Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia

Abstract

<p class="first" id="d1826489e353">There is a <span class="generated">[Related article:]</span> <i>Blood</i> Commentary on this article in this issue. </p><p id="d1826489e364"> <div class="list"> <a class="named-anchor" id="d1826489e366"> <!-- named anchor --> </a> <ul class="so-custom-list"> <li id="d1826489e367"> <div class="so-custom-list-content so-ol"> <p class="first" id="d1826489e368">CD1a CARTs exhibit specific and robust cytotoxicity in vitro and in vivo using both T-ALL cell lines and primary coT-ALL cells. </p> </div> </li> <li id="d1826489e370"> <div class="so-custom-list-content so-ol"> <p class="first" id="d1826489e371">CD1a CARTs are fratricide resistant and exhibit long-term persistence in vivo with antileukemic activity in rechallenge experiments. </p> </div> </li> </ul> </div> </p><p class="first" id="d1826489e375">Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34 ⁺ progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient–derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL. </p><p id="d1826489e383"> <div class="fig panel" id="absf1"> <a class="named-anchor" id="absf1"> <!-- named anchor --> </a> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/140fa1e1-1dcc-45b5-8aaa-c2b39be5a727/PubMedCentral/image/blood882944absf1"/> </div> <div class="panel-content"/> </div> </p>