Telomerase reverse transcriptase ( hTERT ) represents an attractive target for cancer immunotherapy because hTERT is reactivated in most human tumors.
A Phase 1-2 clinical trial evaluated telomerase therapeutic vaccine, administered to patients with metastatic prostate cancer at Duke University Medical Center in Durham.
The results show that the vaccination protocol successfully generated telomerase-specific T-cell responses in 19 of 20 subjects.
The vaccine was well tolerated.
Peak immune responses to vaccination were remarkably high with 1 to 2 percent of circulating CD8+ T-cells, demonstrating anti-telomerase specificity.
Vaccination was associated with a significant increase in PSA doubling time and clearance of circulating tumor cells.
Immune response in the low-dose group
Twelve subjects each received three weekly injections of the vaccine.
Eleven responded with significant levels of telomerase-specific CD8+ T-cells and nine developed significant levels of telomerase-specific CD4+ T-cells.
Subjects who were vaccinated with a modified vaccine containing a lysosomal targeting sequence responded with higher frequencies and magnitudes of CD4+ telomerase-specific T-cells than those vaccinated with the unmodified vaccine.
The telomerase-specific cytotoxic T-lymphocytes (CTLs) isolated from the peripheral blood of vaccinated study subjects killed telomerase targets in vitro.
CTLs from subjects vaccinated with the modified vaccine demonstrated greater killing activity against telomerase targets than CTLs from subjects treated with the unmodified vaccine, suggesting that the improved CD4+ response augments CTL activity.
Immune response in the high-dose group
Eight subjects were treated with six weekly injections of the vaccine to determine if the magnitude of the immune response seen after three weekly injections could be further enhanced.
Six weekly vaccinations resulted in robust CD8+ T-cell responses that peaked two to four weeks after the sixth injection, reaching levels of 1 to 2 percent of circulating CD8+ T-cells exhibiting anti-telomerase specificity.
This high frequency of antigen-specific T-cell responses is comparable to those seen after vaccination for infectious diseases that result in clearance of the infection. The CD8+ telomerase-specific T-cells generated in patients immunized with the modified vaccine exhibited characteristics consistent with the development of central T-cell memory, a finding with important implications for designing an optimized schedule for boosting injections to prolong the duration of the vaccine response.
Clinical response to vaccination
Five subjects in the high-dose group were available for follow-up PSA analysis for at least two months after therapy. The median pre-treatment PSA doubling time in the high-dose group was 2.9 months. After six vaccinations, the median PSA doubling time increased to 100 months, a statistically significant change ( p = 0.04 ).
No significant change in PSA doubling time was seen in seven evaluable patients from the low-dose group.
Eighteen subjects were evaluated for the presence of circulating PSA-expressing prostate cancer cells in their blood before and after therapy.
A total of 10 patients exhibited significant levels of circulating prostate cancer cells before therapy ( 4 from the modified vaccine group and 6 from the unmodified vaccine group ).
Four out of four and five out of six of these patients, respectively, exhibited reduction or clearance of circulating prostate cancer cells after vaccination.
Implications of the data
These data show that telomerase vaccination was associated with a significant impact on PSA doubling time and a reduction or elimination of circulating tumor cells during the time that a measurable, telomerase-specific T-cell response was detectable in the patients blood.
The modified vaccine produced a central T-cell memory response which should enable recall responses to additional vaccinations.
These observations suggest that continued vaccination ( boosting ) to maintain the telomerase-specific T-cell response may enhance clinical impact.
1) Geron, 2005
2) Journal of Immunology,2005