BK virus–specific T-cell immune reconstitution after allogeneic hematopoietic cell transplantation

Abstract

Clinical disease caused by BK virus reactivation is a frequent complication of allogeneic hematopoietic cell transplantation (HCT). Because of the lack of effective antiviral agents, BK virus–specific T cells are emerging as a potential therapy for BK virus disease, but the immune response to BK virus after allogeneic HCT has not been well characterized. Our study describes reconstitution of BK virus–specific T-cell immunity in 77 adult patients after HCT. All patients had urinary symptoms, and urine was tested for BK virus replication; 33 patients were positive for BK virus (cases), and 44 were negative (controls). In BK virus cases, the median time to first positive test was 75 days (range, 2-511). BK virus cases had lower CD4 T-cell counts 3 to 9 months after transplant, but CD8 T-cell counts were similar in cases and controls. BK virus–specific T cells were identified by cytokine flow cytometry in cryopreserved samples collected prospectively. BK virus–specific CD4 T cells producing T helper 1 (Th1) cytokines recovered quickly after HCT. BK virus–specific T cells were detected more frequently in patients with BK virus reactivation at most time points, and CD4 T cells producing Th1 cytokines were more frequent than BK virus–specific cytolytic CD8 T cells. Early detection of interferon-γ+ and cytolytic BK virus–specific CD4 T cells was associated with lower rates of hematuria among cases. Overall, our study describes recovery of BK virus–specific T cells after HCT and the distinct roles for BK virus–specific T cells in the development and resolution of clinical symptoms.

Third-Party BK Virus-Specific Cytotoxic T Lymphocyte Therapy for Hemorrhagic Cystitis Following Allotransplantation

“…5 The targets for BKV-specific cellular immunity include different BKV antigens, such as the large tumor antigen, small tumor antigen, and the capsid proteins VP1, VP2, and VP3, 6 although no immunodominant antigen has been identified. In the immunocompromised host, such as following AHSCT, alterations in the BKV-specific T-cell response is an important factor in BKV reactivation 7 ; however, the precise pathophysiologic mechanisms underlying this phenomenon are not well understood. Manifestations of BKV reactivation range from asymptomatic viruria to hemorrhagic and nonhemorrhagic cystitis, ureteral stenosis, and nephritis, which may result in prolonged hospitalization, renal dysfunction, 5 and increased mortality.…”

Presence of viremia during febrile neutropenic episodes in patients undergoing chemotherapy for malignant neoplasms

“…Moreover, highly immunosuppressive treatment approaches used in hematologic malignancies favor opportunistic infections including viral reactivation 2,5,14 . Persistent viral infections that are commonly reactivated during states of impaired immune surveillance include various members of the herpes virus family and different other viruses including particularly human adenovirus (HAdV) as a prominent example 10,19‐28 . The role of these viruses has been extensively studied in the context of HSCT, and we hypothesized that their contribution to infectious complications in patients undergoing intensive chemotherapy for hematologic neoplasms may be underestimated.…”

“…2,5,14 Persistent viral infections that are commonly reactivated during states of impaired immune surveillance include various members of the herpes virus family and different other viruses including particularly human adenovirus (HAdV) as a prominent example. 10,[19][20][21][22][23][24][25][26][27][28] The role of these viruses has been extensively studied in the context of HSCT, and we hypothesized that their contribution to infectious complications in patients undergoing intensive chemotherapy for hematologic neoplasms may be underestimated. To shed more light on the incidence and potential role of viral infection or reactivation in this setting, we have prospectively screened pediatric and adult patients displaying febrile neutropenic episodes during chemotherapy, primarily for malignant hematologic disorders, to assess the occurrence of viremia by targeting select viruses.…”

Rapid Manufacturing of Highly Cytotoxic Clinical-Grade SARS-CoV-2-specific T Cell Products Covering SARS-CoV-2 and Its Variants for Adoptive T Cell Therapy

“…Therefore, also transferred matched CD4 + T cells harbor the potential to successfully contribute to the elimination of the virus and the infected cells by inducing endogenous CD8 + T cells or vice versa. The effectiveness of CD4 + T cell responses has been demonstrated for AdV ( Sester et al, 2002 ) and polyomavirus BKV ( Espada et al, 2020 ) as well as for SARS-CoV-2 ( Grifoni et al, 2020 ) and is dominated by CD4 + T cells with memory/effector phenotype. On the other hand, the transfer of single-matched HLA-class I-restricted antiviral T cells was sufficient to control CMV infection or reactivation in patients ( Uhlin et al, 2012 ; Grifoni et al, 2020 ).…”