PMID- 35372008 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220405 IS - 2234-943X (Print) IS - 2234-943X (Electronic) IS - 2234-943X (Linking) VI - 12 DP - 2022 TI - Phase 1 Clinical Trial Evaluating the Safety and Anti-Tumor Activity of ADP-A2M10 SPEAR T-Cells in Patients With MAGE-A10+ Head and Neck, Melanoma, or Urothelial Tumors. PG - 818679 LID - 10.3389/fonc.2022.818679 [doi] LID - 818679 AB - BACKGROUND: ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T-cells are genetically engineered autologous T-cells that express a high-affinity melanoma-associated antigen (MAGE)-A10-specific T-cell receptor (TCR) targeting MAGE-A10-positive tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-004 is a phase 1, dose-escalation trial to evaluate the safety and anti-tumor activity of ADP-A2M10 in three malignancies (https://clinicaltrials.gov: NCT02989064). METHODS: Eligible patients were HLA-A*02 positive with advanced head and neck squamous cell carcinoma (HNSCC), melanoma, or urothelial carcinoma (UC) expressing MAGE-A10. Patients underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the MAGE-A10 TCR, and expanded. Patients underwent lymphodepletion with fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 was administered in two dose groups receiving 0.1x10(9) and >1.2 to 6x10(9) transduced cells, respectively, and an expansion group receiving 1.2 to 15x10(9) transduced cells. RESULTS: Ten patients (eight male and two female) with HNSCC (four), melanoma (three), and UC (three) were treated. Three patients were treated in each of the two dose groups, and four patients were treated in the expansion group. The most frequently reported adverse events grade >/=3 were leukopenia (10), lymphopenia (10), neutropenia (10), anemia (nine), and thrombocytopenia (five). Two patients reported cytokine release syndrome (one each with grade 1 and grade 3), with resolution. Best response included stable disease in four patients, progressive disease in five patients, and not evaluable in one patient. ADP-A2M10 cells were detectable in peripheral blood from patients in each dose group and the expansion group and in tumor tissues from patients in the higher dose group and the expansion group. Peak persistence was greater in patients from the higher dose group and the expansion group compared with the lower dose group. CONCLUSIONS: ADP-A2M10 has shown an acceptable safety profile with no evidence of toxicity related to off-target binding or alloreactivity in these malignancies. Persistence of ADP-A2M10 in the peripheral blood and trafficking of ADP-A2M10 into the tumor was demonstrated. Because MAGE-A10 expression frequently overlaps with MAGE-A4 expression in tumors and responses were observed in the MAGE-A4 trial (NCT03132922), this clinical program closed, and trials with SPEAR T-cells targeting the MAGE-A4 antigen are ongoing. CI - Copyright (c) 2022 Hong, Butler, Pachynski, Sullivan, Kebriaei, Boross-Harmer, Ghobadi, Frigault, Dumbrava, Sauer, Brophy, Navenot, Fayngerts, Wolchinsky, Broad, Batrakou, Wang, Solis, Duose, Sanderson, Gerry, Marks, Bai, Norry and Fracasso. FAU - Hong, David S AU - Hong DS AD - Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Butler, Marcus O AU - Butler MO AD - Princess Margaret Hospital Cancer Centre, University of Toronto, Toronto, ON, Canada. FAU - Pachynski, Russell K AU - Pachynski RK AD - Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States. FAU - Sullivan, Ryan AU - Sullivan R AD - Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. FAU - Kebriaei, Partow AU - Kebriaei P AD - Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Boross-Harmer, Sarah AU - Boross-Harmer S AD - Princess Margaret Hospital Cancer Centre, University of Toronto, Toronto, ON, Canada. FAU - Ghobadi, Armin AU - Ghobadi A AD - Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States. FAU - Frigault, Matthew J AU - Frigault MJ AD - Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. FAU - Dumbrava, Ecaterina E AU - Dumbrava EE AD - Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Sauer, Amy AU - Sauer A AD - Adaptimmune LLC, Philadelphia, PA, United States. FAU - Brophy, Francine AU - Brophy F AD - Adaptimmune LLC, Philadelphia, PA, United States. FAU - Navenot, Jean-Marc AU - Navenot JM AD - Adaptimmune LLC, Philadelphia, PA, United States. FAU - Fayngerts, Svetlana AU - Fayngerts S AD - Adaptimmune LLC, Philadelphia, PA, United States. FAU - Wolchinsky, Zohar AU - Wolchinsky Z AD - Adaptimmune Limited, Abingdon, United Kingdom. FAU - Broad, Robyn AU - Broad R AD - Adaptimmune Limited, Abingdon, United Kingdom. FAU - Batrakou, Dzmitry G AU - Batrakou DG AD - Adaptimmune LLC, Philadelphia, PA, United States. FAU - Wang, Ruoxi AU - Wang R AD - Adaptimmune Limited, Abingdon, United Kingdom. FAU - Solis, Luisa M AU - Solis LM AD - Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Duose, Dzifa Yawa AU - Duose DY AD - Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Sanderson, Joseph P AU - Sanderson JP AD - Adaptimmune Limited, Abingdon, United Kingdom. FAU - Gerry, Andrew B AU - Gerry AB AD - Adaptimmune Limited, Abingdon, United Kingdom. FAU - Marks, Diane AU - Marks D AD - Adaptimmune LLC, Philadelphia, PA, United States. FAU - Bai, Jane AU - Bai J AD - Adaptimmune LLC, Philadelphia, PA, United States. FAU - Norry, Elliot AU - Norry E AD - Adaptimmune LLC, Philadelphia, PA, United States. FAU - Fracasso, Paula M AU - Fracasso PM AD - Adaptimmune LLC, Philadelphia, PA, United States. LA - eng SI - ClinicalTrials.gov/NCT02989064 PT - Journal Article DEP - 20220318 PL - Switzerland TA - Front Oncol JT - Frontiers in oncology JID - 101568867 PMC - PMC8972123 OTO - NOTNLM OT - ADP-A2M10 OT - HNSCC OT - MAGE-A10 OT - TCR OT - adoptive cellular therapy OT - melanoma OT - urothelial carcinoma COIS- ABG: holds stock options in Adaptimmune. AS, DB, DM, EN, FB, JB, J-MN, JS, RB, RW, SF, and ZW: employees of Adaptimmune. DH: research/ grant funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Deciphera, Eisai, Erasca, Fate Therapeutics, Genentech, Genmab, Infinity, Kite, Kyowa, Lilly, LOXO, MedImmune, Merck, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, SeaGen, Takeda, Turning Point Therapeutics, Verastem, and VM Oncology; compensation for travel, accommodations, and expenses from AACR, ASCO, Bayer, Genmab, SITC, and Telperian; consulting, speaker, or advisory roles for Acuta, Adaptimmune, Alkermes, Alpha Insights, Amgen, Atheneum, AUM Biosciences, Axiom, Barclays, Baxter, Bayer, Boxer Capital, BridgeBio, CDR-life AG, COG, COR2ed, Ecor1, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point, WebMD, and Ziopharm; other ownership interests in OncoResponse (Founder) and Telperian Inc (Advisor). ED: grant/research support from Aileron Therapeutics, Amgen, Aprea Therapeutics, Astex Pharmaceuticals, Bayer HealthCare Pharmaceuticals Inc., Bellicum Pharmaceuticals, BOLT Therapeutics, Compugen Ltd, Immunocore LTD, Immunomedics, Mereo BioPharma 5 Inc, NCI, PMV Pharma, Sanofi, SeaGen, TRACON Pharmaceuticals Inc., Triumvira, and Unum Therapeutics; advisory board for BOLT Therapeutics. MB: grant/contract funding for investigator-initiated clinical trials from Merck and Takara Bio; advisory boards for Adaptimmune, BMS, EMD Serono, GlaxoSmithKline, Immunocore, Instil Bio, Iovance, Merck, Novartis, Pfizer, and Sanofi; has attended speaking engagements for BMS, Merck, Novartis, and Pfizer; Safety Review Committees for Adaptimmune and GlaxoSmithKline. MF: consultant for Arcellx, BMS, Iovance, Kite, and Novartis. PF: employee of Adaptimmune; holds stock in Adaptimmune and Bristol-Myers Squibb; has received compensation for travel and congress meetings. RS: research support from Amgen and Merck; has received fees as a consultant or SAB member from Array Biopharma, Asana Biosciences, AstraZeneca, BMS, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, and Replimune. RP: grant funding from Janssen; personal fees from AstraZeneca, Bayer, BMS, Dendreon, EMD, Genentech/ Roche, Genomic Health, Jounce Therapeutics, Merck, Sanofi, and Serono/Pfizer; nonfinancial support from BMS and Genentech/Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Adaptimmune Ltd. The funder had the following involvement with the study: study design and analysis and interpretation of the data. EDAT- 2022/04/05 06:00 MHDA- 2022/04/05 06:01 PMCR- 2022/01/01 CRDT- 2022/04/04 05:32 PHST- 2021/11/19 00:00 [received] PHST- 2022/02/18 00:00 [accepted] PHST- 2022/04/04 05:32 [entrez] PHST- 2022/04/05 06:00 [pubmed] PHST- 2022/04/05 06:01 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fonc.2022.818679 [doi] PST - epublish SO - Front Oncol. 2022 Mar 18;12:818679. doi: 10.3389/fonc.2022.818679. eCollection 2022.