Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy
Background Adoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility...
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BMJ Publishing Group
2020-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000247.full |
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| author | Cassian Yee Seth M Pollack Robin L Jones Jianhong Cao Ernest U Conrad Stanley R Riddell Brett A Schroeder Ralph Graeme Black Sydney Spadinger Shihong Zhang Karan Kohli Jose G Mantilla |
| author_facet | Cassian Yee Seth M Pollack Robin L Jones Jianhong Cao Ernest U Conrad Stanley R Riddell Brett A Schroeder Ralph Graeme Black Sydney Spadinger Shihong Zhang Karan Kohli Jose G Mantilla |
| author_sort | Cassian Yee |
| collection | DOAJ |
| description | Background Adoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentation We launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.Conclusion We describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbers NCT04177021, NCT01957709, and NCT03063632. |
| format | Article |
| id | doaj-art-4f0eeb893637483d871416d37af788e7 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-4f0eeb893637483d871416d37af788e72024-11-09T00:05:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2019-000247Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapyCassian Yee0Seth M Pollack1Robin L Jones2Jianhong Cao3Ernest U Conrad4Stanley R Riddell5Brett A Schroeder6Ralph Graeme Black7Sydney Spadinger8Shihong Zhang9Karan Kohli10Jose G Mantilla11Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USASarcoma, Royal Marsden Hospital NHS Trust, London, UKFred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA5 Orthopedic Surgery, University of Texas Health Science Center at Houston, Houston, Texas, USAImmunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, Washington, USANational Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA1 Department of Surgery, University of Washington, Seattle, Washington, USAPathology, University of Washington Medical Center, Seattle, Washington, USABackground Adoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentation We launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.Conclusion We describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbers NCT04177021, NCT01957709, and NCT03063632.https://jitc.bmj.com/content/8/1/e000247.full |
| spellingShingle | Cassian Yee Seth M Pollack Robin L Jones Jianhong Cao Ernest U Conrad Stanley R Riddell Brett A Schroeder Ralph Graeme Black Sydney Spadinger Shihong Zhang Karan Kohli Jose G Mantilla Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy Journal for ImmunoTherapy of Cancer |
| title | Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy |
| title_full | Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy |
| title_fullStr | Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy |
| title_full_unstemmed | Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy |
| title_short | Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy |
| title_sort | histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide based lymphodepletion for adoptive cellular therapy |
| url | https://jitc.bmj.com/content/8/1/e000247.full |
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