Phenotypic and Functional Characterization of Posoleucel, a Multivirus-Specific T Cell Therapy for the Treatment and Prevention of Viral Infections in Immunocompromised Patients

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Severe viral infections are a significant problem for immunocompromised patients such as recipients of allogeneic hematopoietic cell (HCT) or solid organ (SOT) transplants. Posoleucel (PSL) is an off-the-shelf multivirus-specific T cell (VST) investigational product, for the treatment and prevention of infections due to adenovirus (AdV), BK virus (BKV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6) or JC virus (JCV). PSL consists of polyclonal VSTs that expand and are activated in vivo upon recognition of target viral antigens to mediate antiviral activity. Herein we provide data on VST lines illustrating the in vitro phenotypic and functional characteristics of PSL. PSL consists of >90% CD3+ T cells (comprising CD4+ and CD8+ T cells) representing a broad repertoire of T cell receptor (TCR) Vβ families. PSL had a phenotype consistent with effector function as evidenced by upregulation of activation markers CD25 and CD28 and low co-expression of exhaustion markers PD-1, LAG3 and TIM3 (<3%). The majority of PSL VSTs (>95%) expressed central and effector memory markers with minimal naïve (<0.5%) and terminally differentiated effector (<3%) T cells. ELISpot analyses demonstrated PSL specificity for target viral antigens AdV (mean spot-forming cells/2 × 105 VSTs=3,645; n=5), BKV (224), CMV (4,262), EBV (310) and HHV-6 (1,647). Recognition of JCV (due to the high sequence homology of JCV and BKV) was also confirmed by ELISpot. Upon antigen exposure, PSL CD4+ and CD8+ T cells upregulated markers indicative of activation (CD69), degranulation (CD107a) and co-stimulation (4-1BB, CD40L) and produced cytokines indicative of Th1-polarization (GM-CSF, IFNγ, IL-2, TNFα). Additionally, PSL was polyfunctional, producing multiple effector molecules (GrB, IFNγ, IL-2, TNFα) upon viral antigen recognition. The production of GrB and upregulation of CD107a are surrogate markers for cytolytic potential, which was supported by in vitro cytotoxicity assays. PSL specifically lysed viral antigen-expressing target cells with negligible off-target or alloreactivity demonstrated. PSL is enriched for central and effector memory CD4+ and CD8+ T cells that contain a broad repertoire of TCRs with specificity for AdV, BKV, CMV, EBV, HHV-6 and JCV. Upregulation of cell-surface molecules and production of effectors indicative of proliferation, co-stimulation and cytolytic potential show that PSL can mediate a diverse and effective antiviral response. Furthermore, PSL has a low risk for off-target and alloreactive responses as evidenced by its enrichment in memory T cells, low frequency of naïve T cells, and lack of demonstrated alloreactivity in vitro. The efficacy of PSL is being explored in four placebo-controlled clinical trials in HCT and SOT recipients (NCT05179057, NCT05305040, NCT04390113, NCT04605484).

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