Administration of off-the-shelf, expanded, most closely HLA matched, third party viral specific T cells for the therapy of adenovirus related disease in adult immunocompromised patients.

Abstract

Abstract Background Adenovirus is a common lytic DNA virus. However, it causes severe disease in immunocompromised hosts. While Cidofovir is the primary treatment, its nephrotoxicity and limited efficacy restricts use, especially in post-transplant patients on nephrotoxic drugs. Clearance of infection traditionally correlates with the presence of adenovirus-specific T cells and immune reconstitution. This has led to the development of adoptive T cell therapies for the treatment of adenovirus infections. Methods We administered most closely HLA matched third party adenovirus-specific cytotoxic T lymphocytes (CTL) at a dose of 2.0x105 T cells per kilogram to 42 immunocompromised adult patients with either adenovirus viremia or adenovirus disease (infection with end organ damage attributable to adenovirus). The CTLs were manufactured by isolating mononuclear cells from healthy donors, cultured for 14 days with a pool of immunodominant adenovirus peptides in the presence of IL-2, IL-7 and IL-15 and cryopreserved for future use. Patients received physician choice concomitant antiviral therapy. Patients were assessed at baseline and weekly, for three months, after CTL administration for adverse events, GVHD, and response. Response to CTL was defined as one log reduction in adenovirus copy number or reduction by at least one CTCAE grade of symptoms related with adenovirus disease. A complete response (CR) was resolution of symptoms and viremia. Patients who did not respond within 14 days of each CTL dose were eligible for an additional dose. Results 44 patients were enrolled, of which 42 received at least one unit of CTLs. Patients received a median of 1 unit of CTLs, 14 patients received more than one unit, up to a maximum of 5. The median age was 54 (range17-73). Of the 44 patients, 40 had viremia only, two had pneumonia and two had nephritis (diagnosed by BAL and urine studies), no hepatitis. All patients had an underlying hematological malignancy: 34% (15/44) had Acute Myeloid Leukemia, 20% (9/44) had Acute Lymphoid Leukemia, 7% (3/44) had Chronic Myeloid Leukemia, 9% (4/44) Non-Hodgkins Lymphoma, 7% (3/44) Hodgkins Lymphoma, 9% (4/44) Myelofibrosis and 5% (2/44 for each) had Multiple Myeloma, Myelodysplastic Syndrome or another hematological malignancy. 36 patients had undergone a transplantation: 2 autologous and 34 allogeneic. Patients with viremia had a median viral load of 26,000 IU/mL (IQR 1400-184500 IU/ml) 80% (35/42) were on concomitant antiviral therapy for 34/35 it was cidofovir. The infusions were safe and well tolerated. No infusion reactions were noted. No patient suffered grade III/IV aGVHD and only 4.65% (2/43) experienced grade I/II GVHD within six weeks of infusion. No episode of GVHD was attributable to CTLs. No adverse events (of any grade I-IV) or toxicities related to CTL were recorded. The overall response (OR, PR+CR) rate at study completion was 76% (32/42) with 69% (29/42) achieving a CR. One patient with a PR recrudesced (at one month), no CR recrudesced. The median time to PR was 7 days (95% CI 7-14) and the median time to CR was 20 days (95% CI 13-26). The OR rate at 14 days was 53% (22/42) with 29% (12/42) achieving a CR. At 28 days the OR rate was 69% (29/42) with 62% (26/42) achieving a CR. Regarding the patients with end organ disease, both cases of pneumonitis resolved. Creatinine normalized for 1 patient with nephritis, and it remained stable in the other until the patient elected hospice care. No end organ liver damage was seen in these patients. Among patients who responded by day 28 there was no evidence of spontaneous immune reconstitution. Comparing the ALC at time first infusion and at time of first response there was no statistical difference (p=0.46). When comparing responders vs non-responders baseline ALC, viral load, and rate of cidofovir use were not statistically different between the two groups. To explore the effect of viral response on survival we performed a day 28 survival analysis. Those who had achieved an OR by day 28 had an OS of 93% (27/29), in patients who failed to respond the OS was 38% (5/13). To help eliminate early death bias we performed a landmark survival analysis from day 28 to 3 months. The OS was 96.6% (95% CI 82.7-99.4) for responders and 0% for non-responders. Conclusion CTL therapy for adenovirus infection was safe with no infusion reactions or attributable adverse events in this study. CTLs appear efficacious in treating both viremia and adenovirus disease.