“Mini” bank of only 8 donors supplies CMV-directed T cells to diverse recipients

Abstract

Cytomegalovirus (CMV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), and standard antiviral therapies are associated with significant side effects and development of drug-resistant mutants. Adoptively transferred donor-derived CMV-specific T cells (CMVSTs) can provide an alternative treatment modality with few side effects but are not widely available due to their patient-specific nature. Here we report the establishment and use of a bank of CMVSTs derived from just 8 CMV-seropositive donors, with HLA types representing the diverse US population, as an “off-the-shelf” therapy to treat drug-refractory infections. To date, we have screened 29 patients for study participation and identified a suitable line, with ≥2 of 8 shared HLA antigens, for 28 (96.6%) patients with a median of 4 shared HLA antigens. Of these, 10 patients with persistent/refractory CMV infections or disease were eligible for treatment; a single infusion of cells produced 3 partial responses and 7 complete responses, for a cumulative response rate of 100% (95% confidence interval, 69.2-100) with no graft-versus-host disease, graft failure, or cytokine release syndrome. Potential wider use of the tested CMVSTs across transplant centers is made more feasible by our ability to produce sufficient material to generate cells for >2000 infusions from a single donor collection. Our data indicate that a “mini” bank of CMVSTs prepared from just 8 well-chosen third-party donors can supply the majority of patients with an appropriately matched line that produces safe and effective anti-CMV activity post-HSCT.

Characterization of a Cytomegalovirus-Specific T Lymphocyte Product Obtained Through a Rapid and Scalable Production Process for Use in Adoptive Immunotherapy

“…Nevertheless, immediate early 1 protein (IE-1) specific T cells have been demonstrated to have a protective effect (34). Therefore, and since the use of both pp65 and IE-1 peptides has been proven successful by Tzannou and colleagues (35), our future approach would be to use both peptides for the generation of CMV specific T cells. The protocol described in this study allowed us to produce in vitro safe and effective VST after a short expansion of only 14day showing an advantage in time over protocols based on longer expansions (6,33).…”

T-Cell Therapeutics Targeting Human Parainfluenza Virus 3 Are Broadly Epitope Specific and Are Cross Reactive With Human Parainfluenza Virus 1

“…Further defining VSTs targeting HPIV3 will expand their applicability as third party products. Because transplant donor-derived VST production is limited when the donor is unrelated or the stem cell source is cord blood, and it takes many days to generate the product, “off-the-shelf” VST could be used as immediately available products to treat a number of viruses ( 11 , 15 , 16 ). However, this approach has not yet been applied to HPIV3 infections.…”

Rapid GMP-compliant expansion of SARS-CoV-2-specific T cells from convalescent donors for use as an allogeneic cell therapy for COVID-19

“…When cultures were administered a second feeder cell re-stimulation (FR) with autologous irradiated cells at day 14, central memory phenotype was retained at day 21. FR induced a subsequent two log expansion between day [14][15][16][17][18][19][20][21] in all VST cultures tested (n=5). The final VST numbers harvested under optimized conditions from a single CCD buffy coat ranged from 1-4.6x10 9 at day 14, and 0.3-2x10 11 at day 21 following FR ( Fig 5F).…”

“…New therapies to support the immune response to SARS-CoV-2, preventing the collapse of the lymphocyte compartment and supporting protective immunity would have significant impact on outcome for hospitalized patients. Anti-viral T cells specific for viruses such as cytomegalovirus (CMV), adenovirus (ADV) and Epstein Barr Virus (EBV) have been successfully used as adoptive cellular therapies to combat such infections in patients with immune deficiency (17)(18)(19)(20)(21)(22). Following selection of antigen-specific T cells from a blood donation from an individual who has been infected with the relevant virus, T cells may be expanded in vitro to manufacture banks of T cells from HLA-typed donors for repeated infusions in multiple patients with a partial HLA-match.…”

“…Following selection of antigen-specific T cells from a blood donation from an individual who has been infected with the relevant virus, T cells may be expanded in vitro to manufacture banks of T cells from HLA-typed donors for repeated infusions in multiple patients with a partial HLA-match. We and others have adopted this approach in the treatment of EBV or CMV-driven disease (21,22) with evidence of disease remission and low incidence of Graft versus Host Disease (GvHD) (21,22).…”