Adoptive Immune Cell Therapy Using Third Party T-Cell Donors In the Treatment of EBV Related Diseases In Immunodeficient Recipients
Authors: Prockop Susan , Doubrovina Ekaterina , Boulad Farid , Kernan Nancy A , Kobos Rachel , Scaradavou Andromachi , Small Trudy N , Khalaf Ramzi , Barker Juliet , Koehne Guenther , Papadopoulos Esperanza , Young James W. , O'Reilly Richard J. 
Published: October 2019

Abstract
Abstract 487
Adoptive transfer of donor-derived EBV-specific T-cells can induce complete and durable regressions of EBV lymphomas complicating allogeneic hematopoietic progenitor cell transplants (HSCT). However, this treatment has not been broadly applicable due to 1) lack of immediate access to such T-cells and 2) lack of adequate donor cells to generate the virus-specific T-cells required, either because of donor unavailability (e.g. cord blood or some unrelated donors) or seronegativity. To address this we have developed a bank of EBV-specific cells of defined HLA restriction, and are now evaluating the potential of these HLA-partially matched, third party EBV-specific T-cells. We here report results for the first 13 patients treated by this approach, including pts who developed clonal EBV lymphomas following HLA matched (n=2) or disparate (n=1) T-cell depleted HSCT (N=3) or HLA-disparate cord blood transplants (N=3); pts with chemotherapy refractory EBV PTLD (n=2) or EBV+ leiomyosarcomas (LS) (n=3) complicating organ transplants (N=5) and pts with EBV+ CNS lymphomas complicating AIDS or prolonged immunosuppression (N=2). These patients received infusions of third party EBV-CTLs after the failure of a median of 2 prior therapies (0 – 4) including rituximab in all but one case. Three patients had also failed prior infusions with autologous (1) or HSCT donor (2) EBV-CTLs. T-cells from consenting EBV seropositive HLA typed normal donors were sensitized in vitro for at least 28 days with irradiated autologous EBV BLCL transformed with the EBV strain B95.8, and were then tested for sterility virus-specificity and lack of alloreactivity and stored cryopreserved prior to use. The donors were selected based on matching for at least 2 HLA alleles and in most instances, known restriction of the EBV-specific T-cells for epitopes presented by HLA alleles shared by the EBV+ malignancy. Up to 4 courses of T-cells were administered in 3 weekly I.V. infusions of 1 × 106 T cells/kg, each course separated by a 3 week observation period. T cell infusions were well tolerated. One patient developed minor skin GvHD. No other patient developed GVHD or organ allograft rejection. Results for the 13 pts are summarized in Table 1.
Those pts achieving CR, PR or SD had rapid increments in the frequencies of EBV CTLP detected that persisted 14–21 days after each course. Of the 4 pts with PD, none exhibited increases in the frequency of EBV CTLPs in the blood post T-cell infusion. No increase in EBV CTLPs was observed in a patient who progressed after treatment with EBV-specific T-cells from his haplotype disparate HSCT donor. In this case, the donor's EBV-specific T-cells were restricted by an HLA allele not shared by the host-type lymphoma. This patient was then treated with EBV-specific T-cells from a third party donor restricted by an HLA allele shared by the host-type lymphoma. These T-cells expanded post infusion, resulting in a durable CR. Overall, 9 of 13 survive either in CR or sustained PR or SD >6 to > 60 months post treatment. These results provide evidence that third party EBV-specific T-cells, that are partially HLA-matched, and appropriately HLA restricted can induce regressions of EBV-associated lymphomas, PTLD and LS complicating transplantation or prolonged immunodeficiency. A bank of such T-cells can provide an immediately accessible source of T-cells for adoptive therapy for a large proportion of patients developing these life threatening disorders.
N CR PR SD PD Survival EBV+ Lymphoma Post HSCT or CBT 6 4 0 0 2 4 in CR EBV+ PTLD Post Organ Transplant 2 0 1 0 1 1 in PR EBV+ CNS Lymphoma in Immunodeficiency 2 1 0 0 1 1 in CR EBV+ Leiomyosarcoma Post Transplant 3 0 1 2 0 3 in PR or SD 13 5 3 2 4 9

Disclosures:
No relevant conflicts of interest to declare.