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

Abstract

We conducted a Phase I trial of allogeneic T-cells sensitized in vitro against a pool of 15-mer peptides spanning the sequence of CMVpp65 for adoptive therapy of 17 allogeneic hematopoietic cell transplant recipients with CMV viremia or clinical infection persisting despite prolonged treatment with antiviral drugs. All but three of the patients had received T-cell depleted transplants without GVHD prophylaxis with immunosuppressive drugs post transplant. The CMVpp65-specific T-cells (CMVpp65CTLs) generated were oligoclonal and specific for only 1–3 epitopes, presented by a limited set of HLA class I or II alleles. T-cell infusions were well tolerated without toxicity or GVHD. Of 17 patients treated with transplant donor (N=16) or third party (N=1) CMVpp65CTLs, 15 cleared viremia including 3 of 5 with overt disease. In responding patients, the CMVpp65CTLs infused consistently proliferated and could be detected by T-cell receptor (TCR) Vβ usage in CMVpp65/HLA tetramer+ populations for period of 120 days to up to 2 years post infusion. Thus, CMVpp65CTLs generated in response to synthetic 15-mer peptides of CMVpp65 are safe and can clear persistent CMV infections in the post transplant period.

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

“…In haploidentical HSCT, early T-cell recovery is primarily based on peripheral expansion of naïve T cells and it appears delayed when compared with that of HSCT from HLA-identical siblings [87][88][89][90] Long-term immune reconstitution, however, mostly thymus-dependent, appears appropriate to maintain an adequate naïve T cell pool [91][92][93][94]. Adoptively transferred CMV-CTL can be detected long after HSCT and up to 2 years after infusion [95]. There are two main ways to obtain virus-specific T cells (VSTCs): a) in vitro expansion and b) ex vivo separation and in vivo expansion (Fig.1).…”

Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis

“…[35][36][37] In this regard, viral-directed adoptive cellular immunotherapy has emerged to advance the therapeutic approach to viral disease in allogeneic HCT 38,39 and to decrease the need for conventional pharmaceutical agents with harmful end-organ effects. 39,40 This study has several limitations. Inherent to this being a registry study is the incompleteness of the data collected in the CIBMTR database.…”

Immunotherapy for transplantation-associated viral infections

“…PTLD is an aggressive fastpaced tumor that requires urgent treatment, and this must be central to decision making about the source and manufacture methods used to generate EBVSTs. Banks of HLA-matched EBVSTs derived from healthy EBV-seropositive subjects are available where cells Incorporates results of several other published studies (79,80,84). CTL, cytotoxic T lymphocyte; CR, complete response.…”