Abstract 1351: Post-transplantation cyclophosphamide depletes vaccine primed donor T cells and compromises graft-versus-tumor effects in alloBMT model
Authors: Fu Han-Hsuan , Fu Jie , Wang Jie , Jones Richard J. , Fuchs Ephraim , Levitsky Hyam 
Published: August 2015

Graft-versus-host disease (GVHD) remains a major complication of allogeneic bone marrow transplant (alloBMT) for patients with hematologic malignancies. Donor T cell depletion or recipient immunosuppression reduces GVHD, but may increase the risks of infection and relapse. High doses of cyclophosphamide (Cy) in the early post-transplantation period (PT/Cy) have been shown to reduce GVHD incidence by eliminating alloreactive proliferating cells both in the HLA-matched and -haploidentical settings. Donor vaccination with tumor cells or tumor antigens has been shown to reduce the risk of relapse in syngeneic BMT. We wished to explore whether donor vaccination could increase the frequency of the tumor specific T cells and reduce the risk of relapse in the content of alloBMT with PT/Cy.

Donor mice were vaccinated with chicken ovalbumin (OVA) expressing Listeria monocytogenes OVA (Lm-OVA) 7 or 30 days before T cell transfer. Recipients were challenged with thymic lymphoma cells expressing OVA and luciferase (EL4-mOVA-Luci). Splenocytes from naïve or Lm-OVA primed donors were transferred along with T cell depleted bone marrow into lethally irradiated recipients harboring tumor. Half of the recipients were treated with Cy (200 mg/kg IP) on day 2. In the syngeneic setting, we examined anti-tumor immunity after donor/recipient vaccination with tumor antigen and characterized the reconstitution of naïve/memory/effector T cell subsets with or without PT/Cy. Significant numbers of OVA-specific CD8+ effector T cells were found on day 15 after transplantation in mice that did not receive PT/Cy. PT/Cy reduced percentages of KLRG1+ effector CD8+ T cells, but CD27+CD127+ memory T cells were increased in mice receiving vaccine-primed donor cells. Both OVA-specific CD4+ effector and memory T cell numbers increased after PT/Cy. Our data showed that donor vaccination on either day -7 or on day -30 prior to BMT delayed tumor growth and significantly prolonged survival of tumor-bearing mice. In an MHC matched, minor antigen mismatched alloBMT mouse model, we further demonstrated PT/Cy decreased donor T cell mediated graft-versus-tumor (GVT) effects. Among mice receiving PT/Cy, overall and event-free survivals at 120 days after transplantation were 38% (day-30) and 31% (day -7), versus 0% among mice receiving cells from unprimed donors. Among mice treated with PT/Cy, those receiving cells from donors primed on day -7 survived slightly longer than those primed on day -30. All mice receiving PT/Cy were dead of tumor by day 70.

In summary, our data demonstrate that PT/Cy compromised the GVT effect of vaccinating donors with tumor antigen and worsened survival. We also showed that there were Cy-resistant OVA-specific T cells found after PT/Cy. Further work is required to reduce the risk of tumor relapse in the content of this alloBMT platform.

Citation Format: Han-Hsuan Fu, Jie Fu, Jie Wang, Richard J. Jones, Ephraim Fuchs, Hyam Levitsky. Post-transplantation cyclophosphamide depletes vaccine primed donor T cells and compromises graft-versus-tumor effects in alloBMT model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1351. doi:10.1158/1538-7445.AM2015-1351