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Towards gene therapy for EBV-associated Post-Transplant Lymphoproliferative disease: genetically modified EBV-specific Cytotoxic T Lymphocytes induce regression of autologous EBV-induced Lymphoproliferation despite immunosuppression

Ida Ricciardelli, Michael Patrick Blundell, Jennifer Brewin, Martin Pule and Persis J. Amrolia

Key points

  • EBV-CTLs resistant to calcineurin inhibitors mediate durable, potent anti-tumour responses despite immunosuppression in murine model of PTLD.

  • This approach improves immunotherapy efficacy with EBV-CTL for PTLD after SOT and obviate need for immunosuppression withdrawal.

Abstract

EBV associated post-transplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), whilst effective in SCT, is less successful after SOT where life-long immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12). Here we examined the ability of FK506-resistant EBV-CTLs to control EBV-driven tumour progression in the presence of immunosuppression in vivo in a xenogeneic mouse model. NOD/SCID/IL2rγnull mice bearing human B cell lymphoma were injected with autologous CTLs transduced either with CNA12 or eGFP in the presence/absence of FK506. Adoptive transfer of autologous CNA12-CTLs induced dramatic lymphoma regression despite the presence of FK506 whereas eGFP transduced CTLs did not. CNA12-CTLs persisted longer, homed to the tumour and expanded more than eGFP-CTLs in mice treated with FK506. Mice receiving CNA12-CTLs and treated with FK506 survived significantly longer than control treated animals. Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumours in vivo despite ongoing immunosuppression. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy.

  • Submitted January 30, 2014.
  • Accepted August 14, 2014.