Development of a Th1-polarising dendritic cell vaccine driving cytotoxic T-lymphocyte-mediated killing of autologous breast cancer cells in vitro

Identification: 3064


Description

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).

Credits

Credits: None available.

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