Safety of targeting tumor endothelial cell antigens.

The mechanisms underlying discrimination between "self" and "non-self", a central immunological principle, require careful consideration in immune oncology therapeutics where eliciting anti-cancer immunity must be weighed against the risk of autoimmunity due to the self origin of tumors. Whole cell vaccines are one promising immunotherapeutic avenue whereby a myriad of tumor antigens are introduced in an immunogenic context with the aim of eliciting tumor rejection. Despite the possibility collateral damage to healthy tissues, cancer immunotherapy can be designed such that off target autoimmunity remains limited in scope and severity or completely non-existent. Here we provide an immunological basis for reconciling the safety of cancer vaccines, focusing on tumor endothelial cell vaccines, by discussing the following topics: (a) Antigenic differences between neoplastic and healthy tissues that can be leveraged in cancer vaccine design; (b) The layers of tolerance that control T cell responses directed against antigens expressed in healthy tissues and tumors; and, (c) The hierarchy of antigenic epitope selection and display in response to whole cell vaccines, and how antigen processing and presentation can afford a degree of selectivity against tumors. We conclude with an example of early clinical data utilizing ValloVax™, an immunogenic placental endothelial cell vaccine that is being advanced to target the tumor endothelium of diverse cancers, and we report on the safety and efficacy of ValloVax™ for inducing immunity against tumor endothelial antigens.

Baculovirus as delivery system for gene transfer during hypothermic organ preservation.

Concerns over the safety of conventional viral vectors have limited the translation of gene transfer from an exciting experimental procedure to a successful clinical therapy in transplantation. Baculoviruses are insect viruses, but have the ability to enter mammalian cells and deliver potential therapeutic molecules with no evidence of viral replication. This study provides evidence of the ability of recombinant baculovirus to enter mammalian kidneys and livers during cold preservation. Six kidneys and six liver lobules retrieved from large pigs were perfused with University of Wisconsin (UW) solution containing a baculovirus tagged with green fluorescent protein and preserved for 8 h. In addition, six kidneys were perfused with UW containing a baculovirus expressing red fluorescent protein and preserved for 24 h. Green fluorescent virus particles were detected within transduced kidneys and livers after 8 h standard cold storage and red fluorescent protein mRNA was detected in kidneys after 24 h of cold preservation. There were no significant differences in tissue architecture, cell morphology or ATP content between experimental organs and their controls. Ex vivo transduction of organs with recombinant baculovirus during conventional cold preservation was demonstrated with no evidence of additional injury or reduction in cell viability.

Impact of pulsatile perfusion on postoperative outcome of kidneys from controlled donors after cardiac death.

Pulsatile perfusion (PP) might be a cost-effective cold preservation technique to reduce the incidence of delayed graft function (DGF) in kidneys from deceased donors. With the aim to address whether PP can reduce the incidence of DGF in kidneys from controlled donors after cardiac death (cDCD), we compared the clinical outcome of 30 recipients of kidneys from cDCD preserved by static cold storage (cDCD-SCS) with 30 recipients of cDCD kidneys preserved by PP (cDCD-PP). The end-points were the incidence of primary nonfunction (PNF), DGF and acute rejection (AR), the length of hospitalization, 1, 3, 6 and 12-months graft function, graft survival and patient survival. Donor, recipient and preimplantation data were well matched. DGF was significantly lower (53.3% vs. 86.6% P<0.001) and the length of hospitalization shorter (10 vs. 14 days P<0.033) in the cDCD-PP group. Similarly, postoperative and short-term graft function (7 and 30 days and 6 and 12 months, respectively) was statistically better in the cDCD-PP than in the cDCD-SCS. In summary, in this cohort, clinical introduction of PP was associated with a significant reduction of DGF, shorter hospitalization and better graft function than SCS.