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

Abstract

BackgroundAdoptive 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 presentationWe 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.ConclusionWe 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 numbersNCT04177021,NCT01957709, andNCT03063632.

IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy

“…Consistent with prior reports, 10 16 transferred cells in all patients predominantly had a memory phenotype ( figure 2A and B ) 17 with very few cells that were double positive for CD39 and CD103. While few cells expressed PD-1, we also tested for Tim-3, an exhaustion marker that also suggests antigen experience ( online supplemental figure 5 ), and there was a non-statistically significant trend toward higher expression on tet+ cells compared with tet− controls (most pronounced in Cy1, figure 2C and D ).…”

“…20 MHC expression and T-cell infiltration into these tumors can be increased by systemic IFNγ 21 ; however, incorporation of cytokines into ACT regimens must be done with great care. 10 Our data suggest that more could be done to support transferred T cells after the time of infusion, possibly using post-infusion IL-15, a cytokine known to support memory T cells. 18 High IL-7 and IL-15 following lymphodepletion may aid responses for some patients, but as levels fall, transferred T cells may fall as well.…”

“… 20 MHC expression and T-cell infiltration into these tumors can be increased by systemic IFNγ 21 ; however, incorporation of cytokines into ACT regimens must be done with great care. 10 …”

Type I T cells sensitize treatment refractory tumors to chemotherapy through inhibition of oncogenic signaling pathways

“…Moreover, systemic delivery of IFN-γ can be associated with significant toxicity. 32 Studies in animal models have suggested that a primary mode of tumor control by type I T cells is not direct lysis of tumor, but rather the induction of cell cycle arrest by the secretion of IFN-γ. 33 Initiation of cytokine secretion by CD4 T cells after antigen stimulation is an early event.…”

Targeting cancer testis antigens in synovial sarcoma

“… 91 Based on these results IFNγ was combined with NY-ESO-1 specific T cell therapy in a clinical trial but had a fatal complication. 92 Subsequently, a multicenter trial combining IFNγ with PD-1 inhibition has been completed and data analysis is ongoing (NCT03063632).…”