Histiocyte predominant myocarditis resulting from the addition of interferon gamma to cyclophosphamide-based lymphodepletion for adoptive cellular therapy.

Abstract

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.

• Authors: Brett A Schroeder, Ralph Graeme Black, Sydney Spadinger, Shihong Zhang, Karan Kohli, Jianhong Cao, Jose G Mantilla, Ernest U Conrad, Stanley R Riddell, Robin L Jones, Cassian Yee, Seth M Pollack
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 8 Issue 1 (04 2020) ISSN: 2051-1426 [Electronic] England
• PMID: 32269142 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antineoplastic Agents, Alkylating
• Antiviral Agents
• Interferon-gamma
• Cyclophosphamide

Topics

• Adult
• Antineoplastic Agents, Alkylating (adverse effects)
• Antiviral Agents (adverse effects)
• Clinical Trials, Phase I as Topic
• Cyclophosphamide (adverse effects)
• Drug Therapy, Combination
• Histiocytes (drug effects, pathology)
• Humans
• Immunotherapy, Adoptive (methods)
• Interferon-gamma (adverse effects)
• Lymphocyte Depletion (adverse effects)
• Male
• Myocarditis (chemically induced, pathology)
• Prognosis
• Sarcoma, Synovial (immunology, pathology, therapy)