Tuesday, June 3, 2014

Telomerase Peptide Vaccine Tested in Pancreatic Cancer Patients

Telomerase is expressed in 80-95% of cases of pancreatic cancer making it a viable target for cancer therapies.  It follows that a Norwegian study explored the creation of a telomerase peptide vaccine for research subjects with non-resectable (inoperable) pancreatic cancer.  This study was a combined phase I and phase II trial aimed at discovering the proper dosage of the vaccine and its efficacy by measuring its safety, tolerability, and immunogenicity, as well as patient survival.  The peptide chosen for this vaccine, GV1001 is a "promiscuous HLA (human leukocyte antigen) class II epitope", meaning that it is the part of an antigen that the immune system recognizes and binds in a nonspecific manner to HLA molecules.

48 patients were randomly assigned to one of three treatment groups: low, intermediate, and high vaccine dosage.  While all patients were used for safety analysis, only those who received at least 6 injections over a four week period were considered for the evaluation of immunogenicity and survival.  As a measure of safety and toxicity, patients were monitored for adverse reactions during and after receiving their vaccine injection.  Immune response was measured by delayed-type hypersensitivity (DTH) skin test—DTH is an injury of one's tissue caused by the body's mounting of a T cell mediated defense.  T cell response was also monitored via proliferation assays of Acid Citrate Dextrose-blood samples.

None of the 48 patients showed any signs of toxicity or a particularly severe reaction to the injection.  However, every one of the patients were found to have signs of inflammation at the injection site.  Observed side effects included fever in 2% of patients, chills in 10%, pain in 6%, fatigue in 2%, nausea in 12%, and vomiting in 2%.  Interestingly, when separated by dose, the low dose group had the highest frequency of such adverse events at 45% of patients, followed by the intermediate group (41%), and then the high dose group with only 10%.  Just looking at the number of adverse effects, the intermediate group had approximately four times more than either of the the other groups.  This pattern could be partially explained by a sort of culmination effect—the intermediate group received more injections and was followed over a longer period of time.

Patients that tested positive for DTH or were found to have GV1001-specific T cells in their assayed blood samples were considered immune responders.  The intermediate dose group showed the most promising results with the highest proportion of immune responders—75% of evaluable patients in that group (Figure 1A).  This group also developed immune responses faster, stronger, and more often than either of the other dose groups.
Figure 1. Type and percentage of immune responders in patients vaccinated with low, intermediate, and high dose GV1001 (A) and kinetics of immune responses in the three dose groups, as measured by DTH response (B). Bars show accumulated responses in each group
Although patient survival was not the main focus of this study, the research participants were followed after the end of the vaccination testing period to look for a possible survival benefit of the treatment.  The intermediate treatment was found to have a significant positive effect on survival time with a median survival time of 8.6 months, compared to 4.0 months for the low dose and 5.1 months for the high dose (Figure 2A).  When the data is stratified by immune response, immune responders were found to have a median survival 4.3 months longer than non-responders (Figure 2B).
Figure 2. (A) Survival (Kaplan–Meier plot) of the evaluable patients treated with different doses of GV1001. Median survival (95% conf. int.): Low-dose group (n=8); 119 days (31–190), intermediate dose group (n=16); 260 days (133–337), and high-dose group (n=14); 153 days (106–249). Intermediate vs low dose; P=0.006, intermediate vs high dose; P=0.05 (log-rank). (B) Survival (Kaplan–Meier plot) of all immune responders (n=24) vs all non-responders (n=14) in the whole evaluable study population. Median survival (95% confidenCe interval) was; 216 days (146–323) for the immune responders and 88 days (53–190) for the non-responders. P=0.0001 (log-rank).
It is encouraging that the vaccine was found to be so safe and without major physiological side effects and the finding of increased survival time is promising.  The correlation between increased survival time and mounting of an immune response seems intuitive as patients who were non-responders would be less able to fight off or recover from any sort of infection or other diseased state.  I would be curious to know the other treatments that patients received post vaccination (if any), as the research article failed to note these details.  Without knowing more about their medical history and ongoing treatment regimen, one cannot tease out if the survival is more likely attributable to the vaccinations or something else. 

Another thought going forward:  given that GV10001 is a promiscuous epitope, it could be used in the creation of a broad spectrum cancer vaccine.  The possibility of a cancer vaccine that works on multiple types of cancer is really exciting and seems an efficient focus for researchers of cancer therapies.

S L Bernhardt, M K Gjertsen, S Trachsel, M Møller, J A Eriksen, M Meo, T Buanes, et al. (2006). Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. British Journal of Cancer. doi:10.1038/sj.bjc.6603437