Rapidly expanded partially HLA DRB1–matched fungus-specific T cells mediate in vitro and in vivo antifungal activity

Abstract

Invasive fungal infections are a major cause of disease and death in immunocompromised hosts, including patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). Recovery of adaptive immunity after HSCT correlates strongly with recovery from fungal infection. Using initial selection of lymphocytes expressing the activation marker CD137 after fungal stimulation, we rapidly expanded a population of mainly CD4+ T cells with potent antifungal characteristics, including production of tumor necrosis factor α, interferon γ, interleukin-17, and granulocyte-macrophage colony stimulating factor. Cells were manufactured using a fully good manufacturing practice–compliant process. In vitro, the T cells responded to fungal antigens presented on fully and partially HLA-DRB1 antigen–matched presenting cells, including when the single common DRB1 antigen was allelically mismatched. Administration of antifungal T cells lead to reduction in the severity of pulmonary and cerebral infection in an experimental mouse model of Aspergillus. These data support the establishment of a bank of cryopreserved fungus-specific T cells using normal donors with common HLA DRB1 molecules and testing of partially HLA-matched third-party donor fungus-specific T cells as a potential therapeutic in patients with invasive fungal infection after HSCT.

A Shifted Composition of the Lung Microbiota Conditions the Antifungal Response of Immunodeficient Mice

“…Both Rag1 -/and NSG mice were more susceptible to infection compared to wild-type mice at 3 days post infection, as shown by increased fungal burden and more severe histopathology (Figure 4). Conversely, at 7 days post infection, while NSG mice were still more susceptible to infection, in agreement with published data [18], Rag1 -/mice appeared more resistant, as shown by improved histopathology and a trend towards a reduced fungal burden (Figure 4).…”

“…Both Rag1 -/-and NSG mice were more susceptible to infection compared to wild-type mice at 3 days post infection, as shown by increased fungal burden and more severe histopathology (Figure 4). Conversely, at 7 days post infection, while NSG mice were still more susceptible to infection, in agreement with published data [18], Rag1 -/-mice appeared more resistant, as shown by improved histopathology and a trend towards a reduced fungal burden (Figure 4). We evaluated the composition of the lung microbiome in these mice and found significant differences in compositional structure at the phylum level between the different groups, as measured by the Jaccard (p = 0.007) and Bray-Curtis (p = 0.016) indexes.…”

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

“…Ex vivo generated Rhizopus oryzae-specific T cells cross-reacted with either Aspergillus fumigatus or Rhizopus (microsporus, pusillus), Mucor circinelloides, Penicillium chrysogenum and Candida albicans [71,77]. Cross-protective immunity was also documented on multi-FSTs [59,76,79] and mp-STs targeting 3 viruses and Aspergillus fumigatus [81,82]. These data suggest an enhanced breadth of fungal recognition, however, whether the broad anti-fungal crossimmunity observed in vitro can provide global fungal protection in vivo, remains to be answered in clinical trials.…”

“…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).…”

“…Tramsen et al generated a memory, Th1 T cell line with tri-fungal specificity against Candida albicans, Aspergillus fumigatus, and Rhizopus oryzae [79]. Likewise, Gottlieb's group has proved the feasibility of generating multi-FSTs targeting Aspergillus terreus, Candida krusei and Rhizopus oryzae [76] and recently Candida krusei and Aspergillus terreus [59]. To further unleash the potential of adoptive immunotherapy, Khanna et al increased the range of targeting against 2-3 viruses and 1-2 fungi [80].…”