Virus-Specific T Cells for the Immunocompromised Patient

Abstract

While progress has been made in the treatment of both hematologic cancers and solid tumors, chemorefractory or relapsed disease often portends a dismal prognosis, and salvage chemotherapy or radiation expose patients to intolerable toxicities and may not be effective. Hematopoietic stem cell transplant offers the promise of cure for many patients, and while mismatched, unrelated or haploidentical donors are increasingly available, the recipients are at higher risk of severe immunosuppression and immune dysregulation due to graft versus host disease. Viral infections remain a primary cause of severe morbidity and mortality in this patient population. Again, many therapeutic options for viral disease are toxic, may be ineffective or generate resistance, or fail to convey long-term protection. Adoptive cell therapy with virus-specific T cells (VSTs) is a targeted therapy that is efficacious and has minimal toxicity in immunocompromised patients with CMV and EBV infections in particular. Products have since been generated specific for multiple viral antigens (multi-VST), which are not only effective but also confer protection in 70–90% of recipients when used as prophylaxis. Notably, these products can be generated from either virus-naive or virus-experienced autologous or allogeneic sources, including partially matched HLA-matched third-party donors. Obstacles to effective VST treatment are donor availability and product generation time. Banking of third-party VST is an attractive way to overcome these constraints and provide products on an as-needed basis. Other developments include epitope discovery to broaden the number of viral antigens targets in a single product, the optimization of VST generation from naive donor sources, and the modification of VSTs to enhance persistence and efficacy in vivo.

A case of immune reconstitution syndrome complicating progressive multifocal leukoencephalopathy after kidney transplant: Clinical, pathological, and radiographic features

“…Larger studies are clearly needed to confirm the efficacy of this approach and to ascertain the true incidence and consequences of IRIS with adoptive T cell transfer. In addition, certain challenges related to the development of adoptive T cell therapies (eg, donor availability, HLA matching, and product generation time) must be overcome for such a treatment modality to become commonplace . A clinical trial of adoptive T cell therapy for PML is underway (NCT02694783).…”

Challenges of CAR- and TCR-T cell–based therapy for chronic infections

“…Viral infections or relapses developing in immunosuppressed patients (i.e., patients after hematopoietic stem cell or organ transplantation with human cytomegalovirus or EBV reactivation) have been shown to be responsive to adoptive immunotherapy with autologous in vitro expanded virus-specific T cells derived from memory or naive T cell populations (Houghtelin and Bollard, 2017). These expanded virus-specific T cells can be substituted by autologous T cells engineered in vitro through the introduction of pathogen-specific CAR or TCRs.…”

Viral Infections in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Literature Review

“…In vivo expansion of virus specific CTLs was seen after a single infusion which resulted in persistent clearance of viral antigenemia [127,128]. Most methods generate varied levels of CD4 and CD8 T cells and this polyclonal phenotype helps persistence of VS CTLs in vivo [128].…”