Evaluating multivirus-specific T cells from both cord blood and bone marrow transplant donors: a phase 1 perspective

      CMV, EBV and adenovirus are problematic in patients after stem cell (SCT) and cord blood transplantation (CBT) and are associated with morbidity and mortality. Deficiencies in conventional therapeutics have increased interest in an immunotherapeutic approach to viral disorders. We have developed 2 strategies to grow multivirus-specific donor-derived T-cells (mCTL) from peripheral blood (PB) and naive cord blood (CB). Using an adenoviral-vector expressing CMVpp65 to modify monocytes, DC and EBV-LCL we generated a single culture of mCTL (n=34). PB mCTL(Mean SFC:adeno:86, EBV:183, CMV:648) had more spot forming cells (SFC) than CB(adeno:83, EBV:117, CMV:36) but both contained cells specific for at least 1 virus. We infused 25 patients with PB mCTL and 9 patients with CB mCTL. Patients received CTL infusions from 35-164days(median 84) post transplant at a median of 5x10e7 cells/m2 with no toxicity or GvHD >grade II. We observed up to a 5-fold increase in CMV- and EBV-specific T-cells by 4weeks post-CTL as measured by IFN-g ELISPOT assay. 26 viral reactivations were observed in patients before or immediately after mCTL infusion. In the absence of conventional therapy, 8 of the 11 patients with CMV infection became negative for CMV in the blood within 7d of mCTL infusion, with a coinciding rise in CMV-specific CTL in PB. Each of 8 patients with high EBV loads cleared their virus, as did 7 of 7 patients with adenoviral infections/disease. Overall the response rate in both groups was 88%. This study demonstrates that mCTL derived from the PB of seropositive donors as well as the CB of virus naive donors expand in vivo and are active against multiple viruses. Furthermore, by restoring immunity to multiple viruses simultaneously, the need for continued prophylaxis with pharmacotherapy is eliminated, thus, improving the efficiency and cost effectiveness of protecting SCT and CBT recipients from these potentially lethal viruses.
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