Prophylactic antigen‐specific T‐cells targeting seven viral and fungal pathogens after allogeneic haemopoietic stem cell transplant

Abstract

Objectives. Adoptive immunotherapy using donor-derived antigen-specific T-cells can prevent and treat infection after allogeneic haemopoietic stem cell transplant (HSCT). Methods. We treated 11 patients with a prophylactic infusion of 2 9 10 7 cells per square metre donor-derived T-cells targeting seven infections (six viral and one fungal) following HSCT. Targeted pathogens were cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, varicella zoster virus, influenza, BK virus (BKV) and Aspergillus fumigatus. Results. T-cell products were successfully generated in all patients with 10 products responsive to 6 or 7 infections. T-cell infusions were associated with increases in antigen-experienced activated CD8 + T-cells by day 30. CMV, EBV and BKV reactivation occurred in the majority of patients and was well controlled except where glucocorticoids were administered soon after T-cell infusion. Three patients in that circumstance developed CMV tissue infection. No patient required treatment for invasive fungal infection. The most common CMV and EBV TCR clonotypes in the infusion product became the most common clonotypes seen at day 30 post-T-cell infusion. Donors and their recipients were recruited to the study prior to transplant. Grade III/IV graft-versus-host disease developed in four patients. At a median follow-up of 390 days post-transplant, six patients had died, 5 of relapse, and 1 of multi-organ failure. Infection did not contribute to death in any patient. Conclusion. Rapid reconstitution of immunity to a broad range of viral and fungal infections can be achieved using a

Reinforcing the Immunocompromised Host Defense against Fungi: Progress beyond the Current State of the Art

“…Although FSTs have been shown to increase the resistance against Aspergillus fumigatus infection or prolong the survival of mice with invasive pulmonary mycosis [59][60][61], as of today, and in contrast to the numerous VST trials, there are only two completed, clinical trials of adoptive T cell immunotherapy against fungal diseases [41,62]. In the first study, conducted 16 years ago, Perrucio et al showed that the administration of anti-Aspergillus T cell clones was safe, enhanced the control of Aspergillus antigenemia and improved the survival of transplanted patients with invasive aspergillosis as compared to the control cohort not receiving immunotherapy (survived patients 9/10 vs. 7/13, respectively).…”

“…In the first study, conducted 16 years ago, Perrucio et al showed that the administration of anti-Aspergillus T cell clones was safe, enhanced the control of Aspergillus antigenemia and improved the survival of transplanted patients with invasive aspergillosis as compared to the control cohort not receiving immunotherapy (survived patients 9/10 vs. 7/13, respectively). Since then, only recently, Gottlieb's group evaluated the safety and biological efficacy of administering mobilized donor peripheral blood-derived specific T cells with activity against Aspergillus, CMV, adenovirus, EBV, varicella-zoster virus (VZV), influenza, and BKV, as prophylaxis of fungal and viral reactivation and/or disease following allogeneic HCT [62]. Grade III/IV graft-versus-host disease (GvHD) was developed in 4/11 patients, however, the early prophylactic administration (median 37 days post-HCT) of multipathogen-specific T cells (mp-STs) did not allow the dissociation of the GvHD risk that could be derived from the mp-STs from the GvHD risk originating from the transplant procedure per se, which is expected to be high anyway, early post-transplant.…”

“…Grade III/IV graft-versus-host disease (GvHD) was developed in 4/11 patients, however, the early prophylactic administration (median 37 days post-HCT) of multipathogen-specific T cells (mp-STs) did not allow the dissociation of the GvHD risk that could be derived from the mp-STs from the GvHD risk originating from the transplant procedure per se, which is expected to be high anyway, early post-transplant. In terms of their efficacy as fungal prophylaxis in particular, none of the enrolled patients including 4 and 2 patients who had positive PCR for Aspergillus post HCT and prior to T cell transfer, respectively, required antifungal treatment for invasive fungal infection [62]. An ongoing clinical trial (EudraCT #2013-002914-11) at the Universitätsklinikum Würzburg with highly awaited results, assesses the efficacy of adoptive immunotherapy with donor-derived anti-Aspergillus T cells in HCT recipients with probable or proven invasive aspergillosis.…”

“…The use of heat-treated conidia or fungal extracts as antigen source seems to be an ideal antigenic stimuli of T cells, as they contain a plethora of antigens and epitopes which in turn can be targeted through a range of HLA types, thus making feasible the generation of FSTs from all donors, irrespective of their HLA alleles. Indeed, heat-treated conidia or lysate of Aspergillus Fumigatus were used for the expansion of Aspergillus-specific T cells administered in both clinical trials of adoptive immunotherapy with FSTs [41,62]. However, the variability in the quantity of antigens contained in the fungal lysates, along with the potential inclusion of molecules involved in immune evasion [118], makes the preparation of a GMP-compliant fungal lysate complex, demanding and profitless, therefore limiting its commercial availability.…”

“…Indeed, Tramsen et al [79] and Khanna et al [80] observed a notable decrease in the frequencies of antigen-specific T cells in multi-fungus/pathogen-specific cultures versus single-pathogen cell lines, probably attributed to antigenic competition arising from shared antigen-bearing antigen-presenting cells, as well as from the varying frequencies of subsets of antigen-specific Tcells in the starting PBMCs [120,121]. To overcome antigenic competition, Gottlieb's group has stimulated individual cultures of viral-and fungal-specific T cells, which they subsequently combined and expanded further after restimulation [62]. We have recently mitigated antigenic competition showing rapid and GMP-compliant generation of a multi-pathogen-specific T cell product as well as a CRISR/CAS9-edited glucocorticoid-resistant multi-pathogen-specific T cell product simultaneously targeting up to 4 viruses and Aspergillus fumigatus, to overcome pathogen-specific T cells' susceptibility to steroids [81,82].…”