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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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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. |
format | Online Article Text |
id | pubmed-9980914 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
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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