Data from Common Trajectories of Highly Effective CD19-Specific CAR T Cells Identified by Endogenous T-cell Receptor Lineages
Taylor L. WilsonHyunjin KimChing‐Heng ChouDeanna LangfittRobert C. MettelmanAnastasia A. MinervinaE. Kaitlynn AllenJean‐Yves MétaisMikhail V. PogorelyyJanice M. RiberdyMireya Paulina VelasquezPratibha KottapalliSanchit TrivediScott R. OlsenTimothy LockeyCatherine WillisMichael M. MeagherBrandon M. TriplettAimee C. TalleurStephen GottschalkJeremy Chase CrawfordPaul G. Thomas
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<div>Abstract<p>Current chimeric antigen receptor-modified (CAR) T-cell products are evaluated in bulk, without assessing functional heterogeneity. We therefore generated a comprehensive single-cell gene expression and T-cell receptor (TCR) sequencing data set using pre- and postinfusion CD19-CAR T cells from blood and bone marrow samples of pediatric patients with B-cell acute lymphoblastic leukemia. We identified cytotoxic postinfusion cells with identical TCRs to a subset of preinfusion CAR T cells. These effector precursor cells exhibited a unique transcriptional profile compared with other preinfusion cells, corresponding to an unexpected surface phenotype (TIGIT<sup>+</sup>, CD62L<sup>lo</sup>, CD27<sup>−</sup>). Upon stimulation, these cells showed functional superiority and decreased expression of the exhaustion-associated transcription factor TOX. Collectively, these results demonstrate diverse effector potentials within preinfusion CAR T-cell products, which can be exploited for therapeutic applications. Furthermore, we provide an integrative experimental and analytic framework for elucidating the mechanisms underlying effector development in CAR T-cell products.</p>Significance:<p>Utilizing clonal trajectories to define transcriptional potential, we find a unique signature of CAR T-cell effector precursors present in preinfusion cell products. Functional assessment of cells with this signature indicated early effector potential and resistance to exhaustion, consistent with postinfusion cellular patterns observed in patients.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-9-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 2007</a></i></p></div>Cell therapy
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Chimeric antigen receptor (CAR) T cell therapies targeting CD19 and CD22 have been successful for treating B cell cancers, but CAR T cells targeting non–B cell cancers remain unsuccessful. We propose that rather than being strictly a side effect of therapy, the large number of CAR interactions with normal B cells may be a key contributor to clinical CAR T cell responses.
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Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.
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Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults with a poor prognosis with relapsed or refractory (R/R) B-cell lineage ALL (B-ALL). Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown excellent response rates in RR B-ALL, but most patients relapse due to poor persistence of CAR T-cell therapy or other tumor-associated escape mechanisms. In addition, anti-CD19 CAR T-cell therapy causes several serious side effects such as cytokine release syndrome and neurotoxicity. In this review, we will discuss novel CAR targets, CAR constructs, and various strategies to boost CARs for the treatment of RR B-ALL. In addition, we discuss a few novel strategies developed to reduce the side effects of CAR.
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To review recent data and relevant of the role of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for B-cell non-Hodgkin lymphoma (NHL).Review and compilation of the most recent and relevant data published in full text and abstract forms of anti-CD19 CAR T-cell therapy for B-cell NHL.Different anti-CD19 CAR T-cell therapy products have been tested and shown significant clinical activity across B-cell NHL patients. The objective responses in relapsed DLBCL, FL and MCL were 50-83%, 83-93% and 93%, respectively.Anti-CD19 CAR T-cell therapy is a viable option for poor risk refractory B-cell NHLs.
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Abstract Backgroud : The unprecedented efficacy of chimeric antigen receptor (CAR) T-cell immunotherapy of CD19 + B-cell malignancies has opened a new and useful way for the treatment of malignant tumor. Nonetheless, there are still formidable challenges in the field of CAR-T cell therapy, such as the biodistribution of CAR-T cells in vivo. Methods : We demonstrated the distribution of CAR-T cells in the absence of target cells or with target cells in the mice and the dynamic changes in the patient blood over time after infusion were deteced by qPCR and FACS. Results : CAR-T cells still proliferated in the mice without target cells and peaked at 2 weeks. However, CAR-T cells did not increase significantly in the presence of target cells within 2 weeks after infusion, but expanded at 6 weeks. In the clinical trial, we found that CAR-T cells peaked at 7-21days after infusion and can last for as long as 510 days in the peripheral blood of patients. Simultaneously, mild side-effects were noted which can be effectively controlled within two months in these patients. Conclusions : CAR-T cells can expand themselves with or without target cells in mice. CAR-T cells can persistence for a long time in patients.
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