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Conduit CAR: Redirecting CAR T-Cell Specificity with A Universal and Adaptable Bispecific Antibody Platform

The success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies has altered the treatment paradigm for patients with these diseases. Nevertheless, the occurrence of relapse due to antigen escape or heterogeneous antigen expression on tumors remains a challenge for firs...

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Autores principales: Borrok, M. Jack, Li, Yonghai, Harvilla, Paul B., Vellalore Maruthachalam, Bharathikumar, Tamot, Ninkka, Prokopowitz, Christine, Chen, Jun, Venkataramani, Sathya, Grewal, Iqbal S., Ganesan, Rajkumar, Singh, Sanjaya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980914/
https://www.ncbi.nlm.nih.gov/pubmed/36874404
http://dx.doi.org/10.1158/2767-9764.CRC-21-0150
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author Borrok, M. Jack
Li, Yonghai
Harvilla, Paul B.
Vellalore Maruthachalam, Bharathikumar
Tamot, Ninkka
Prokopowitz, Christine
Chen, Jun
Venkataramani, Sathya
Grewal, Iqbal S.
Ganesan, Rajkumar
Singh, Sanjaya
author_facet Borrok, M. Jack
Li, Yonghai
Harvilla, Paul B.
Vellalore Maruthachalam, Bharathikumar
Tamot, Ninkka
Prokopowitz, Christine
Chen, Jun
Venkataramani, Sathya
Grewal, Iqbal S.
Ganesan, Rajkumar
Singh, Sanjaya
author_sort Borrok, M. Jack
collection PubMed
description The success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies has altered the treatment paradigm for patients with these diseases. Nevertheless, the occurrence of relapse due to antigen escape or heterogeneous antigen expression on tumors remains a challenge for first-generation CAR T-cell therapies as only a single tumor antigen can be targeted. To address this limitation and to add a further level of tunability and control to CAR T-cell therapies, adapter or universal CAR T-cell approaches use a soluble mediator to bridge CAR T cells with tumor cells. Adapter CARs allow simultaneous or sequential targeting of multiple tumor antigens, control of immune synapse geometry, dose control, and the potential for improved safety. Herein, we described a novel CAR T-cell adapter platform that relies on a bispecific antibody (BsAb) targeting both a tumor antigen and the GGGGS (G(4)S) linker commonly used in single-chain Fv (ScFv) domains expressed on CAR T-cell surfaces. We demonstrated that the BsAb can bridge CAR T cells to tumor cells and potentiate CAR T-cell activation, proliferation, and tumor cell cytolysis. The cytolytic activity of CAR T-cells was redirected to different tumor antigens by changing the BsAb in a dose-dependent manner. This study highlights the potential of G(4)S-displaying CAR T cells to be redirected to engage alternative tumor-associated antigens (TAA). SIGNIFICANCE: New approaches are needed to address relapsed/refractory disease and manage potential toxicities associated with CAR T-cell therapy. We describe an adapter CAR approach to redirect CAR T cells to engage novel TAA-expressing cells via a BsAb targeting a linker present on many clinical CAR T-cell therapeutics. We anticipate the use of such adapters could increase CAR T-cell efficacy and reduce potential CAR-associated toxicities.
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spelling pubmed-99809142023-03-03 Conduit CAR: Redirecting CAR T-Cell Specificity with A Universal and Adaptable Bispecific Antibody Platform Borrok, M. Jack Li, Yonghai Harvilla, Paul B. Vellalore Maruthachalam, Bharathikumar Tamot, Ninkka Prokopowitz, Christine Chen, Jun Venkataramani, Sathya Grewal, Iqbal S. Ganesan, Rajkumar Singh, Sanjaya Cancer Res Commun Research Article The success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies has altered the treatment paradigm for patients with these diseases. Nevertheless, the occurrence of relapse due to antigen escape or heterogeneous antigen expression on tumors remains a challenge for first-generation CAR T-cell therapies as only a single tumor antigen can be targeted. To address this limitation and to add a further level of tunability and control to CAR T-cell therapies, adapter or universal CAR T-cell approaches use a soluble mediator to bridge CAR T cells with tumor cells. Adapter CARs allow simultaneous or sequential targeting of multiple tumor antigens, control of immune synapse geometry, dose control, and the potential for improved safety. Herein, we described a novel CAR T-cell adapter platform that relies on a bispecific antibody (BsAb) targeting both a tumor antigen and the GGGGS (G(4)S) linker commonly used in single-chain Fv (ScFv) domains expressed on CAR T-cell surfaces. We demonstrated that the BsAb can bridge CAR T cells to tumor cells and potentiate CAR T-cell activation, proliferation, and tumor cell cytolysis. The cytolytic activity of CAR T-cells was redirected to different tumor antigens by changing the BsAb in a dose-dependent manner. This study highlights the potential of G(4)S-displaying CAR T cells to be redirected to engage alternative tumor-associated antigens (TAA). SIGNIFICANCE: New approaches are needed to address relapsed/refractory disease and manage potential toxicities associated with CAR T-cell therapy. We describe an adapter CAR approach to redirect CAR T cells to engage novel TAA-expressing cells via a BsAb targeting a linker present on many clinical CAR T-cell therapeutics. We anticipate the use of such adapters could increase CAR T-cell efficacy and reduce potential CAR-associated toxicities. American Association for Cancer Research 2022-03-22 /pmc/articles/PMC9980914/ /pubmed/36874404 http://dx.doi.org/10.1158/2767-9764.CRC-21-0150 Text en © 2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Research Article
Borrok, M. Jack
Li, Yonghai
Harvilla, Paul B.
Vellalore Maruthachalam, Bharathikumar
Tamot, Ninkka
Prokopowitz, Christine
Chen, Jun
Venkataramani, Sathya
Grewal, Iqbal S.
Ganesan, Rajkumar
Singh, Sanjaya
Conduit CAR: Redirecting CAR T-Cell Specificity with A Universal and Adaptable Bispecific Antibody Platform
title Conduit CAR: Redirecting CAR T-Cell Specificity with A Universal and Adaptable Bispecific Antibody Platform
title_full Conduit CAR: Redirecting CAR T-Cell Specificity with A Universal and Adaptable Bispecific Antibody Platform
title_fullStr Conduit CAR: Redirecting CAR T-Cell Specificity with A Universal and Adaptable Bispecific Antibody Platform
title_full_unstemmed Conduit CAR: Redirecting CAR T-Cell Specificity with A Universal and Adaptable Bispecific Antibody Platform
title_short Conduit CAR: Redirecting CAR T-Cell Specificity with A Universal and Adaptable Bispecific Antibody Platform
title_sort conduit car: redirecting car t-cell specificity with a universal and adaptable bispecific antibody platform
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980914/
https://www.ncbi.nlm.nih.gov/pubmed/36874404
http://dx.doi.org/10.1158/2767-9764.CRC-21-0150
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