TY - JOUR
T1 - Limited efficacy of APRIL CAR in patients with multiple myeloma indicate challenges in the use of natural ligands for CAR T-cell therapy
AU - Lee, Lydia
AU - Lim, Wen Chean
AU - Galas-Filipowicz, Daria
AU - Fung, Kent
AU - Taylor, Julia
AU - Patel, Dominic
AU - Akbar, Zulaikha
AU - Alvarez Mediavilla, Elena
AU - Wawrzyniecka, Patrycja
AU - Shome, Debarati
AU - Reijmers, Rogier M.
AU - Gregg, Trillian
AU - Wood, Leigh
AU - Day, William
AU - Cerec, Virginie
AU - Ferrari, Mathieu
AU - Thomas, Simon
AU - Cordoba, Shaun
AU - Onuoha, Shimobi
AU - Khokhar, Nushmia
AU - Peddareddigari, Vijay
AU - Al-Hajj, Muhammad
AU - Cavet, Jim
AU - Zweegman, Sonja
AU - Rodriguez-Justo, Manuel
AU - Youg, Kwee
AU - Pule, Martin
AU - Popat, Rakesh
N1 - Funding Information: MP and RP are supported by the UK National Institute of Health research UCLH Biomedical research center. LSHL is supported by the UK medical Research Council. Preclinical development of the APRIL CAR was supported by Bloodwise and Kay Kendell Leukemia Fund. VP, NK, KY and RP designed the clinical study. RP, JC and SZ recruited patients. VC and LW were involved in trial management. WD and MA-H were responsible for translational data. DG-F, DP, MR-J and LSHL processed and analysed clinical samples. WCL, KF, JT, ZA, EAM, MF, ST, SC and SO generated the research data. MP and LSHL wrote the manuscript. MP is guarantor for this manuscript. Funding Information: LSHL, KY and MP are inventors on patents relevant to this paper filed by UCL and are entitled to share of royalties there from. KY and MP owns equity in Autolus Therapeutics. WCL, JT, ZA, WD, VC, MF, ST, SC, SO, NK, VP, MA-H and MP are either current present or former employees of Autolus Therapeutics. LSHL and KY receive research funding from Autolus Therapeutics. Funding Information: LSHL is funded by the MRC (MR/S001883/1), AUTO2 trial was funded and sponsored by Autolus Therapeutics Publisher Copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.
PY - 2023/6/30
Y1 - 2023/6/30
N2 - 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.
AB - 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.
KW - T-lymphocytes
KW - clinical trials as topic
KW - immunotherapy
KW - immunotherapy, adoptive
UR - http://www.scopus.com/inward/record.url?scp=85164002380&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/jitc-2023-006699
DO - https://doi.org/10.1136/jitc-2023-006699
M3 - Article
C2 - 37399355
SN - 2051-1426
VL - 11
JO - Journal for Immunotherapy of Cancer
JF - Journal for Immunotherapy of Cancer
IS - 6
M1 - 006699
ER -