Safety and activity of CTX130, a CD70-targeted allogeneic CRISPR-Cas9-engineered CAR T-cell therapy, in patients with relapsed or refractory T-cell malignancies (COBALT-LYM): a single-arm, open-label, phase 1, dose-escalation study.

Autor:	Iyer SP; Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: spiyer@mdanderson.org., Sica RA; Department of Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY, USA., Ho PJ; Institute of Haematology, Royal Prince Alfred Hospital and University of Sydney, Camperdown, NSW, Australia., Prica A; Princess Margaret Cancer Centre, Toronto, Canada., Zain J; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA., Foss FM; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA., Hu B; Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Beitinjaneh A; Division of Transplantation and Cellular Therapy, University of Miami Hospital and Clinics, Sylvester Comprehensive Cancer Center, Miami, FL, USA., Weng WK; Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Kim YH; Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA., Khodadoust MS; Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA., Huen AO; Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Williams LM; CRISPR Therapeutics, Boston, MA, USA., Ma A; CRISPR Therapeutics, Boston, MA, USA., Huang E; CRISPR Therapeutics, Boston, MA, USA., Ganpule A; CRISPR Therapeutics, Boston, MA, USA., Nagar SD; CRISPR Therapeutics, Boston, MA, USA., Sripakdeevong P; CRISPR Therapeutics, Boston, MA, USA., Cullingford EL; CRISPR Therapeutics, Boston, MA, USA., Karnik S; CRISPR Therapeutics, Boston, MA, USA., Dequeant ML; CRISPR Therapeutics, Boston, MA, USA., Patel JN; CRISPR Therapeutics, Boston, MA, USA., He XS; CRISPR Therapeutics, Boston, MA, USA., Li Z; CRISPR Therapeutics, Boston, MA, USA., He QA; CRISPR Therapeutics, Boston, MA, USA., Mendonez JH; CRISPR Therapeutics, Boston, MA, USA., Keegan A; CRISPR Therapeutics, Boston, MA, USA., Horwitz SM; Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Jazyk:	angličtina
Zdroj:	The Lancet. Oncology [Lancet Oncol] 2024 Nov 28. Date of Electronic Publication: 2024 Nov 28.
DOI:	10.1016/S1470-2045(24)00508-4
Abstrakt:	Background: Effective treatment options are scarce for relapsed or refractory T-cell lymphoma. This study assesses the safety and activity of CTX130 (volamcabtagene durzigedleucel), a CD70-directed, allogeneic chimeric antigen receptor (CAR) immunotherapy manufactured from healthy donor T cells, in patients with relapsed or refractory T-cell lymphoma. Methods: This single-arm, open-label, phase 1 study was done at ten medical centres across the USA, Australia, and Canada in patients (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma or cutaneous T-cell lymphoma, who had received at least one or at least two previous systemic therapy lines, respectively, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients underwent lymphodepletion with fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 (intravenously daily for 3 days), followed by intravenous CTX130 infusion at dose levels ranging from 3 × 10 7 CAR+ T cells (dose level 1) to 9 × 10 8 CAR+ T cells (dose level 4). The primary endpoint was the incidence of adverse events, defined as dose-limiting toxicities occurring within 28 days post-infusion. Secondary endpoints included objective response rate. Safety and activity analyses were performed on data from all patients who received CTX130. The trial is registered with ClinicalTrials.gov (NCT04502446) and EudraCT (2019-004526-25) and is closed to enrolment. Findings: Between Aug 28, 2020, and May 30, 2023, 41 patients were enrolled and 39 (95%) received CTX130. The median patient follow-up was 7·4 months (IQR 3·1-12·2). 21 (54%) of 39 patients were female and 18 (46%) were male. 24 (62%) patients were White, eight (21%) were Black, three (8%) were Asian, three (8%) were from other racial or ethnic groups, and one (3%) was not reported. The median number of previous lines of anticancer therapy was 2·5 (IQR 1·3-4·0) for patients with peripheral T-cell lymphoma and 5·0 (IQR 5·0-7·0) for patients with cutaneous T-cell lymphoma. Cytokine release syndrome was the most common adverse event, occurring in 26 (67%) of 39 patients (23 were grade 1-2, two were grade 3, and one was a grade 4 dose-limiting toxicity at dose level 4). Grade 1-2 neurotoxic events were observed in four (10%) of 39 patients. The most common grade 3-4 adverse events were neutropenia (14 [36%]), anaemia (11 [28%]), and thrombocytopenia (six [15%]). Serious adverse events occurred in 25 (64%) patients, with CTX130-related serious adverse events in 14 (36%) patients, the most common related serious adverse event being cytokine release syndrome in 11 (28%) patients. 21 patients died, 16 from progressive disease and five from adverse events considered unrelated to CTX130 treatment. 18 of 39 patients (46·2% [95% CI 30·1-62·8) had an objective response. Of those treated at dose level 3 and higher, 16 of 31 patients (51·6% [33·1-69·8]) had objective responses, including six (19·4% [7·5-37·5]) with complete response and ten (32·3% [16·7-51·4]) with a partial response. Interpretation: In patients with heavily pretreated T-cell lymphoma, CTX130 showed manageable safety and a promising objective response rate. This study shows that allogeneic, readily available CAR T cells can be safely given to patients with relapsed or refractory T-cell lymphoma. A next-generation CAR T-cell therapy containing additional potency gene edits (CTX131) is in clinical development. Funding: CRISPR Therapeutics. Competing Interests: Declaration of interests SPI reports institutional support from CRISPR Therapeutics, Acrotech, and Rhizen, institutional contracts from CRISPR Therapeutics, Innate, Merck, Trillium/Pfizer, Seagen, DrenBio, and Acrotech, consulting fees from Yingli and Electra/Star, unpaid participation on an advisory board for Ranok Therapeutics, participation in the Indo American Cancer Association, and equity interest in IMPaRT.ai (Technology). RAS reports working as an investigator on a CRISPR Therapeutics trial, receipt of a Paul Calabresi Career Development Award K12 NIH grant, a grant to study CAR T in a disadvantaged population cohort (Kite), receipt of consulting fees and support for attending a consulting meeting from CRISPR Therapeutics, and receipt of consulting fees from BioHeng. PJH reports working as an investigator on a CRISPR Therapeutics trial, participation on an advisory board for Antengene, Gilead, iTeos Therapeutics, Janssen, and Pfizer, and receipt of medical writing support from Novartis. AP reports working as an investigator on a CRISPR Therapeutics trial and receipt of honoraria from Seattle Genetics, AstraZeneca, and AbbVie. JZ reports payment made from CRISPR Therapeutics for institutional research support and speaker bureau fees from Kyowa Kirin. FMF reports working as an investigator on a CRISPR Therapeutics trial, speaker fees from Seagen, honoraria from Kyowa Kirin and Acrotech, and serving as a volunteer officer on The United States Cutaneous Lymphoma Consortium. BH reports consulting fees from AbbVie, working as an investigator for Genentech, Celgene, CRISPR Therapeutics, Morphosys, Caribou Biosciences, Repare Therapeutics, Artiva Biotherapeutics, Newave, AstraZeneca, and ImmPACT Bio, payment for presentation by OncLive, MJH Life Sciences, Binaytara Foundation, Total Health Conferencing, Dava Oncology, and Curio Science, payment for preparation of educational materials from Eli Lilly, and participation on an advisory board for TG Therapeutics, ADC Therapeutics, Bristol Meyers Squibb, Novartis, GenMab, ImmPact Bio, SeaGen, Regeneron, and Caribou Biosciences. AB reports working as an investigator on a CRISPR Therapeutics trial, institutional research grants from Kite, Autolus, ATARA, TESSA, Angiocrine, Juno, Lyell, and CRISPR, and payment from Autolus and Kite for educational events. W-KW reports working as an investigator on a CRISPR Therapeutics trial. YHK reports working as an investigator on a CRISPR Therapeutics trial and institutional research support from CRISPR Therapeutics for this trial, institutional grants from Kyowa Kirin, Innate, Corvus, and Dren Bio, royalties from UpToDate, consulting fees from Citius, Kyowa Kirin, CRISPR Therapeutics, and Dren Bio, membership to the board of directors for the Cutaneous Lymphoma Foundation and International Society for Cutaneous Lymphomas, and being a panel member for NCCN. MSK reports working as an investigator on a CRISPR Therapeutics trial, receipt of research funding from Nutcracker Therapeutics, receipt of an NIH grant 1K08CA207882, and participation on an advisory board for Myeloid Therapeutics. AOH reports institutional support from CRISPR Therapeutics, Rhizen, Trillium, Kyowa Kirin, and Kymera. SMH reports institutional support from ADC Therapeutics, Affimed, Aileron, Celgene, CRISPR Therapeutics, Daiichi Sankyo, Forty Seven, Kyowa Hakko Kirin, Takeda, Seattle Genetics, Trillium Therapeutics, and SecuraBio, partial support for this trial from the NIH/NCI Cancer Center Support Grant P30CA008748, and receipt of payment for educational events from Abcuro, Autolus, Auxilus Pharma, Corvus, Cimeio Therapeutics, Daiichi Sankyo, Dren Bio, Kyowa Hakko Kirin, March Bio, ONO Pharmaceuticals, Secura Bio, Shoreline Biosciences, Takeda, Tubulis, and Yingli Pharma. JHM, LMW, AM, EH, AG, SDN, PS, ELC, SK, M-LD, JNP, ZL, QAH, and AK report CRISPR Therapeutics employment and equity interest. XSH reports working as a contractor for CRISPR Therapeutics. PS reports being an inventor on a patent application filed by CRISPR Therapeutics/Nkarta. SK and AK report support from CRISPR Therapeutics for travel or attending meetings. (Copyright © 2024 Elsevier Ltd. 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