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Abstract
Background TCR gamma alternate reading frame protein (TARP) is a tumor antigen and it can be found most commonly in prostate cancer. Previously, our group investigated two types of vaccines targeting two overlapping epitopes of TARP (TARP Study, NCT00972309) and showed safety and immunogenicity in participants with stage D0 prostate cancer and HLA-A2.1 Here, we report the results of the ME-TARP Study, which administered the updated multi-epitope TARP dendritic cell (DC) vaccine to eligible TARP Study participants.
Methods Previous TARP Study participants with adequate performance and organ function were enrolled. After the consent, participants underwent with apheresis. Two million DCs pulsed with five overlapping synthetic long peptides (SLPs) and two HLA-A2 restricted peptides of TARP were administered at Weeks 3, 6, 9, 12, 15, and 24 (figure 1–2). Patients were assessed every 3 weeks during the treatment and every 12 weeks for a total of 24 months. PSA Doubling Time (PSADT) and the slope of PSADT change were assessed in patients who were not exposed to androgen deprivation therapy (ADT). Restaging scans were obtained every 12 months and personalized for patients with known metastatic lesions.
Results Among 41 TARP Study participants, 14 participants were eligible to enroll in the ME-TARP study (figure 3). The enrollment interval between the two studies was 95 (median; range 46–122) months. Thirteen participants were evaluable for safety. Six were still ADT-naive and available for PSADT slope log calculation and four of ADT-naïve patients showed no increase in the PSADT slope after the vaccination. Adverse events were mainly self-limited grade 1–2 injection site reactions in all patients. Ten of the 13 participants were the responders in the TARP study who showed a decreased PSADT slope log value at Week 24 or 48. Paired baseline and post-vaccination peripheral blood samples of the ME-TARP study showed HLA-A2 TARP tetramer responses. Five (83%) of 6 ADT-naive patients showed >1000 interferon gamma ELISpots when stimulated by TARP peptides. Interestingly, Patient 114 who previously showed the highest TARP-specific CD8 T cell perforin response (>20-fold increase) after in vitro stimulation among all participants of the TARP Study showed a negative PSA velocity in the ME-TARP study. Further immune correlatives are under way.
Conclusions Re-vaccination targeting the same TARP antigen several years after initial vaccination in HLA-A2 patients with prostate cancer was safe. Vaccine peptide-specific immune responses were detected at the time of enrollment in the subsequent study which might suggest vaccine-induced immune memory.
Acknowledgements This research has been supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH). Authors of this report appreciate the support from NIH Clinical Center and the participants of the studies. The study team appreciates significant contribution to the study data management from Ms. Nasheda Sapp and she is greatly missed.
Trial Registration NCT02362464.
Reference
Wood L, Fojo A, Roberson B. TARP vaccination is associated with slowing in PSA velocity and decreasing tumor growth rates in patients with Stage D0 prostate cancer. Oncoimmunol 2016;5(8):e1197459.
Ethics Approval The study was approved by the NIH IRB Ethics, approval number 15C0076 (ME-TARP Study) and IRB001630 (secondary research of TARP Study).
TARP peptides used in the TARP Study and the ME-TARP study. In the TART study, two HLA-A2 restricted peptides, TARP29-37EE and TARP 29-37-9V with epitope enhancement. In the ME-TARP study, five overlapping synthetic long peptides (SLPs) were added
Manufacturing of ME-TARP DC. Manufacturing of ME-TARP DC: Manufacturing of the multiepitope-TARP dendritic cell vaccine (ME-TARP DC) using peripheral blood monocytes from the patients
Study enrollment. The patients who had been enrolled in the TARP Study were reviewed for eligibility of the ME-TARP Study. Of 41 patients from the TARP Study, 14 participants enrolled in the ME-TARP Study
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