Abstract
Many cancers, including myeloid leukaemia express the cancer testis antigen (CTA) DDX43 (HAGE) and/or the oncogene Wilms’ tumour (WT1). Here we demonstrate that HAGE/WT1-ImmunoBody® vaccines derived T-cells can kill ex-vivo human CML cell lines expressing these antigens and significantly delay B16/HHDII+/DR1+/HAGE+/WT1+ tumour growth in the HHDII/DR1 mice and prolonged mouse survival in the prophylactic setting in comparison to non-immunised control mice. We show that immunisation of HHDII/DR1 mice with HAGE- and WT1-ImmunoBody® DNA vaccines in a prime-boost regime in two different flanks induce significant IFN-γ release by splenocytes from treated mice, and a significant level of cytotoxicity against tumour targets expressing HAGE/WT1 in vitro. More importantly, the combined HAGE/WT1 ImmunoBody® vaccine significantly delayed tumour growth in the B16/HHDII+/DR1+/HAGE+/WT1+ tumour model and prolonged mouse survival in the prophylactic setting in comparison to non-immunised control mice. Overall, this work demonstrates that combining both HAGE- and WT1-ImmunoBody® into a single vaccine is better than either vaccine alone. This combination vaccine could be given to patients whose cancer expresses HAGE and WT1 in parallel with existing therapies in order to decrease the chance of disease progression and relapse.
Highlights
The role of a cancer vaccine is to stimulate cellular immune responses that effectively lead to anti-tumour cytotoxic Tlymphocyte (CTL) responses
It has been found that a 30-mer peptide sequence [QTGTGKTLCYLMPGFIHLVLQPSLKGQRNR]/[position: 286316] derived from the helicase antigen (HAGE) protein is associated with high immunogenicity, as detected using an ex-vivo IFN-g Enzyme-Linked ImmunoSpot (ELISpot) assay [22]
As for the other targets, a significantly higher percentage of B16/HAGE+ cells was killed when the CTLs used were derived from mice immunised with the combined approach (Figure 4D, at almost 60%) than when they were derived from mice immunised with either HAGE or Wilms tumour (WT1) vaccine individually (50% and 45%, respectively). This difference is shown to be a statistically significance at 1:100 (P-value=0.0032, n=3 and P-value=0.0002, n=3) in HAGE and WT1 groups, respectively. These findings demonstrate that the sequences contain within HAGE- and WT1-ImmunoBody® derived vaccines either individually or in combination was endogenously processed and displayed on the surface of antigen presenting cells (APCs) in association with HLA-A2 molecules leading to the development of professional CTLs which are able of recognising and killing antigen-expressing target cells
Summary
The role of a cancer vaccine is to stimulate cellular immune responses that effectively lead to anti-tumour cytotoxic Tlymphocyte (CTL) responses. In addition it has been found to be elevated in uterine leiomyosarcoma and carcinosarcomas [4] as well as epithelial ovarian cancer [5] It is frequently used as a marker of minimal residual disease in chronic myeloid and acute leukaemia [6] having been found to be overexpressed in malignant but not healthy haematopoietic cells. WT1 is one of a number of leukaemia associated antigens that have been considered as promising targets for immunotherapy because of their ability to elicit specific immune responses against antigenbearing cancerous cells while sparing normal tissues. No single antigen met all of the top subcriteria such as therapeutic function, immunogenicity and having already been in clinical trials, WT1 was identified as the top ranked antigen for these criteria and WT1 is overexpressed in most de novo acute myeloid leukaemia (AML) cases [8] and in chronic myeloid leukaemia (CML) [9]. WT1 was shown to be expressed in 50–100% cases of blast crisis but not in chronic or accelerated phase cases [10]
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