Novel strategies for adoptive therapy following HLA disparate transplants

Abstract

Transplants of SBA-E- allogeneic marrow or G-CSF mobilized CD34+ (ISOLEX) E- peripheral blood progenitor cells which are adequately depleted of T-cells, when administered without post-transplant immunosuppression now induce consistent engraftment with low incidences of acute and chronic GVHD both in HLA matched and HLA disparate recipients. Furthermore, the incidence of relapse post transplant is not increased in patients transplanted for AML, MDS or ALL. In our series, the incidence of severe infections in HLA-matched recipients of such T-cell depleted grafts also does not differ from that detected following similarly matched unmodified grafts. However, in recipients of HLA-haplotype disparate T-cell depleted grafts, the risk of lethal viral infections is increased and prolonged. In many cases, this risk is closely correlated with failures of immunodominant virus-specific donor T-cells transferred in the graft to recognize infected host cells because they are restricted by HLA alleles not shared by the host. To address this limitation, we have developed a panel of artificial antigen presenting cells, each expressing a single prevalent HLA-allele. Using this panel, we are able to selectively generate virus-specific cytotoxic T-cells of desired HLA restriction, to insure their effectiveness in HLA haplotype-disparate transplant recipients. We have also shown that partially HLA-matched, third party-derived EBV-specific T-cells, selected from our bank of previously generated and characterized GMP-grade cell lines on the basis of their HLA restriction, can induce durable remissions of rituximab-refractory EBV lymphomas. These approaches may thus provide new, immediately accessible resources for the generation and broad application of immune cell therapies to treat and prevent severe viral diseases post transplant.