Research ArticleImmunotherapy

CMV-specific T cells generated from naïve T cells recognize atypical epitopes and may be protective in vivo

Science Translational Medicine  29 Apr 2015:
Vol. 7, Issue 285, pp. 285ra63
DOI: 10.1126/scitranslmed.aaa2546

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Sourcing CMV immunotherapy

Immunotherapy—such as adoptive T cell therapy—is making headway in treating cancer, autoimmunity, and infectious disease. Indeed, adoptive transfer of cytomegalovirus (CMV)–specific T cells can restore immunity to the virus. However, these cells have been primarily derived from memory cells from CMV-seropositive individuals, which limits the donor pool. Now, Hanley et al. demonstrate that CMV-specific T cells can be derived from naïve T cells taken from CMV-seronegative people. These cells react to different epitopes than the memory cell–derived T cells but with similar avidity. What’s more, these cells were associated with periods of CMV-free survival when transplanted into patients. These data support expanded trials of adoptive therapy of CMV-restricted T cells from seronegative donors.

Abstract

Adoptive transfer of cytomegalovirus (CMV)–specific T cells derived from adult seropositive donors can effectively restore antiviral immunity after transplantation. However, CMV-seronegative donors lack CMV-specific memory T cells, which restricts the availability of virus-specific T cells for immunoprophylaxis. We demonstrate the feasibility of deriving CMV-specific T cells from naïve cells for T cell therapy. Naïve T cells primed to recognize CMV were restricted to different, atypical epitopes than T cells derived from CMV-seropositive individuals; however, these two cell populations had similar avidities. CMV-seropositive individuals also had T cells recognizing these atypical epitopes, but these cells had a lower avidity than those derived from the seronegative subjects, which suggests that high-avidity T cells to these epitopes may be lost over time. Indeed, recipients of cord blood (CB) grafts who did not develop CMV were found by clonotypic analysis to have T cells recognizing atypical CMVpp65 epitopes. Therefore, we examined unmanipulated CB units and found that T cells with T cell receptors restricted by atypical epitopes were the most common, which may explain why these T cells expanded. When infused to recipients, naïve donor–derived virus-specific T cells that recognized atypical epitopes were associated with prolonged periods of CMV-free survival and complete remission. These data suggest that naïve-derived T cells from seronegative patients may be an additional source of cells for CMV immunoprophylaxis.

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