Background: Adoptive Immunotherapy with virus-specific T cells (VST) derived from hematopoietic stem cell (HSC) donors has been highly successful in preventing or treating CMV and other viruses in previous trials, but previously, VST could not be produced from adult virus-naïve donors. While "off the shelf" third party VSTs can offer a short term therapeutic approach for these patients, third party donor VSTs do not contribute to long term virus-specific immune reconstitution in these patients. Hence, we developed a novel approach to manufacture CMV-specific VST from CMV-naïve donors utilizing CD45RA selection and serial stimulation with virus peptide pulsed antigen presenting cells.

Objective: To determine if VST derived from CMV-naïve donors are safe and effective in preventing or treating CMV infection in patients following hematopoietic stem cell transplantation.

Methods: VST were produced from peripheral blood of CMV-naïve HSC donors. CMV-specific T-cells were produced via immunomagnetic selection of CD45RA+ cells, which were stimulated with dendritic cells pulsed with 15-mer peptide pools encompassing CMV antigens pp65 and IE1. VST were stimulated twice more over 3 weeks with EBV-lymphoblastoid cells pulsed with CMV peptides. EBV and adenovirus-specific VST were produced from the same donors in a separate culture with a single stimulation of peripheral blood mononuclear cells with peptide pools encompassing the EBV antigens EBNA1 and LMP2 and the adenovirus antigens hexon and penton. Recipients received CMV-specific and EBV/adenovirus-specific VST as a combined infusion at or after day +28 post HSCT. VST expansion following infusion was measured via Interferon-g ELISpot from peripheral blood and TCRV-beta sequencing.

Results: Four clinical CMV-specific products have been produced to date from CMV-naïve adult donors, and 3 patients have been treated with a median follow-up time of 2 months. All patients received a single VST infusion at a dose of 5x10E6/m2, split equally between the CMV and EBV/adenovirus-specific components. All patients tolerated the infusions well with no toxicities or graft versus host disease. Two of the patients were treated prophylactically, and remain free of CMV, EBV, and adenovirus. One patient was treated for existing CMV reactivation. In the patient with CMV reactivation, activity against CMV-pp65 and IE1 initially fell, then rose and stabilized after infusion (IE1 Spot forming cells (SFC), range: 10-42; pp65 SFC: 16-159). CMV viral level remained detectable at low levels only (110-308 IU/ml), and the patient never developed viral disease.

Conclusions: CMV-specific VST derived from CMV-naïve donors appear to be safe, and may be clinically efficacious in vivo and offer a solution to enhance long term immune reconstitution to CMV in high risk patients after HSCT.

Disclosures

Bollard: Torque: Membership on an entity's Board of Directors or advisory committees; Neximmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees.

Topics:
antigens, cmv reactivation, cytomegalovirus, cytomegalovirus infections, donors, follow-up, graft-versus-host disease, hematopoietic stem cell transplantation, infusion procedures, interferon type ii

Author notes

*

Asterisk with author names denotes non-ASH members.

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© 2017 by The American Society of Hematology
2017
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