Abstract
Abstract 963
Lymphomatoid granulomatosis (LYG) is a rare angiocentric/angiodestructive EBV+ B-cell lymphoproliferative disorder. LYG has a spectrum of clinical aggressiveness and histological grading. Grading relates to the number of EBV-positive B-cells with grade I /II being usually polyclonal or oligoclonal and grade III monoclonal. Historical outcomes of patients treated with steroids and/or chemotherapy have been poor with median survivals of 14 months. We have shown that LYG is associated with reduced CD8+ and CD4+ T-cells, and hypothesized that patients have defective immune surveillance of EBV+ B-cells. We are investigating the use of interferon-alpha (IFα) for grade I/II disease and have characterized the maturation, exhaustion, and homeostatic potential of bulk and antigen-specific CD8 T-cells. Patients with grade III disease are treated with DA-EPOCH-R. Characteristics of 53 patients on study include male sex 68%; median age (range) 46 (17-67) and median ECOG P.S. 1 (0-3). Disease sites include lung 98%, CNS 38%, kidney 15%, skin 17% and liver 19%. LYG grades are I –30%, II-26% and III-44%. Prior treatment was none –28%, chemotherapy+/− R-34% and steroids alone – 40% of patients. Herein, we report the outcome of patients with grade I/II LYG treated with IFα. IFα was commenced at 7.5 MIU TIW and dose escalated until best response and then continued for 1 year. Of 31 patients with grade I/II LYG treated with IFα, 28 were evaluable for response. Of these, 17 (60%) achieved a complete remission and 6 (21%) patients progressed with grade III disease and received chemotherapy. Of 10 patients with CNS disease, 9 achieved a CR with IFα. At a median follow-up time of 5 years, the progression-free survival of grade I/II LYG was 56%. The median time to remission was 9 months (3-40) and median IFα dose was 20 MIUs (7-40). Median EBV viral loads at study entry were 18 copies/106 genome equivalents (0-22727) (normal<200). We looked at T-cell kinetics in patients who achieved complete remission and observed statistically significant recovery in both CD4 (p=0.034) and CD8 p=0.034) cells after interferonα. We were interested in further elucidating T-cell function and used polychromatic flow cytometry to characterize CD8 T-cells in the peripheral blood of patients before and after IFα. In 17 patient samples, cells were stained with peptide-MHC I (pMHCI) multimers directed against T-cells specific for epitopes from latent and lytic EBV proteins along with antibodies defining CD8 sub-populations. Influenza or cytomegalovirus-specific pMHCI multimers were controls. We observed no difference in the frequency of EBV specific CD8 T-cells in the blood of LYG patients compared to controls. However, CD27 and PD1 expression appeared to be altered in the bulk CD8+ T-cells and in selected EBV-specific populations in LYG patients; these changes were marginally significant. Following completion of IFα, expression of PD-1, CD27 and CD127 were at normal levels. Evidence from some LYG patients suggests that IL2 production by EBV-specific T-cells is lost during LYG, and normalized after therapy. Our results suggest that LYG, an EBV-associated disease, may arise in the setting of a global deficit in CD8 T-cells with selected defects in EBV-specific immunity that resolve with successful therapy.
Disclosures:
No relevant conflicts of interest to declare.
Semaphorin 3A induces cytoskeletal paralysis in tumor-specific CD8+ T cells
