Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation
Background Cytomegalovirus (CMV) reactivation after unmanipulated haploidentical stem cell transplantation (SCT) frequently occurs, causing life-threatening morbidities and transplantation failure. Pre-emptive therapy upon the detection of CMV viremia using antiviral agents is currently the standard...
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| Format: | Article |
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BMJ Publishing Group
2024-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/1/e007735.full |
| _version_ | 1797326899080331264 |
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| author | Yu Wang Lu Wang Chao Ma Peng Chen Ning Lu Jishan Du Jiaojun Sun Xu Qilong Liping Dou Dai-Hong Liu |
| author_facet | Yu Wang Lu Wang Chao Ma Peng Chen Ning Lu Jishan Du Jiaojun Sun Xu Qilong Liping Dou Dai-Hong Liu |
| author_sort | Yu Wang |
| collection | DOAJ |
| description | Background Cytomegalovirus (CMV) reactivation after unmanipulated haploidentical stem cell transplantation (SCT) frequently occurs, causing life-threatening morbidities and transplantation failure. Pre-emptive therapy upon the detection of CMV viremia using antiviral agents is currently the standard of care but it was associated with significant toxicity. The CMV antigen-specific cytotoxic T lymphocyte therapy was limited by the time-consuming manufacture process and relatively low success rate. More effective and safer approaches for the treatment of CMV reactivation after haploidentical SCT are in urgent need.Methods A single-arm, open-label, phase I clinical trial evaluating the safety and efficacy of CMV-targeting T cell receptor-engineered T (CMV-TCR-T) cell therapy as the first-line pre-emptive therapy for patients with CMV reactivation after haploidentical peripheral blood SCT (PBSCT) was conducted in the Chinese PLA General Hospital. Six patients with CMV reactivation after haploidentical SCT were adoptively transferred by one to three doses of SCT donors-derived CMV-TCR-T cells. This trial was a dose-escalation study with doses ranging from 1×103 CMV-TCR-T cells/kg body weight per dose to 5×105 CMV-TCR-T cells/kg per dose.Results Except for the grade 1 cytokine release syndrome observed in one patient and mild fever in two patients, no other adverse events were observed. Four patients had response within a month after CMV-TCR-T cell infusion without the administration of any antiviral agents. The other two patients who initially did not respond to CMV-TCR-T cell therapy had salvage ganciclovir and foscarnet administration and then had rapid CMV clearance. The CMV-TCR-T cells displayed overall robust expansion and persistence in the peripheral blood after infusion. The CMV-TCR-T cells were first detected in the peripheral blood of these patients 3–7 days after the first dose of CMV-TCR-T infusion, rapidly expanded and persisted for at least 1–4 months, providing long-term protection against CMV reactivation. In one patient, the CMV-TCR-T cells started to expand even when the anti-graft-versus-host disease reagents were still being used, further indicating the proliferation potential of CMV-TCR-T cells.Conclusions Our study first showed CMV-TCR-T cell as a highly feasible, safe and effective first-line pre-emptive treatment for CMV reactivation after haploidentical PBSCT.Trial registration number ClinicalTrials.gov Registry (NCT05140187). |
| first_indexed | 2024-03-08T06:30:50Z |
| format | Article |
| id | doaj.art-ec07bc43639e479dbeb97757a1d04c96 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-08T06:30:50Z |
| publishDate | 2024-01-01 |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-ec07bc43639e479dbeb97757a1d04c962024-02-03T11:55:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-01-0112110.1136/jitc-2023-007735Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantationYu Wang0Lu Wang1Chao Ma2Peng Chen3Ning Lu4Jishan Du5Jiaojun Sun6Xu Qilong7Liping Dou8Dai-Hong Liu9Beijing Immunnotech Applied Science, Beijing, ChinaDepartment of Neurology, General Hospital of Northern Theater Command, Shenyang, Liaoning Province, ChinaChinese PLA General Hospital, Beijing, ChinaChinese PLA General Hospital, Beijing, ChinaChinese PLA General Hospital, Beijing, ChinaChinese PLA General Hospital, Beijing, ChinaBeijing Immunnotech Applied Science, Beijing, ChinaBeijing Immunnotech Applied Science, Beijing, ChinaChinese PLA General Hospital, Beijing, ChinaChinese PLA General Hospital, Beijing, ChinaBackground Cytomegalovirus (CMV) reactivation after unmanipulated haploidentical stem cell transplantation (SCT) frequently occurs, causing life-threatening morbidities and transplantation failure. Pre-emptive therapy upon the detection of CMV viremia using antiviral agents is currently the standard of care but it was associated with significant toxicity. The CMV antigen-specific cytotoxic T lymphocyte therapy was limited by the time-consuming manufacture process and relatively low success rate. More effective and safer approaches for the treatment of CMV reactivation after haploidentical SCT are in urgent need.Methods A single-arm, open-label, phase I clinical trial evaluating the safety and efficacy of CMV-targeting T cell receptor-engineered T (CMV-TCR-T) cell therapy as the first-line pre-emptive therapy for patients with CMV reactivation after haploidentical peripheral blood SCT (PBSCT) was conducted in the Chinese PLA General Hospital. Six patients with CMV reactivation after haploidentical SCT were adoptively transferred by one to three doses of SCT donors-derived CMV-TCR-T cells. This trial was a dose-escalation study with doses ranging from 1×103 CMV-TCR-T cells/kg body weight per dose to 5×105 CMV-TCR-T cells/kg per dose.Results Except for the grade 1 cytokine release syndrome observed in one patient and mild fever in two patients, no other adverse events were observed. Four patients had response within a month after CMV-TCR-T cell infusion without the administration of any antiviral agents. The other two patients who initially did not respond to CMV-TCR-T cell therapy had salvage ganciclovir and foscarnet administration and then had rapid CMV clearance. The CMV-TCR-T cells displayed overall robust expansion and persistence in the peripheral blood after infusion. The CMV-TCR-T cells were first detected in the peripheral blood of these patients 3–7 days after the first dose of CMV-TCR-T infusion, rapidly expanded and persisted for at least 1–4 months, providing long-term protection against CMV reactivation. In one patient, the CMV-TCR-T cells started to expand even when the anti-graft-versus-host disease reagents were still being used, further indicating the proliferation potential of CMV-TCR-T cells.Conclusions Our study first showed CMV-TCR-T cell as a highly feasible, safe and effective first-line pre-emptive treatment for CMV reactivation after haploidentical PBSCT.Trial registration number ClinicalTrials.gov Registry (NCT05140187).https://jitc.bmj.com/content/12/1/e007735.full |
| spellingShingle | Yu Wang Lu Wang Chao Ma Peng Chen Ning Lu Jishan Du Jiaojun Sun Xu Qilong Liping Dou Dai-Hong Liu Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation Journal for ImmunoTherapy of Cancer |
| title | Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation |
| title_full | Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation |
| title_fullStr | Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation |
| title_full_unstemmed | Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation |
| title_short | Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation |
| title_sort | adoptive transfer of cmv specific tcr t cells for the treatment of cmv infection after haploidentical hematopoietic stem cell transplantation |
| url | https://jitc.bmj.com/content/12/1/e007735.full |
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