|Full title:||A phase I Dose Escalation trial of immunisation with autologous dendritic cells loaded with NY-ESO-1 and αLPHA galactosylceramide in patients with high-risk surgically resected stage II, III or IV melanoma
A phase II trial of immunisation with autologous dendritic cells loaded with NY-ESO-1 and αLPHA-galactosylceramide in patients with high-risk surgically resected stage II, III or IV melanoma
|Status:||Open to recruitment (Phase II)|
|Our aim was to undertake a Phase I dose escalation study, leading up to the Phase II clinical trial, to evaluate the immunological effects and safety of a potential new adjuvant therapy for surgically resected high-risk melanoma patients. The therapy is based upon the injection of DC-based vaccines comprising autologous DCs loaded with peptides, with the aim of eliciting T cells with specificity to the peptide sequences.
The Phase I dose escalation study aimed to establish a safe dose for vaccines which also include α-GalCer. The Phase II study, will specifically evaluate whether including α-GalCer in the vaccine will improve the size and function of the induced T cell response as a consequence of invoking the helper function of NKT cells.
The use of synthetic long peptides in DC-based vaccines will be investigated, both for their exciting recent track record in clinical trials and the precision in monitoring immune responses that they enable. As noted above, there is a strong rationale for selecting long peptides from the cancer testis antigen NY-ESO-1 as an immunological target in melanoma patients, particularly in the setting of minimal residual disease.
While vaccine-induced T cell responses to NY-ESO-1 have been reported in melanoma patients, including to DC-based vaccination, measurable responses in the blood were not always seen in all patients. In the Phase II trial, the possibility that some patients may not induce measurable responses might reduce the statistical power to test the hypothesis that α -GalCer enhances T cell responses. Therefore additional “model” antigens have been included in the DC-based vaccines for this study. These are peptides from influenza virus, to which most of the patients will have been exposed, meaning that “memory” populations of influenza-specific T cells will be present in the majority of trial participants. Upon re-exposure to peptides derived from influenza that have been loaded onto the injected DC-based vaccines, these T cell populations should rapidly expand to measurable quantities. The capacity of α-GalCer to enhance this T cell response could therefore be assessed in many of the patients. Importantly, even patients who do not have measurable memory T cells specific for the influenza peptides before vaccination may show measurable responses after vaccination with the peptides; such responses may occur due to expansion of memory T cells present at below the detectable level pre-vaccination, or due to the priming of naïve cells.
Careful consideration has been given to the route of vaccination. The Malaghan Institute of Medical Research/WBCC’s first trial of DC-based vaccines in patients with advanced B cell malignancies was via the intravenous (IV) route, but subsequent local studies have been via the intradermal (i.d.) route, in line with international trends. However there is little evidence to show a specific clinical benefit to any specific route. The protocol is dependent on the injected DCs gaining access to NKT cells, which are known to be in large quantities in spleen and liver, and found in much reduced levels in the peripheral lymph nodes. For this reason, α-GalCer has been predominantly tested in patients via the IV route, either as a free single agent, or loaded onto DCs. The Malaghan Institute animal studies have clearly shown significant benefit to injecting α-GalCer-loaded DCVs by the IV route, rather than through the skin.
To our knowledge this phase II clinical trial will be the first study in patients to combine peptides and α-GalCer on the same dendritic cells. The Phase I dose escalation study ended in March 2015 and demonstrated a safe dose of vaccine for the Phase II clinical trial. The Phase II clinical trial is ongoing.
|Lead Investigators:||Scientific: Professor Ian Hermans Clinical: Dr Catherine Barrow|
|Contact:||Rebecca Hu (firstname.lastname@example.org, tel: 09 923 9643)|
|Funder:||Health Research Council|
|Trial Registry reference:||ACTRN12612001101875 (click for more details)|
|Ethics number:||Phase I 13/NTB/6 Phase II 13/NTB/5|