Fractionated initial infusion and booster dose of ARI0002h, a humanised, BCMA-directed CAR T-cell therapy, for patients with relapsed or refractory multiple myeloma (CARTBCMA-HCB-01): a single-arm, multicentre, academic pilot study.

Autor:	Oliver-Caldés A; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., González-Calle V; Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain., Cabañas V; Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla, University of Murcia, Murcia, Spain., Español-Rego M; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., Rodríguez-Otero P; Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBERONC, Pamplona, Pamplona, Spain., Reguera JL; Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC), University of Seville, Seville, Spain., López-Corral L; Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain., Martin-Antonio B; Department of Experimental Hematology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, University Autonomous of Madrid, Madrid, Spain., Zabaleta A; Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBERONC, Pamplona, Pamplona, Spain., Inogés S; Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBERONC, Pamplona, Pamplona, Spain., Varea S; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., Rosiñol L; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., López-Díaz de Cerio A; Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBERONC, Pamplona, Pamplona, Spain., Tovar N; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., Jiménez R; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., López-Parra M; Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain., Rodríguez-Lobato LG; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., Sánchez-Salinas A; Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla, University of Murcia, Murcia, Spain., Olesti E; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., Calvo-Orteu M; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., Delgado J; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., Pérez-Simón JA; Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC), University of Seville, Seville, Spain., Paiva B; Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBERONC, Pamplona, Pamplona, Spain., Prósper F; Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBERONC, Pamplona, Pamplona, Spain., Sáez-Peñataro J; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., Juan M; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., Moraleda JM; Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla, University of Murcia, Murcia, Spain., Mateos MV; Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain., Pascal M; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., Urbano-Ispizua A; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain., Fernández de Larrea C; Hospital Clínic de Barcelona. IDIBAPS. University of Barcelona, Barcelona, Spain. Electronic address: cfernan1@clinic.cat.
Jazyk:	angličtina
Zdroj:	The Lancet. Oncology [Lancet Oncol] 2023 Aug; Vol. 24 (8), pp. 913-924. Date of Electronic Publication: 2023 Jul 03.
DOI:	10.1016/S1470-2045(23)00222-X
Abstrakt:	Background: Chimeric antigen receptor (CAR) T-cell therapy is a promising option for patients with heavily treated multiple myeloma. Point-of-care manufacturing can increase the availability of these treatments worldwide. We aimed to assess the safety and activity of ARI0002h, a BCMA-targeted CAR T-cell therapy developed by academia, in patients with relapsed or refractory multiple myeloma. Methods: CARTBCMA-HCB-01 is a single-arm, multicentre study done in five academic centres in Spain. Eligible patients had relapsed or refractory multiple myeloma and were aged 18-75 years; with an Eastern Cooperative Oncology Group performance status of 0-2; two or more previous lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; refractoriness to the last line of therapy; and measurable disease according to the International Myeloma Working Group criteria. Patients received an initial fractionated infusion of 3 × 10 6 CAR T cells per kg bodyweight in three aliquots (0·3, 0·9, and 1·8 × 10 6 CAR-positive cells per kg intravenously on days 0, 3, and 7) and a non-fractionated booster dose of up to 3 × 10 6 CAR T cells per kg bodyweight, at least 100 days after the first infusion. The primary endpoints were overall response rate 100 days after first infusion and the proportion of patients developing cytokine-release syndrome or neurotoxic events in the first 30 days after receiving treatment. Here, we present an interim analysis of the ongoing trial; enrolment has ended. This study is registered with ClinicalTrials.gov, NCT04309981, and EudraCT, 2019-001472-11. Findings: Between June 2, 2020, and Feb 24, 2021, 44 patients were assessed for eligibility, of whom 35 (80%) were enrolled. 30 (86%) of 35 patients received ARI0002h (median age 61 years [IQR 53-65], 12 [40%] were female, and 18 [60%] were male). At the planned interim analysis (cutoff date Oct 20, 2021), with a median follow-up of 12·1 months (IQR 9·1-13·5), overall response during the first 100 days from infusion was 100%, including 24 (80%) of 30 patients with a very good partial response or better (15 [50%] with complete response, nine [30%] with very good partial response, and six [20%] with partial response). Cytokine-release syndrome was observed in 24 (80%) of 30 patients (all grade 1-2). No cases of neurotoxic events were observed. Persistent grade 3-4 cytopenias were observed in 20 (67%) patients. Infections were reported in 20 (67%) patients. Three patients died: one because of progression, one because of a head injury, and one due to COVID-19. Interpretation: ARI0002h administered in a fractioned manner with a booster dose after 3 months can provide deep and sustained responses in patients with relapsed or refractory multiple myeloma, with a low toxicity, especially in terms of neurological events, and with the possibility of a point-of-care approach. Funding: Instituto de Salud Carlos III (co-funded by the EU), Fundación La Caixa, and Fundació Bosch i Aymerich. Competing Interests: Declaration of interests AO-C declares support for attending meetings from Janssen. VG-C declares receiving honoraria from Janssen, Pfizer, Bristol Myers Squibb (BMS)/Celgene, and GSK; support for attending meetings or travel from Janssen and GSK; and participation on data safety monitoring or advisory board from Janssen. VC declares receiving honoraria from Janssen, BMS, Sanofi, GSK, and Amgen; support for attending meetings or travel from Janssen; and participation on data safety monitoring or advisory board from Janssen, Sanofi, and Amgen. PR-O declares receiving honoraria from consulting activities from BMS, Janssen, Sanofi, Abbvie, Pfizer, Roche, and GSK; honoraria from lectures from BMS, Janssen, Sanofi and GSK; support for attending meetings or travel from Abbvie; and participation on data safety monitoring or advisory board from Janssen. JLR declares receiving consulting fees from Janssen; honoraria from Janssen, Amgen, Sanofi, Kite/Gilead, Novartis, and BMS; support for attending meetings or travel from Kite/Gilead; and participation on data safety monitoring or advisory board from Janssen, BMS, and Novartis. LL-C declares receiving honoraria from Kite/Gilead, Celgene, Janssen, and Novartis; support for attending meetings or travel from Kite/Gilead, Celgene, Janssen, and Novartis; and participation on data safety monitoring or advisory board from Janssen. BM-A declares to be co-inventor in the patent of ARI0002. LR declares honoraria from Janssen, BMS/Celgene, Amgen, Takeda, Sanofi, and GSK; participation on data safety monitoring or advisory board of Janssen, BMS-Celgene, Amgen, Takeda, Sanofi, and GSK. ML-P declares receiving consulting fees from Celgene/BMS; honoraria from Janssen and Kite/Gilead; and participation on data safety monitoring or advisory board from Celgene/BMS and Novartis. LGR-L declares honoraria from Janssen, GSK, Sanofi, and BMS; travel grants from Janssen, Amgen, GSK, Pfizer and Sanofi; and participation on data safety monitoring or advisory board from GSK and Sanofi. AS-S declares receiving travel grants from Jazz Pharmaceuticals, Pfizer, and MSD. JAP-S declares research and travel support Takeda, Abbvie, Gilead, AMGEN, Jazz, Alexion, Pierre Fabre and Beigene; educational activities, speaker, and advisory fees with Gilead, Jazz, Alexion, AMGEN, Novartis, Janssen, BMS, and MSD; and participation on data safety monitoring or advisory board from Gilead, Jazz, Alexion, AMGEN, Novartis, Janssen, BMS and MSD. BP reports research funding from BMS, GSK, Roche, Beigene, and Sanofi; consultancy fees from BMS, GSK, Janssen, Sanofi and Takeda; honoraria from Adaptive, Amgen, Becton Dickinson, BMS/Celgene, GSK, Janssen, Sanofi, and Roche; and support for attending meetings from GSK. FP declares receiving grants from the Spanish Ministry of Health (ISCIII) and the Government of Navarra; honoraria from Janssen, Oryzon, Dialectica, Novartis, Instituto Roche, Servier, ViviaBiotech, and Techspert; support for attending meetings or travel from Gilead, Celgene, and Janssen; and a leadership or fiduciary role in RICORS Terav and IDISNA. MJ declares receiving research or travel support by Fundació Bancaria la Caixa, ISCIII, and CellNex Teleom; honoraria from educational activities, speaker, and advisory roles with Miltenyi and indirectly with sponsors of congresses; and participation on data safety monitoring or advisory boards with MAB Gyala. JMM declares receiving honoriaria from Gilead/Kite, Novartis, BMS/Celgene, and Roche; travel grants, accommodation, and expenses from Jazz Pharma, Gilead-Kite, Janssen, and Sandoz; and consulting or advisory board fees in Jazz Pharma, Novartis, and Sandoz. M-VM declares honoraria derived from lectures and participation in advisory boards from Janssen, BMS/Celgene, Takeda, Amgen, GSK, Pfizer, Regeneron, Roche, and Sanofi. MP declares receiving honoraria from Thermofisher Scientific and LetiPharma. AU-I declares receiving grants from the Spanish Ministry of Health (ISCIII); honoraria for lectures from BMS and Gilead; support for attending meetings from Amgen; 23% of participation in ARI-002 patent ARI-001 patent in preparation; advisory board fees and participation in Miltenyi biomedicine; being coordinator of the Spanish group of CAR T-cell therapy. CFL declares receiving grants through his institution from BMS, Janssen, and Amgen; honoraria from Amgen, Janssen, BMS, GSK, and Sanofi; support for attending meetings or travel from Janssen, BMS, GSK, and Amgen; and participation in data safety monitoring or advisory boards with Janssen, BMS, Amgen, Pfizer, and Sanofi. All other authors declare no competing interests. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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