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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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Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely regressed RCC xenograft tumors. We also report results from 16 patients with relapsed/refractory ccRCC who received CTX130 in a phase I, multicenter, first-in-human clinical trial. No patients encountered dose-limiting toxicity, and disease control was achieved in 81.3% of patients. One patient remains in a durable complete response at 3 years. Finally, we report on a next-generation CAR T construct, CTX131, in which synergistic potency edits to CTX130 confer improved expansion and efficacy in preclinical studies. These data represent a proof of concept for the treatment of ccRCC and other CD70+ malignancies with CD70- targeted allogeneic CAR T cells. Significance: Although the role of CAR T cells is well established in hematologic malignancies, the clinical experience in solid tumors has been disappointing. This clinical trial demonstrates the first complete response in a patient with RCC, reinforcing the potential benefit of CAR T cells in the treatment of solid tumors., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Allergen immunotherapy is currently the only disease-modifying treatment available for allergic rhinitis and allergic asthma., Objectives: We sought to evaluate the induction of sustained tolerance to allergen when anti-IL-4 was combined with a suboptimal course of grass pollen subcutaneous immunotherapy (SCIT) using the allergen-induced skin late-phase response (LPR) and exploratory immune monitoring as surrogate markers of therapeutic response., Methods: In this randomized, double-blind, 3-group parallel design trial, 37 participants with seasonal allergic rhinitis received suboptimal SCIT (30,000 standardized quality units) in combination with anti-IL-4 (VAK694) and suboptimal SCIT (30,000 standardized quality units) plus placebo antibody or double placebo (placebo SCIT and placebo antibody) restricted to 13 weeks before the grass pollen season. The primary end point was the size of the LPR at 12 months. Exploratory end points included measures of the immunomodulatory activity of treatment by using IL-4 and IL-10 FluoroSpot assays, flow cytometry of T cells, and measurement of IgE, IgG4, and facilitated antigen binding., Results: Both active treatment arms led to a substantial and sustained reduction of the LPR with no additional suppression with addition of anti-IL-4. Treatment with anti-IL-4 and SCIT compared with SCIT alone led to a sustained reduction in allergen-specific IL-4-producing cell counts (P < .01). Both active treatment arms led to induction of dual IL-4/IL-10-producing cells during the pollen season., Conclusion: The combination of anti-IL-4 with SCIT provided no additional benefit over SCIT alone in suppressing the allergen-induced skin LPR. A larger trial is needed to assess whether the observed ex vivo downregulation of TH2 responses might translate into clinical benefit., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)