Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study
Background Not all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical tri...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001185.full |
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| author | Yukari Kobayashi Masaaki Sato Kazuhiro Kakimi Hirokazu Matsushita Ryuji Suzuki Takahiro Karasaki Keita Masuzawa Koji Nagaoka Akihiro Hosoi Shinnosuke Ikemura Kentaro Kitano Ichiro Kawada Tadashi Manabe Tomohiro Takehara Toshiaki Ebisudani Kazuhiro Nagayama Yukio Nakamura Hiroyuki Yasuda Kenzo Soejima Jun Nakajima |
| author_facet | Yukari Kobayashi Masaaki Sato Kazuhiro Kakimi Hirokazu Matsushita Ryuji Suzuki Takahiro Karasaki Keita Masuzawa Koji Nagaoka Akihiro Hosoi Shinnosuke Ikemura Kentaro Kitano Ichiro Kawada Tadashi Manabe Tomohiro Takehara Toshiaki Ebisudani Kazuhiro Nagayama Yukio Nakamura Hiroyuki Yasuda Kenzo Soejima Jun Nakajima |
| author_sort | Yukari Kobayashi |
| collection | DOAJ |
| description | Background Not all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical trial of adoptive cell therapy using zoledronate-expanded autologous Vγ9Vδ2 T-cells for treatment-refractory NSCLC.Methods NSCLC patients who had undergone at least two regimens of standard chemotherapy for unresectable disease or had had at least one treatment including chemotherapy or radiation for recurrent disease after surgery were enrolled in this open-label, single-arm, multicenter, phase 2 study. After preliminary testing of Vγ9Vδ2 T-cell proliferation, autologous peripheral blood mononuclear cells were cultured with zoledronate and IL-2 to expand the Vγ9Vδ2 T-cells. Cultured cells (>1×109) were intravenously administered every 2 weeks for six injections. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), best objective response rate (ORR), disease control rate (DCR), safety and immunomonitoring. Clinical efficacy was defined as median PFS significantly >4 months.Results Twenty-five patients (20 adenocarcinoma, 4 squamous cell carcinoma and 1 large cell carcinoma) were enrolled. Autologous Vγ9Vδ2 T-cell therapy was administered to all 25 patients, of which 16 completed the foreseen course of 6 injections of cultured cells. Median PFS was 95.0 days (95% CI 73.0 to 132.0 days); median OS was 418.0 days (179.0–479.0 days), and best overall responses were 1 partial response, 16 stable disease (SD) and 8 progressive disease. ORR and DCR were 4.0% (0.1%–20.4%) and 68.0% (46.5%–85.1%), respectively. Severe adverse events developed in nine patients, mostly associated with disease progression. In one patient, pneumonitis and inflammatory responses resulted from Vγ9Vδ2 T-cell infusions, together with the disappearance of a massive tumor.Conclusions Although autologous Vγ9Vδ2 T-cell therapy was well tolerated and may have an acceptable DCR, this trial did not meet its primary efficacy endpoint.Trial registration number UMIN000006128 |
| format | Article |
| id | doaj-art-f5b5256b534f4a6ea4c4a4d120cae28c |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-f5b5256b534f4a6ea4c4a4d120cae28c2024-11-09T20:30:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001185Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 studyYukari Kobayashi0Masaaki Sato1Kazuhiro Kakimi2Hirokazu Matsushita3Ryuji Suzuki4Takahiro Karasaki5Keita Masuzawa6Koji Nagaoka7Akihiro Hosoi8Shinnosuke Ikemura9Kentaro Kitano10Ichiro Kawada11Tadashi Manabe12Tomohiro Takehara13Toshiaki Ebisudani14Kazuhiro Nagayama15Yukio Nakamura16Hiroyuki Yasuda17Kenzo Soejima18Jun Nakajima191 Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, JapanDepartment of Thoracic Surgery, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan6 Cancer Immunology Data Multi-Level Integration Unit, Medical Sciences Innovation Hub Program (MIH), RIKEN, Chuo-ku, Tokyo, JapanDivision of Translational Oncoimmunology, Aichi Cancer Center Research Institute, Nagoya, JapanAff134 Repertoire Genesis Incorporation Ibaraki Osaka Japan3 Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, JapanDepartment of Respiratory Medicine, Kitasato University Kitasato Institute Hospital, Tokyo, Japan1The University of Tokyo Hospital, Tokyo, Bunkyo-ku, Japan1 Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, JapanDivision of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan3 Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan2 Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Shinjuku-ku, Tokyo, JapanDivision of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan2 Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Shinjuku-ku, Tokyo, Japan2 Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine Graduate School of Medicine, Shinjuku-ku, Tokyo, Japan3 Department of Thoracic Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan4 Repertoire Genesis Inc, Ibaraki-Shi, Osaka, JapanDivision of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan5 Clinical and Translational Research Center, Keio University Hospital, Shinjuku-ku, Tokyo, JapanDepartment of Thoracic Surgery, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, JapanBackground Not all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical trial of adoptive cell therapy using zoledronate-expanded autologous Vγ9Vδ2 T-cells for treatment-refractory NSCLC.Methods NSCLC patients who had undergone at least two regimens of standard chemotherapy for unresectable disease or had had at least one treatment including chemotherapy or radiation for recurrent disease after surgery were enrolled in this open-label, single-arm, multicenter, phase 2 study. After preliminary testing of Vγ9Vδ2 T-cell proliferation, autologous peripheral blood mononuclear cells were cultured with zoledronate and IL-2 to expand the Vγ9Vδ2 T-cells. Cultured cells (>1×109) were intravenously administered every 2 weeks for six injections. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), best objective response rate (ORR), disease control rate (DCR), safety and immunomonitoring. Clinical efficacy was defined as median PFS significantly >4 months.Results Twenty-five patients (20 adenocarcinoma, 4 squamous cell carcinoma and 1 large cell carcinoma) were enrolled. Autologous Vγ9Vδ2 T-cell therapy was administered to all 25 patients, of which 16 completed the foreseen course of 6 injections of cultured cells. Median PFS was 95.0 days (95% CI 73.0 to 132.0 days); median OS was 418.0 days (179.0–479.0 days), and best overall responses were 1 partial response, 16 stable disease (SD) and 8 progressive disease. ORR and DCR were 4.0% (0.1%–20.4%) and 68.0% (46.5%–85.1%), respectively. Severe adverse events developed in nine patients, mostly associated with disease progression. In one patient, pneumonitis and inflammatory responses resulted from Vγ9Vδ2 T-cell infusions, together with the disappearance of a massive tumor.Conclusions Although autologous Vγ9Vδ2 T-cell therapy was well tolerated and may have an acceptable DCR, this trial did not meet its primary efficacy endpoint.Trial registration number UMIN000006128https://jitc.bmj.com/content/8/2/e001185.full |
| spellingShingle | Yukari Kobayashi Masaaki Sato Kazuhiro Kakimi Hirokazu Matsushita Ryuji Suzuki Takahiro Karasaki Keita Masuzawa Koji Nagaoka Akihiro Hosoi Shinnosuke Ikemura Kentaro Kitano Ichiro Kawada Tadashi Manabe Tomohiro Takehara Toshiaki Ebisudani Kazuhiro Nagayama Yukio Nakamura Hiroyuki Yasuda Kenzo Soejima Jun Nakajima Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study Journal for ImmunoTherapy of Cancer |
| title | Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study |
| title_full | Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study |
| title_fullStr | Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study |
| title_full_unstemmed | Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study |
| title_short | Adoptive transfer of zoledronate-expanded autologous Vγ9Vδ2 T-cells in patients with treatment-refractory non-small-cell lung cancer: a multicenter, open-label, single-arm, phase 2 study |
| title_sort | adoptive transfer of zoledronate expanded autologous vγ9vδ2 t cells in patients with treatment refractory non small cell lung cancer a multicenter open label single arm phase 2 study |
| url | https://jitc.bmj.com/content/8/2/e001185.full |
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