Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study
Background Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 imm...
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BMJ Publishing Group
2023-06-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/6/e007162.full |
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| author | Fiona Reid Sophie Papa John Maher Jean-Pierre Jeannon James Spicer Victoria Gibson Selvam Thavaraj Michael Metoudi Christopher Fisher Nicholas Beckley-Hoelscher Andrew Hope Maria Elstad Antonella Adami Richard Beatson Molly Sarah George Daniela Achkova Evangelia Williams Sefina Arif Abdel Douri Marc Delord Mike Lyne Dharshene Shivapatham Sakina Gooljar Arindam Mitra Linda Gomm Cienne Morton Rhonda Henley-Smith Alice Santambrogio Cynthia Andoniadou Sarah Allen Gary J R Cook Ana C Parente-Pereira David M Davies Farzin Farzaneh Anna Schurich Teresa Guerrero-Urbano |
| author_facet | Fiona Reid Sophie Papa John Maher Jean-Pierre Jeannon James Spicer Victoria Gibson Selvam Thavaraj Michael Metoudi Christopher Fisher Nicholas Beckley-Hoelscher Andrew Hope Maria Elstad Antonella Adami Richard Beatson Molly Sarah George Daniela Achkova Evangelia Williams Sefina Arif Abdel Douri Marc Delord Mike Lyne Dharshene Shivapatham Sakina Gooljar Arindam Mitra Linda Gomm Cienne Morton Rhonda Henley-Smith Alice Santambrogio Cynthia Andoniadou Sarah Allen Gary J R Cook Ana C Parente-Pereira David M Davies Farzin Farzaneh Anna Schurich Teresa Guerrero-Urbano |
| author_sort | Fiona Reid |
| collection | DOAJ |
| description | Background Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues.Methods We undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1–4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107−1×109 T4+ T-cells, administered without prior lymphodepletion.Results Despite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product.Conclusions These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC. |
| format | Article |
| id | doaj-art-b063f323295e4e8c8c98076bb8db4029 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-06-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-b063f323295e4e8c8c98076bb8db40292025-02-02T13:15:13ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-06-0111610.1136/jitc-2023-007162Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy studyFiona Reid0Sophie Papa1John Maher2Jean-Pierre Jeannon3James Spicer4Victoria Gibson5Selvam Thavaraj6Michael Metoudi7Christopher Fisher8Nicholas Beckley-Hoelscher9Andrew Hope10Maria Elstad11Antonella Adami12Richard Beatson13Molly Sarah George14Daniela Achkova15Evangelia Williams16Sefina Arif17Abdel Douri18Marc Delord19Mike Lyne20Dharshene Shivapatham21Sakina Gooljar22Arindam Mitra23Linda Gomm24Cienne Morton25Rhonda Henley-Smith26Alice Santambrogio27Cynthia Andoniadou28Sarah Allen29Gary J R Cook30Ana C Parente-Pereira31David M Davies32Farzin Farzaneh33Anna Schurich34Teresa Guerrero-Urbano35School of Life Course & Population Sciences, King`s College London, London, UKSchool of Cancer & Pharmaceutical Sciences, King`s College London, London, UK4Leucid Bio, London, UKENT Department, Guy`s and St Thomas` Hospitals NHS Trust, London, UK2King’s College London, London, UKSchool of Nursing, Midwifery and Social Work, The University of Queensland, St Lucia, Queensland, AustraliaHead and Neck Pathology, Guy`s and St Thomas` NHS Foundation Trust, London, UKSchool of Cancer & Pharmaceutical Sciences, King`s College London, London, UKGood Manufacturing Practice Unit, Guy’s and St Thomas’ Biomedical Research Centre, Guy`s and St Thomas` NHS Foundation Trust, London, UKDepartment of Biostatistics and Health Informatics, Institute of Psychiatry Psychology & Neuroscience, King`s College London, London, UK1 Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool, UKSchool of Life Course & Population Sciences, King`s College London, London, UKSchool of Cancer & Pharmaceutical Sciences, King`s College London, London, UKSchool of Cancer & Pharmaceutical Sciences, King`s College London, London, UKDepartment of Infectious Diseases, School of Immunology & Microbial Sciences, King`s College London, London, UKSchool of Cancer & Pharmaceutical Sciences, King`s College London, London, UKDepartment of Immunobiology, School of Immunology & Microbial Sciences, King`s College London, London, UKDepartment of Immunobiology, School of Immunology & Microbial Sciences, King`s College London, London, UKSchool of Life Course & Population Sciences, King`s College London, London, UKSchool of Life Course & Population Sciences, King`s College London, London, UKGuy’s and St Thomas’ Biomedical Research Centre, Guy`s and St Thomas` NHS Foundation Trust and King’s College London, London, UKGuy’s and St Thomas’ Biomedical Research Centre, Guy`s and St Thomas` NHS Foundation Trust and King’s College London, London, UKGood Manufacturing Practice Unit, Guy’s and St Thomas’ Biomedical Research Centre, Guy`s and St Thomas` NHS Foundation Trust, London, UKGood Manufacturing Practice Unit, Guy’s and St Thomas’ Biomedical Research Centre, Guy`s and St Thomas` NHS Foundation Trust, London, UKGuy’s and St Thomas’ Biomedical Research Centre, Guy`s and St Thomas` NHS Foundation Trust and King’s College London, London, UKGuy’s and St Thomas’ Biomedical Research Centre, Guy`s and St Thomas` NHS Foundation Trust and King’s College London, London, UKHead and Neck Pathology, Guy`s and St Thomas` Hospitals NHS Trust, London, UKFaculty of Dentistry, Oral and Craniofacial Sciences, Guy`s Hospital, King`s College London, London, UKFaculty of Dentistry, Oral and Craniofacial Sciences, Guy`s Hospital, King`s College London, London, UKFrailty at the Front Door Team, Integrated Care Team for the older person, Cork University Hospital, IrelandLondon School of Biomedical Engineering and Imaging Sciences, King`s College London, London, UKSchool of Cancer & Pharmaceutical Sciences, King`s College London, London, UKSchool of Cancer & Pharmaceutical Sciences, King`s College London, London, UKSchool of Cancer & Pharmaceutical Sciences, King`s College London, London, UKDepartment of Infectious Diseases, School of Immunology & Microbial Sciences, King`s College London, London, UKOncology, Guy`s and St Thomas` Hospitals NHS Trust, London, UKBackground Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues.Methods We undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1–4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107−1×109 T4+ T-cells, administered without prior lymphodepletion.Results Despite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product.Conclusions These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.https://jitc.bmj.com/content/11/6/e007162.full |
| spellingShingle | Fiona Reid Sophie Papa John Maher Jean-Pierre Jeannon James Spicer Victoria Gibson Selvam Thavaraj Michael Metoudi Christopher Fisher Nicholas Beckley-Hoelscher Andrew Hope Maria Elstad Antonella Adami Richard Beatson Molly Sarah George Daniela Achkova Evangelia Williams Sefina Arif Abdel Douri Marc Delord Mike Lyne Dharshene Shivapatham Sakina Gooljar Arindam Mitra Linda Gomm Cienne Morton Rhonda Henley-Smith Alice Santambrogio Cynthia Andoniadou Sarah Allen Gary J R Cook Ana C Parente-Pereira David M Davies Farzin Farzaneh Anna Schurich Teresa Guerrero-Urbano Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study Journal for ImmunoTherapy of Cancer |
| title | Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study |
| title_full | Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study |
| title_fullStr | Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study |
| title_full_unstemmed | Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study |
| title_short | Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study |
| title_sort | intratumoral pan erbb targeted car t for head and neck squamous cell carcinoma interim analysis of the t4 immunotherapy study |
| url | https://jitc.bmj.com/content/11/6/e007162.full |
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