Adoptive Immunotherapy With CMV-specific Cytotoxic T Lymphocytes for Stem Cell Transplant Patients With Refractory CMV Infections

Abstract

Adoptive immunotherapy with cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) is an effective strategy for preventing and treating viral reactivation following allogeneic stem cell transplantation (SCT). We have previously shown that CMV CTL can be generated in 1-2 weeks by stimulating donor lymphocytes with peptide mixes derived from full length pp65 and IE1. We conducted a multi-institutional study of CMV specific CTL for patients with persistent or anti-viral resistant CMV infections following allogeneic SCT, to determine the safety, feasibility, and immunologic effects of this approach. We were successful in stimulating CTL from 10/10 donors with pooled CMV overlapping peptide mixes. Five of the 7 subjects who met infusion criteria had new onset CMV specific CTL activity detected within 4-6 weeks post infusion. Of the two subjects who did not have immunologic responses post-infusion, one received CTL with a low viability post-thawing, and the other patient was receiving cyclosporine A and systemic corticosteroids at the time of the infusion, achieving only a low, transient increase (10%) in pp65 specific activity. There was no GVHD attributable to these infusions. These findings indicate that the infusion of CTL stimulated over 1-2 weeks with overlapping CMV peptides can result in virus specific immune reconstitution in SCT recipients, without exacerbations of GVHD.

Immunotherapy with Donor T Cells Sensitized with Overlapping Pentadecapeptides for Treatment of Persistent Cytomegalovirus Infection or Viremia

“…Thus, Bao et al 52 employed overlapping peptides of CMVpp65 and IE-1 to generate transplant donor-derived CMV specific T-cells for treatment of CMV viremia persisting despite antiviral treatment for >2 weeks in 7 patients, including 5 who had received T-cell depleted haploidentical grafts. Of these, 3 cleared CMV viremia and 3 had significant reduction of viral load, each associated with increments in circulating levels of CMV-specific T-cells.…”

Successful treatment of post‐transplant CMV meningoencephalitis with third‐party CMV virus‐specific T cells: Lessons learned

“…HSCT recipients with active disease who receive third‐party VSTs have response rates of approximately 70%; in a donor‐specific setting this rate approaches 70%‐90%. However, these results usually refer to CMV persistent viremia and not to active CMV disease …”

“…Impaired T‐cell immunity and subsequent insufficient viral control contribute to the frequency of viral infections post‐HSCT. In recent years, adoptive T‐cell therapy has been reported to provide a significant chance of cure for patients with viral infections following HSCT . However, most reported cases in which adoptive T‐cell therapy was used for CMV involved patients with persistent CMV DNAemia (hereafter referred to as viremia) and not with CMV disease.…”

Virus-specific T-cell banks for 'off the shelf' adoptive therapy of refractory infections

“…For example, in patients with EBV lymphomas involving the gastrointestinal tract and mesenteric nodes who have failed treatments with Rituximab, circulating levels of EBVDNA may be low or absent despite the presence of growing lesions. Conversely, in patients treated for CMV and adenovirus, levels of viral DNA in the blood often increase transiently shortly after T-cell infusion, 8, 12, 19 potentially reflecting lysis of infected cell targets by the infused T-cells. Thus, there is a continuing need for new diagnostic approaches permitting early detection and prediction of patients who are responding to T-cell therapy.…”