Third Party Donor Derived CMV Specific T Cells for the Treatment of Refractory CMV Viremia and Disease after Hematopoietic Stem Cell Transplant

Adoptive immunotherapy with transplant donor derived virus specific T cells is an effective strategy for the treatment of CMV viremia and disease arising after an allogeneic hematopoietic stem cell (HSCT). This approach is not readily applicable if the donor is seronegative or not available to provide lymphocytes for in vitro expansion for CMV specific cytotoxic T lymphocytes (CMV-CTL) lines or if the CMV CTL lines derived from non-identical donors are restricted by non-shared HLA alleles.

To date, we have treated 38 consecutive patients with overt CMV disease (N=12) or CMV viremia (N=26) persisting despite >2 weeks of antiviral drugs with in vitroexpanded CMV-CTLs derived from an HLA partially matched third party donor. CMV CTLS were selected from a bank of 132 lines generated under GMP conditions from normal HSCT donors specifically consented for use of their T cells in patients other than their designated transplant recipient. Patients were recipients of unmodified (n=6), T cell depleted (n=27) or unrelated cord blood (n=5) HSCT.

Third party CMV-CTLs were selected on the basis of HLA matching at a minimum of 2/8 recipient alleles and HLA restriction of the T cells by one or more HLA alleles present in the patient. A total of 24 distinct CMV-CTL lines were used. The HLA restriction of the CMV CTLs was at a single HLA allele (n=19), at two alleles (n=4) and at >than two alleles (n=1). Patients received infusions of 3rd party CMV-CTLs after failing at least 14 days, and a median of 113 (26-402) days of prior therapy with a median of 4 anti-viral agents. Patients received 3 weekly infusions most at 1x10⁶CMV-CTL/kg/infusion. Four patients were evaluated only for toxicity from CMV-CTLs based on changes in their concomitant anti-viral therapy close to the time of CMV-CTL therapy. Responses in patients treated for viremia alone were considered complete if the viremia resolved completely and partial if it fell by 2 logs. Responses in disease were considered complete (CR) if all detectable CMV viremia and disease resolved and partial (PR) if patients became asymptomatic.

Of the 25 evaluable patients with viremia alone 5 achieved CR, and 9 PR. In 5 CMV viremia was reduced by less than 2 logs, and 6 had progressive viremia or developed disease. Of the 8 evaluable patients treated for disease 2 achieved a CR, 3 a PR, one had stable disease and two progressed. A total of nine patients ultimately died of CMV. There were limited toxicities associated with CMV CTL infusions. Two patients developed progression of presumed CMV pneumonitis. No patients developed de novo GvHD or a flare of prior GvHD in association with mis-matched third party CMV CTLs.

This study demonstrates a high response rate among patients with otherwise refractory CMV viremia and disease. CMV CTLs can be effective when selected based on restriction to shared alleles despite significant HLA disparity. The bank of CMV specific T cells can provide an immediate source of HLA partially matched appropriately restricted T cells for adoptive immunotherapy to treat CMV viremia and disease including disease isolated to the CNS. This enables treatment early in the course of disease and the use of CMV-CTL lines previously prepared and characterized in terms of HLA restriction. This is anticipated to maximize the response rate as well as minimize toxicity from anti-viral therapy.