Development of a Th1-polarising dendritic cell vaccine driving cytotoxic T-lymphocyte-mediated killing of autologous breast cancer cells in vitro
Michele Tomasicchio1*, Lynn Semple1, Ali Esmail1 Richard Meldau1, Phillippa Randall1, Anil Pooran1, Malika Davids1, Suzette Oelofse1, Rolanda Londt1, Lydia Carncross2, Jennifer Downs2, David Anderson2, Francois Malherbe2, Thuran Naiker2, Eugene Panieri2, Nickolas Novitsky3, Keertan Dheda1,4
* Corresponding author
1Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa; 2 Department of General Surgery, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa;
3 National Health Laboratory Services (NHLS), Groote Schuur Hospital, Haematology, Cape Town, South Africa, Division of Haematology, University of Cape Town, Cape Town, South Africa; 4Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa
Background: Breast cancer remains one of the leading causes of cancer-associated death worldwide. Conventional treatment of stage 3 and 4 cancers are associated with substantial toxicity and suboptimal efficacy. Dendritic cell (DC) vaccines have therefore been investigated as a potential immunotherapeutic intervention. However, published data regarding investigational DC vaccines have not shown efficacy against autologous tumour cells, which have a highly variable and heterogeneous antigenic repertoire.
Methods: We recruited 12 female patients with stage 1, 2 or 3 breast cancer and primed/matured their DCs post-phlebotomy, ex vivo, with autologous tumour-specific lysate and a maturation cocktail. The efficacy of the vaccine was evaluated by its ability to elicit a cytotoxic T-lymphocyte response to autologous breast cancer cells in vitro.
Results: We were able to optimally prime and mature breast cancer patient-derived DCs ex vivo (p ≤ 0.001) as assessed by the upregulation of CD80 (69%), CD86 (78%), CCR7 (62%) and CD83 (73%) when compared to the immature DCs. These primed/matured DCs produced high levels of the Th1 effector cytokine, IL12-p70 (1.2 ng/ml; p < 0.0001) compared to DCs primed/matured with tumour lysate or an interferon-containing cocktail alone. We further show the primed and matured DCs enhance antigen-specific CD8+ T-cell responses as assessed with HER-2 (4.5%; p < 0.005) and MUC-1 (19%; p < 0.05) tetramers. The primed/matured DCs could elicit a robust and dose-dependent antigen-specific cytotoxic T-lymphocyte response (65%) which was tumoricidal to autologous breast cancer cells in vitro (p < 0.005) compared to T-lymphocyte that remained un-primed. Lastly, we showed that the primed/matured DCs post-cryopreservation maintained high viability, preserved their mature phenotype, and remained free of endotoxins or mycoplasma.
Conclusion: We have developed a DC vaccine that is cytotoxic to autologous breast cancer cells in vitro. The tools and technology generated here will now be applied in a phase I/IIa clinical trial.
Funding: The current study was funded by the National Research Foundation (NRF) Technology and Human Resources for Industry Programme (THRIP).