally.</div>
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Abstract
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<p>
Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy. Due to their HLA-independent mode of action, allogeneic Vγ9Vδ2 T cells can be considered for clinical application. To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy, the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized, and clinical safety and efficacy also need to be proven. Therefore, we developed a novel formula to improve the expansion of peripheral γδ T cells from healthy donors. Then, we used a humanized mouse model to validate the therapeutic efficacy of expanded γδ T cells in vivo; furthermore, the expanded γδ T cells were adoptively transferred into late-stage liver and lung cancer patients. We found that the expanded cells possessed significantly improved immune effector functions, including proliferation, differentiation, and cancer cell killing, both in vitro and in the humanized mouse model. Furthermore, a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells. Among these 132 patients, 8 liver cancer patients and 10 lung cancer patients who received ≥5 cell infusions showed greatly prolonged survival, which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy. Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy, which will inspire further clinical investigations and eventually benefit cancer patients.
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<strong class="sub-title">
Keywords:
</strong>
Allogeneic γδ T cells; Cell therapy; Humanized mice; Liver cancer; Lung cancer; New expansion formula.
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Conflict of interest statement
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">A PCT patent (PCT/CN2019/075491) for the new formula for γδ T-cell expansion was filed. D.K. is a member of the Scientific Advisory Boards of Incysus, Imcheck, and Lava Therapeutics.</p>
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<p> Fig. 1 </p>
</strong>
<div class="figure-caption-contents"><p> New formula (NF) significantly promoted… </p></div>
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<p> Fig. 1 </p>
</strong>
<div class="figure-caption-contents"><p> New formula (NF) significantly promoted the proliferation and differentiation and reduced the apoptosis… </p></div>
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Fig. 1
</strong>
<div class="figure-caption-contents">New formula (NF) significantly promoted the proliferation and differentiation and reduced the apoptosis of Vγ9Vδ2 T cells. <b>a</b> Absolute cell counts on various indicated days were calculated by using flow cytometry (anti-TCR Vδ2-PE and anti-CD3-FITC antibodies). Here, 5×10<sup>6</sup> PBMCs were used in each group to test two culture medium formulas (six individual donors). The time points analyzed were days 0, 3, 6, 9, 12, 15, 18, 21, 24, 27, and 30. <b>b</b> Cell proliferation was evaluated by staining for Ki-67 (seven individual donors). <b>c</b> The new formula significantly promoted cell mitosis, as evidenced by G1-phase reduction and S-phase augmentation (six individual donors). <b>d</b> The new formula (NF) could induce the differentiation of Vγ9Vδ2 T cells, as shown by significant increases in the percentages of effector memory (EM; CD45RA<sup></sup>CD27<sup></sup>) and terminally differentiated (EMRA; CD45RA<sup>+</sup>CD27<sup></sup>) Vγ9Vδ2 T cells and significant decreases in the percentages of naive (CD45RA<sup>+</sup>CD27<sup>+</sup>) and central memory (CD45RA<sup></sup>CD27<sup>+</sup>) cells, compared with the old formula (OF) (six individual donors). <b>e</b> Cell apoptosis was significantly decreased with the new formula compared to the old formula. Cell apoptosis was assayed on day 14 (normal culture time) and day 21 (long-term culture) (six individual donors). <b>f</b> The new formula enhanced the expression levels of costimulatory molecules on γδ T cells (six individual donors). MFI mean fluorescence intensity. The levels of costimulatory molecules (CD80, CD86, and HLA class-II) on Vγ9Vδ2 T cells were measured by flow cytometry, showing that NF cells expressed significantly higher levels of these costimulatory molecules than OF cells. Error bars represent the standard error of the mean (SEM). *<i>p</i>&lt;0.05; **<i>p</i>&lt;0.01; ***<i>p</i>&lt;0.001</div>
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alt="Fig. 2" />
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<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
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<strong class="figure-label">
<p> Fig. 2 </p>
</strong>
<div class="figure-caption-contents"><p> NF cells possess stronger cellular… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 2 </p>
</strong>
<div class="figure-caption-contents"><p> NF cells possess stronger cellular energy metabolism, including both mitochondrial respiration and glycolysis,… </p></div>
</div>
<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 2
</strong>
<div class="figure-caption-contents">NF cells possess stronger cellular energy metabolism, including both mitochondrial respiration and glycolysis, than OF cells. <b>a</b> Metabolic results were obtained with a Seahorse XF analyzer. The ECAR was assessed after the addition of 25mM glucose (gluc) and in response to the metabolic inhibitors oligomycin (oligo) and 2DG. O<sub>2</sub> consumption rates (OCRs) were measured in real time under basal conditions and in response to the indicated mitochondrial inhibitors (three repetitions, mean ± SEM). A1 Quantitative comparisons of mitochondrial functions, including basal respiration, maximum respiration, ATP production and spare respiration capacity, between NF cells and OF cells were performed. A2 Quantitative comparisons of glycolytic metabolism, including glycolysis, the glycolytic capacity and the glycolytic reserve, between NF cells and OF cells were performed. Data are representative of three independent experiments. <b>b</b> Gene set enrichment analysis (GSEA) identified similarities between OF cells and NF cells. The expression of glycolysis-related genes was upregulated in NF cells. <b>c</b> The heat map illustrates the expression of glycolysis-related genes in NF cells versus OF cells. Red: upregulated; blue: downregulated. <b>d</b> The distribution of mitochondria was observed by confocal microscopy, showing that NF cells possessed higher mitochondrial fluorescence than OF cells. Cells were stained by using MitoTracker (red), DAPI (blue) and an anti-Vδ2 antibody (green) for confocal visualization. <b>e</b> The fluorescence intensity of mitochondria was statistically analyzed by flow cytometry (three repetitions, mean±SEM). *<i>p</i>&lt;0.05; **<i>p</i>&lt;0.01; ***<i>p</i>&lt;0.001</div>
</figcaption>
</figure>
<figure class="figure-item "
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itemprop="associatedMedia"
data-slide-index="2"
data-label-slug="fig-3">
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href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3217/8027668/20ee3f985865/41423_2020_515_Fig3_HTML.jpg"
itemprop="contentUrl"
aria-describedby="figure-caption-2"
role="button"
data-image-width="778"
data-image-height="362"
data-image-alt="Fig. 3"
data-pmc-id="PMC8027668"
data-figure-id="Fig3">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-2"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3217/8027668/04bacfe7d909/41423_2020_515_Fig3_HTML.gif"
alt="Fig. 3" />
</a>
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<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
<div class="caption-wrap">
<strong class="figure-label">
<p> Fig. 3 </p>
</strong>
<div class="figure-caption-contents"><p> New formula upregulates the expression… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 3 </p>
</strong>
<div class="figure-caption-contents"><p> New formula upregulates the expression levels of CD107a, NKG2D, IFN-γ, and TNF-α and… </p></div>
</div>
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 3
</strong>
<div class="figure-caption-contents">New formula upregulates the expression levels of CD107a, NKG2D, IFN-γ, and TNF-α and potentiates the in vitro cytotoxicity of Vγ9Vδ2 T cells. <b>a</b> TNF-α, IFN-γ, CD107a, and NKG2D levels were measured after 14 days following stimulation for 6h with anti-CD3 (5μg/mL) and anti-CD28 (1μg/mL) antibodies. Data are shown as the mean fluorescence intensity (MFI). <b>b</b> The new formula could significantly enhance the in vitro antitumor cytotoxicity of Vγ9Vδ2 T cells, as shown by killing assay results obtained for A549, Jurkat, MCF-7, BJAB, K562, Raji, and Daudi target cells. The Vγ9Vδ2 T cells were cocultured for 6h with CFSE-labeled tumor cells at a 10:1 ratio. Each linked line between OF and NF in all graphs represents an individual γδ T-cell line. **<i>p</i>&lt;0.01; ***<i>p</i>&lt;0.001</div>
</figcaption>
</figure>
<figure class="figure-item "
itemscope itemtype="http://schema.org/ImageObject"
itemprop="associatedMedia"
data-slide-index="3"
data-label-slug="fig-4">
<a class="figure-link"
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itemprop="contentUrl"
aria-describedby="figure-caption-3"
role="button"
data-image-width="718"
data-image-height="854"
data-image-alt="Fig. 4"
data-pmc-id="PMC8027668"
data-figure-id="Fig4">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3217/8027668/7f0e6bd58465/41423_2020_515_Fig4_HTML.gif"
alt="Fig. 4" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="718">
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<div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true">
<div class="caption-wrap">
<strong class="figure-label">
<p> Fig. 4 </p>
</strong>
<div class="figure-caption-contents"><p> NF-γδ T cells displayed potent… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 4 </p>
</strong>
<div class="figure-caption-contents"><p> NF-γδ T cells displayed potent antitumor activity in humanized mice. <b> a </b> The protocol… </p></div>
</div>
<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 4
</strong>
<div class="figure-caption-contents">NF-γδ T cells displayed potent antitumor activity in humanized mice. <b>a</b> The protocol for establishing lung cancer in humanized mice and evaluating the therapeutic effects of NF cells and OF cells. Seven days after inoculation of GFP-549 cells into humanized mice, NF cells and OF cells were adoptively transferred i.v. into the humanized mice. Mice treated with PBS were used as the control. <b>b</b> Macroscopic tumor inspection of tumors from untreated, OF-cell-treated, and NF-cell-treated mice. For the NF-cell-treated group, one mouse had a recurrent tumor on day 125, and two mice were tumor-free when sacrificed on day 238. <b>c</b> Survival curves of the three groups, suggesting that NF cells could significantly prolong survival time of tumor-bearing mice. <b>d</b> Tumor volume comparisons among the untreated, OF-cell-treated, and NF-cell-treated groups, showing that NF cells have optimal therapeutic effects on tumor development. <b>e</b> Live imaging to visualize the colocalization of A549 cancer cells and γδ T cells in humanized mice (views of the lower limb region of mice). NF cells or OF cells were prelabeled with DiR (red color) and then transferred i.v. into mice. The live imaging data indicated that only NF cells (red) visually colocalized with tumor cells (green) when monitored at 48h post infusion. Data are presented as the mean±SEM. *<i>p</i>&lt;0.05; **<i>p</i>&lt;0.01; ***<i>p</i>&lt;0.001</div>
</figcaption>
</figure>
<figure class="figure-item "
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data-slide-index="4"
data-label-slug="fig-5">
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itemprop="contentUrl"
aria-describedby="figure-caption-4"
role="button"
data-image-width="748"
data-image-height="265"
data-image-alt="Fig. 5"
data-pmc-id="PMC8027668"
data-figure-id="Fig5">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-4"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3217/8027668/1dc7c56a0510/41423_2020_515_Fig5_HTML.gif"
alt="Fig. 5" />
</a>
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<div class="caption-wrap">
<strong class="figure-label">
<p> Fig. 5 </p>
</strong>
<div class="figure-caption-contents"><p> Overall survival of patients with… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Fig. 5 </p>
</strong>
<div class="figure-caption-contents"><p> Overall survival of patients with advanced liver cancer or lung cancer infused with… </p></div>
</div>
<figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Fig. 5
</strong>
<div class="figure-caption-contents">Overall survival of patients with advanced liver cancer or lung cancer infused with allogeneic Vγ9Vδ2 T cells expanded using the new formula. <b>a</b>, <b>b</b> Overall survival curves were plotted by comparing γδ T-cell-treated patients and patients not treated with γδ T cells. The survival time of the γδ T-cell-treated patients was calculated starting from the date of the first infusion until June 2020. For the liver cancer group, the median survival time of the untreated patients was 8.1 months; in contrast, the median survival time of the γδ T-cell-treated patients was 23.1 months. <i>P</i>=0.0002. For the lung cancer group, the median survival time of the untreated patients was 9.1 months; however, the median survival time was 19.1 months for the γδ T-cell-treated patients. <i>P</i>=0.0028</div>
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