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.

Keywords: CD8-positive T-lymphocytes; immunotherapy, adoptive; oncology; sarcoma.

Conflict of interest statement

Competing interests: None declared.

© 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.

Figures

Figure 1

Trial schema. IFN-γ, interferon gamma.

Figure 2

(A) Persistence of transferred T cells as absolute values. Percent tetramer positive derived from peripheral CD8+ T cells. (B) CT scan showing pretreatment and post-treatment lung. (C) Forehead soft tissue mass. (D) Pretreatment lung (left) and post-treatment forehead mass (right) stained for NY-ESO-1. (E) Lung (left) stained for HLA-ABC, forehead mass (right) stained for HLA-ABC.

Figure 3

Histological sections of the heart at autopsy demonstrate myocyte necrosis and marked mononuclear inflammation (A, H&E ×200). Immunohistochemical stains highlight a mixed population of inflammatory cells composed of predominantly CD68+ histiocytes (D) and few CD3 +T cells (B). CD20 stain does not demonstrate a significant B-cell population (C).