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© 2023 Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background

We used a proliferating ligand (APRIL) to construct a ligand-based third generation chimeric antigen receptor (CAR) able to target two myeloma antigens, B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor.

Methods

The APRIL CAR was evaluated in a Phase 1 clinical trial (NCT03287804, AUTO2) in patients with relapsed, refractory multiple myeloma. Eleven patients received 13 doses, the first 15×106 CARs, and subsequent patients received 75,225,600 and 900×106 CARs in a 3+3 escalation design.

Results

The APRIL CAR was well tolerated. Five (45.5%) patients developed Grade 1 cytokine release syndrome and there was no neurotoxicity. However, responses were only observed in 45.5% patients (1×very good partial response, 3×partial response, 1×minimal response). Exploring the mechanistic basis for poor responses, we then compared the APRIL CAR to two other BCMA CARs in a series of in vitro assays, observing reduced interleukin-2 secretion and lack of sustained tumor control by APRIL CAR regardless of transduction method or co-stimulatory domain. There was also impaired interferon signaling of APRIL CAR and no evidence of autoactivation. Thus focusing on APRIL itself, we confirmed similar affinity to BCMA and protein stability in comparison to BCMA CAR binders but reduced binding by cell-expressed APRIL to soluble BCMA and reduced avidity to tumor cells. This indicated either suboptimal folding or stability of membrane-bound APRIL attenuating CAR activation.

Conclusions

The APRIL CAR was well tolerated, but the clinical responses observed in AUTO2 were disappointing. Subsequently, when comparing the APRIL CAR to other BCMA CARs, we observed in vitro functional deficiencies due to reduced target binding by cell-expressed ligand.

Details

Title
Limited efficacy of APRIL CAR in patients with multiple myeloma indicate challenges in the use of natural ligands for CAR T-cell therapy
Author
Lee, Lydia 1   VIAFID ORCID Logo  ; Lim, Wen Chean 2 ; Galas-Filipowicz, Daria 1 ; Fung, Kent 1 ; Taylor, Julia 2 ; Patel, Dominic 3 ; Zulaikha Akbar 2 ; Elena Alvarez Mediavilla 1 ; Wawrzyniecka, Patrycja 4 ; Shome, Debarati 4 ; Reijmers, Rogier M 4   VIAFID ORCID Logo  ; Trillian Gregg 4 ; Wood, Leigh 5 ; Day, William 2 ; Cerec, Virginie 2 ; Ferrari, Mathieu 2 ; Simon, Thomas 2 ; Cordoba, Shaun 2 ; Onuoha, Shimobi 2 ; Khokhar, Nushmia 2 ; Peddareddigari, Vijay 2 ; Al-Hajj, Muhammad 2 ; Cavet, Jim 6 ; Zweegman, Sonja 7 ; Rodriguez-Justo, Manuel 3 ; Kwee Yong 1 ; Martin, Pule 8 ; Popat, Rakesh 5 

 Research Department of Haematology, UCL Cancer Institute, London, UK 
 Autolus Ltd, London, UK 
 Department of Pathology, UCL Cancer Institute, London, UK 
 Lumicks, Amsterdam, The Netherlands 
 Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK 
 The Christie NHS Foundation Trust, Manchester, UK 
 Vrije Univ Amsterdam, Amsterdam, The Netherlands 
 Research Department of Haematology, UCL Cancer Institute, London, UK; Autolus Ltd, London, UK 
First page
e006699
Section
Immune cell therapies and immune cell engineering
Publication year
2023
Publication date
Jun 2023
Publisher
BMJ Publishing Group LTD
e-ISSN
20511426
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2831440375
Copyright
© 2023 Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.