First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumors
Rationale of the trial Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202...
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BMJ Publishing Group
2024-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/7/e008668.full |
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| author | Ignacio I Wistuba Mamta Kalra Linus Backert Martin Wermke Edwin R Parra Jason John Luke Apostolia M Tsimberidou Sebastian Bunk Mohammad B Hossain Andrea Mayer-Mokler Arun Satelli Norbert Hilf Steffen Walter Cedrik M Britten Van K Morris Tobias A W Holderried Winfried H Alsdorf Katrin Wetzko Borje S Andersson Sandra Grund-Gröschke Katrin Aslan Anantha Marisetty Swapna Satam Jens Hukelmann M Alper Kursunel Karine Pozo Andreas Acs Melissa Baumeister Claudia Wagner Oliver Schoor Ali S Mohamed Delfi Krishna |
| author_facet | Ignacio I Wistuba Mamta Kalra Linus Backert Martin Wermke Edwin R Parra Jason John Luke Apostolia M Tsimberidou Sebastian Bunk Mohammad B Hossain Andrea Mayer-Mokler Arun Satelli Norbert Hilf Steffen Walter Cedrik M Britten Van K Morris Tobias A W Holderried Winfried H Alsdorf Katrin Wetzko Borje S Andersson Sandra Grund-Gröschke Katrin Aslan Anantha Marisetty Swapna Satam Jens Hukelmann M Alper Kursunel Karine Pozo Andreas Acs Melissa Baumeister Claudia Wagner Oliver Schoor Ali S Mohamed Delfi Krishna |
| author_sort | Ignacio I Wistuba |
| collection | DOAJ |
| description | Rationale of the trial Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors.Trial design The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of 16 patients. IMA202 consists of autologous genetically modified cytotoxic CD8+ T cells expressing a T cell receptor (TCR), which is specific for a nine amino acid peptide derived from MAGEA1. Eligible patients underwent leukapheresis, T cells were isolated, transduced with lentiviral vector carrying MAGEA1-specific TCR and following lymphodepletion (fludarabine/cyclophosphamide), infused with a median of 1.4×109 specific T cells (range, 0.086×109–2.57×109) followed by interleukin 2.Safety of IMA202 No DLT was observed. The most common grade 3–4 adverse events were cytopenias, that is, neutropenia (81.3%), lymphopenia (75.0%), anemia (50.0%), thrombocytopenia (50.0%) and leukopenia (25.0%). 13 patients experienced cytokine release syndrome, including one grade 3 event. Immune effector cell-associated neurotoxicity syndrome was observed in two patients and was grade 1 in both.Efficacy of IMA202 Of the 16 patients dosed, 11 (68.8%) patients had stable disease (SD) as their best overall response (Response Evaluation Criteria in Solid Tumors V.1.1). Five patients had initial tumor shrinkage in target lesions and one patient with SD experienced continued shrinkage in target lesions for 3 months in total but had to be classified as progressive disease due to progressive non-target lesions. IMA202 T cells were persistent in peripheral blood for several weeks to months and were also detectable in tumor tissue. Peak persistence was higher in patients who received higher doses.Conclusion In conclusion, IMA202 had a manageable safety profile, and it was associated with biological and potential clinical activity of MAGEA1-targeting genetically engineered TCR-T cells in a poor prognosis, multi-indication solid tumor cohort.Trial registration numbers NCT04639245, NCT05430555. |
| format | Article |
| id | doaj-art-6a562891133f4ee084b42c34b2d77b3e |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-6a562891133f4ee084b42c34b2d77b3e2025-02-03T12:10:12ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-07-0112710.1136/jitc-2023-008668First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumorsIgnacio I Wistuba0Mamta Kalra1Linus Backert2Martin Wermke3Edwin R Parra4Jason John Luke5Apostolia M Tsimberidou6Sebastian Bunk7Mohammad B Hossain8Andrea Mayer-Mokler9Arun Satelli10Norbert Hilf11Steffen Walter12Cedrik M Britten13Van K Morris14Tobias A W Holderried15Winfried H Alsdorf16Katrin Wetzko17Borje S Andersson18Sandra Grund-Gröschke19Katrin Aslan20Anantha Marisetty21Swapna Satam22Jens Hukelmann23M Alper Kursunel24Karine Pozo25Andreas Acs26Melissa Baumeister27Claudia Wagner28Oliver Schoor29Ali S Mohamed30Delfi Krishna311The University of Texas MD Anderson Cancer Center, Houston, TX, USA1Immatics US Inc., Stafford, TX, USA2Immatics Biotechnologies GmbH, Tübingen, Germany14Technical University Dresden – NCT/UCC Early Clinical Trial Unit, Dresden, Germany1The University of Texas MD Anderson Cancer Center, Houston, TX, USACancer Immunotherapeutics Center, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USADepartment of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USAImmatics Biotechnologies GmbH, Tuebingen, GermanyImmatics US, Inc, Houston, Texas, USA1Immatics Biotechnologies GmbH, Tuebingen, GermanyImmatics US, Inc, Houston, Texas, USA1Immatics Biotechnologies GmbH, Tuebingen, Germany2Immatics US Inc., Stafford, TX, USA1Immatics Biotechnologies GmbH, Tuebingen, GermanyDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center Division of Cancer Medicine, Houston, Texas, USADepartment of Hematology, Oncology, Immunooncology, Stem Cell Transplantation, and Rheumatology, University Hospital Bonn, Bonn, GermanyDepartment of Oncology, Hematology, and Bone Marrow Transplantation with Section Pneumology, University Hospital Hamburg-Eppendorf, Hamburg, Germany3TU Dresden, Medical Faculty C.-G.-Carus, NCT/UCC Early Clinical Trial Unit/Department of Medicine I, Dresden, GermanyThe University of Texas MD Anderson Cancer Center, Houston, Texas, USAImmatics Biotechnologies GmbH, Tuebingen, Germany2Immatics Biotechnologies GmbH, Tubingen, GermanyImmatics US, Inc, Houston, Texas, USAImmatics Biotechnologies GmbH, Tuebingen, GermanyImmatics Biotechnologies GmbH, Tuebingen, GermanyImmatics Biotechnologies GmbH, Tuebingen, Germany6Immatics US, Inc., Stafford, TX, USAImmatics Biotechnologies GmbH, Tuebingen, GermanyImmatics Biotechnologies GmbH, Tuebingen, Germany1Immatics Biotechnologies GmbH, Tuebingen, GermanyImmatics Biotechnologies GmbH, Tuebingen, GermanyImmatics US, Inc, Houston, Texas, USA6Immatics US, Inc., Stafford, TX, USARationale of the trial Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors.Trial design The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of 16 patients. IMA202 consists of autologous genetically modified cytotoxic CD8+ T cells expressing a T cell receptor (TCR), which is specific for a nine amino acid peptide derived from MAGEA1. Eligible patients underwent leukapheresis, T cells were isolated, transduced with lentiviral vector carrying MAGEA1-specific TCR and following lymphodepletion (fludarabine/cyclophosphamide), infused with a median of 1.4×109 specific T cells (range, 0.086×109–2.57×109) followed by interleukin 2.Safety of IMA202 No DLT was observed. The most common grade 3–4 adverse events were cytopenias, that is, neutropenia (81.3%), lymphopenia (75.0%), anemia (50.0%), thrombocytopenia (50.0%) and leukopenia (25.0%). 13 patients experienced cytokine release syndrome, including one grade 3 event. Immune effector cell-associated neurotoxicity syndrome was observed in two patients and was grade 1 in both.Efficacy of IMA202 Of the 16 patients dosed, 11 (68.8%) patients had stable disease (SD) as their best overall response (Response Evaluation Criteria in Solid Tumors V.1.1). Five patients had initial tumor shrinkage in target lesions and one patient with SD experienced continued shrinkage in target lesions for 3 months in total but had to be classified as progressive disease due to progressive non-target lesions. IMA202 T cells were persistent in peripheral blood for several weeks to months and were also detectable in tumor tissue. Peak persistence was higher in patients who received higher doses.Conclusion In conclusion, IMA202 had a manageable safety profile, and it was associated with biological and potential clinical activity of MAGEA1-targeting genetically engineered TCR-T cells in a poor prognosis, multi-indication solid tumor cohort.Trial registration numbers NCT04639245, NCT05430555.https://jitc.bmj.com/content/12/7/e008668.full |
| spellingShingle | Ignacio I Wistuba Mamta Kalra Linus Backert Martin Wermke Edwin R Parra Jason John Luke Apostolia M Tsimberidou Sebastian Bunk Mohammad B Hossain Andrea Mayer-Mokler Arun Satelli Norbert Hilf Steffen Walter Cedrik M Britten Van K Morris Tobias A W Holderried Winfried H Alsdorf Katrin Wetzko Borje S Andersson Sandra Grund-Gröschke Katrin Aslan Anantha Marisetty Swapna Satam Jens Hukelmann M Alper Kursunel Karine Pozo Andreas Acs Melissa Baumeister Claudia Wagner Oliver Schoor Ali S Mohamed Delfi Krishna First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumors Journal for ImmunoTherapy of Cancer |
| title | First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumors |
| title_full | First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumors |
| title_fullStr | First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumors |
| title_full_unstemmed | First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumors |
| title_short | First-in-human dose escalation trial to evaluate the clinical safety and efficacy of an anti-MAGEA1 autologous TCR-transgenic T cell therapy in relapsed and refractory solid tumors |
| title_sort | first in human dose escalation trial to evaluate the clinical safety and efficacy of an anti magea1 autologous tcr transgenic t cell therapy in relapsed and refractory solid tumors |
| url | https://jitc.bmj.com/content/12/7/e008668.full |
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