Adoptive T-Cell Therapy with 3^rd Party CMV-pp65-Specific CTLs for CMV Viremia and Disease Arising after Allogeneic Hematopoietic Stem Cell Transplant

Adoptive immunotherapy with transplant donor-derived virus-specific T-cells is effective in the treatment of CMV viremia and disease complicating allogeneic hematopoietic stem cell transplant (HCT), but is not available if the donor is seronegative or unavailable to provide lymphocytes. In addition, CMV-specific T-cell lines (CMV-CTLs) from non-identical donors may be restricted by HLA alleles not shared by the patient, rendering them ineffective. This limitation has become more problematic with increased use of haploidentical HCT donors.

We treated 50 transplant recipients with third party donor-derived CMVpp65-specific T-cells between 10/14/11 and 11/28/16, evaluable for response assessment as of 6/20/17. Patients had received an unmodified (n=11) or T-cell depleted HCT (n=33) or a cord blood (n=6), transplant. Fifteen were treated for overt CMV disease involving CNS (N=6) GI (N=10) and Lung (N=2) and 35 for CMV viremia persisting despite >2 weeks of induction therapy with 1-3 antiviral agents. Treatment with CMVpp65-CTLs was initiated at a median of 151 (29-4940) days post transplant and 128 (7-564) days after CMV reactivation. One patient was treated for CMV colitis developing more than 10 years after transplant due to immune suppression for chronic graft versus host disease. Patients had received a median of 3 (1-6) prior antiviral treatments.

Third party CMVpp65-CTLs were selected from a bank of 186 lines generated under GMP conditions from normal HCT donors who specifically consented to use of their T cells in patients other than their designated transplant recipient. Selection was made on the basis of HLA restriction by at least one HLA allele shared by the patient and HCT donor, and matching for > 2/10 recipient alleles. If such a line was not available, a patient could be treated with a line matched at only one HLA allele as long as the restriction was through that matched allele. Patients received 3 weekly infusions of approximately 1x10⁶ CMVpp65-CTL/kg/infusion. Patients were sequentially evaluated for clinical and radiographic changes, quantifications of CMV DNA by PCR and IFN+ CMVpp65-specific T-cells in the blood. Responses were assessed 28-42 days after the first of each cycle of CMVpp65-CTLs. Response in patients with CMV disease was considered complete (CR) if all sites were cleared of virus by biopsy and blood sampling and partial (PR) if symptoms resolved and viremia met criteria of PR. In patients treated for persistent viremia, responses were complete if CMV DNA was cleared in repeated testing, and partial if the level of CMV fell based on the testing method by >50% (N=2) or by 2log10 (N=12).

Of the 50 patients 18 had a complete and 14 a partial response for an overall response rate of 64%. Response rates in patients with disease (5CR+4PR/15) were similar to those of patients with persistent viremia (13CR+10PR/35). In patients treated for viremia alone, survival at 6 months was 65.7% and in those with disease 60.0% (a). More extensively pretreated patients who received CMVpp65 CTLs > 100 days post CMV initial detection fared as well as those treated earlier (62.1% vs. 66.7% OS) (b). Patients who responded to CMVpp65-CTL therapy (CR or PR) had an improved survival with 6 month overall survival of 81.3% (b) and 12 month overall survival of 62.1% (c); only 1 of these 32 patients died of CMV. In contrast 7 of 18 non-responding patients died of CMV; overall survival in this cohort was 33.3% at 6 months. By 12 months, 8 non-responding patients had died of CMV and overall survival had decreased to 22.2%.

Toxicities associated with CMVpp65-CTL infusions in this cohort are limited with 5 patients experiencing adverse events of > grade 3 severity deemed possibly related to CMVpp65-CTL therapy. Two of these patients died, one due to sepsis and one due to progression of CMV.

This study demonstrates a high response rate among patients with otherwise refractory CMV viremia and disease. The bank of CMVpp65-CTLs can provide an immediate source of HLA partially-matched appropriately restricted T cells for adoptive immunotherapy to treat persistent CMV viremia and CMV disease, including disease isolated to the CNS. The availability of 3rd party CMVpp65-CTLs enables treatment early in the course of disease and may thereby improve response rates while minimizing toxicity from anti-viral therapy.

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