OTHER VIRAL INFECTIONS IN TRANSPLANTATION

E. Doubrovina¹, B. Oflaz-sozmen¹, N. Kernan¹, J. Young², S. Abramson³, J. Barker², F. Boulad³, H. Castro-malaspina², J. Teruya-feldstein³, D. Filippa³, A. Jakubowski², E. Kanaeva³, E. Papadopoulos², S. Prockop³, A. Scaradavou³, T. Small³, R. O'reilly^3
1Pediatrics, Memorial Sloan-Kettering Cancer Center, New York/UNITED STATES OF AMERICA, ²Medicine, Memorial Sloan-Kettering Cancer Center, New York/UNITED STATES OF AMERICA, ³Pediatrics, Memorial Sloan-Kettering Cancer Center, New york/UNITED STATES OF AMERICA

Body: EBV-associated malignancies (EBV-M) developing after HSCT or organ transplants are often fatal. We treated in 26 patients who developed EBV-lymphoma (EBV-L) with EBV-CTL following either HSCT (n=22), including HLA-matched (n=8) and non-identical (n=14) T-cell depleted (n=17) or unmodified (n=2) HSCT and cord blood grafts (CBT) (n=3) or following OT (n=4). All patients had clinical and radiologic evidence of rapidly growing tumors of Waldeyer’s ring and/or intestines, liver, lung or CNS and rising blood levels of EBV DNA. Biopsies showed B cell, EBV⁺ lymphoma in 24 pts that were monoclonal (12/14 tested) and were usually of donor origin post-HSCT (10/14 tested) and host origin post-OT (3/4). Of 26 pts 20 had failed (n=12) or recurred (n=8) following Rituximab treatment. EBV-CTLs were generated from the transplant donors for 18 patients (16 HSCT, 2 OT) and from HLA partially matched related or unrelated third party normal donors for 8 patients (3 HSCT, 3CBT, 2 OT). T-cells sensitized with autologous EBV-BLCL transformed by B95.8 EBV strain (B95.8-BLCL) and tested for specificity, lack of alloreactivity and sterility. Treatment included 3-5 weekly infusions of EBV-CTL (10⁶Tcells/kg/dose). Tumor responses, EBV DNA levels and quantitations of tetramer⁺, IFNg⁺EBV-specific T cells and EBV CTLp by limiting dilution analysis (LDA) were monitored. Infusions were well tolerated; no pts developed GVHD or organ rejection. Of the 22 pts with EBV-lymphoma post-HSCT, 2 died too early to be evaluated (<14 days), 14 achieved CR, 1 had SD, 5 had progression (PD). Of 6 pts primarily treated with EBV-CTL 5(83%) achieved CR, versus 9/14 (64%) who failed Rituximab. CR rate was similar in pts on no immunosuppressives (71%) versus pts on calcineurin inhibitors (75%) or steroids (67%). Pts with single site of disease fared better than patients with multiple sites (100% versus 60% CR). However, all sites of disease, including CNS, were comparably responsive to therapy. CTLp frequencies rose 10-200 fold by 2-3 weeks post-infusion in patients achieving CR and were temporally associated with disease regression and clearance of EBV DNA. Such increases were not seen in any pt with PD. EBV-CTLs inducing CRs in 8 patients studied lysed both B95.8-BLCL and spontaneous EBV⁺BLCL transformants(S-BLCL) isolated from the patient’s blood or involved tissues; EBV-CTLs given to 3 non-responders on no immunosuppression lysed B95.8-BLCL, but not S-BLCL of donor origin isolated from the patients. In two instances, in which the EBV-M is of host origin, the EBV-CTLs were restricted by the HLA alleles not shared by the host origin EBV tumor. Of 2 pts post-OT with EBV⁺clonal lymphoma both achieved PR; 2 with EBV⁺leomyosarcoma achieved stable disease. These responses have been sustained for 2 -12 years on no other therapy. Following each infusion of EBV-CTL the EBV-specific T cells persisted at least for 2-3 weeks. Thus, EBV-CTLs can induce durable remissions of EBV-associated malignancies after HSCT or OT. However, the efficacy may be compromised in Rituximab refractory disease or by failure of EBV-CTL to recognize the endogenous EBV strain or an EBV⁺tumor of host origin lacking the T-cell s’restricting HLA alleles.

Disclosure: All authors have declared no conflicts of interest.