DNA Vaccine Encoding Prostatic Acid Phosphatase (PAP) Elicits Long-term T-cell Responses in Patients With Recurrent Prostate Cancer

Abstract

SummaryProstatic acid phosphatase (PAP) is a tumor antigen in prostate cancer and the target of several anti-tumor vaccines in earlier clinical trials. Ultimately, the goal of anti-tumor vaccines is to elicit a sustainable immune response, able to eradicate a tumor, or at least restrain its growth. We have investigated plasmid DNA vaccines and have previously conducted a phase 1 trial in which patients with recurrent prostate cancer were vaccinated with a DNA vaccine encoding PAP. In this study, we investigated the immunologic efficacy of subsequent booster immunizations, and conducted more detailed longitudinal immune analysis, to answer several questions aimed at guiding optimal schedules of vaccine administration for future clinical trials. We report that antigen-specific cytolytic T-cell responses were amplified after immunization in 7 of 12 human leukocyte antigen-A2-expressing individuals, and that multiple immunizations seemed necessary to elicit PAP-specific interferon-γ-secreting immune responses detectable by enzyme-linked immunosorbent spot assay. Moreover, among individuals who experienced a ≥200% increase in prostate-specific antigen doubling time, long-term PAP-specific interferon-γ-secreting T-cell responses were detectable in 6 of 8, but in only 1 of 14 individuals without an observed change in prostate-specific antigen doubling time (P=0.001). Finally, we identified that immune responses elicited could be further amplified by subsequent booster immunizations. These results suggest that future trials using this DNA vaccine, and potentially other anti-tumor DNA vaccines, could investigate ongoing schedules of administration with periodic booster immunizations. Moreover, these results suggest that DNA vaccines targeting PAP could potentially be combined in heterologous immunization strategies with other vaccines to further augment PAP-specific T-cell immunity. Despite the significant effort in developing and evaluating anti-tumor vaccines, there is little consensus as to the "best" antigens to target and the optimal means of targeting these antigens. The prioritization of anti-tumor vaccine antigens, in fact, has been the focus of recent efforts led by the National Cancer Institute. 12 Most vaccine approaches targeting individual antigens have focused on eliciting CD8 + T cells, as these are part of the adaptive arm of the immune system with direct cytolytic activity. Consequently, to specifically elicit CD8 + T cells, most approaches have used antigen-loaded antigen-presenting cellular vaccines [13][14][15] or genetic vaccines using viral vaccines or naked DNA plasmids. [3][4][5]8,10 Of these particular approaches, DNA vaccines are generally believed to be a "weaker" immunization strategy given the absence of a concurrent inflammatory antiviral response, and the low level of in-vivo transfection of antigen-presenting cells that occurs after direct administration. However, we have been particularly interested in DNA vaccines as a simpler means of antigen-specific immunization given our experience i...

Prostate Cancer Immunotherapy: Beyond Immunity to Curability

“…An alternative immunotherapeutic approach for prostate cancer-associated antigens uses cell-free DNA plasmids (24,25). Despite their relative ease of GMP production and less complex regulatory issues, so far these vaccines have been unable to induce a high frequency of NCI RECIST criteria clinical responses or strong immune responses in the clinic.…”

Development of animal models underlining mechanistic connections between prostate inflammation and cancer

“…In contrast to TRAMP mice, the castration in TRAP rats at 5 or 20 wk of age completely prevented or induced a complete involution of androgen-dependent prostate tumors in the most of transgenic rats [45,46] . Of therapeutic interest, since the prostate-specific antigen and prostate acid phosphatase (PAP) are expressed in rat prostate as observed in human prostate but not in mouse prostate, TRAP rats may constitute a good animal model to test novel vaccine strategies targeting these antigens [46,52] . For instance, it has been observed that the immunization of Lewis TRAP rats with a DNA vaccine encoding PAP triggered an autologous PAP-specific T-cell responses in transgenic rats [46] .…”

DNA Vaccines for Prostate Cancer

“…No significant adverse events were detected, and ten of 22 patients generated PAP-specific T-cell responses immediately after immunization [57]. Responses observed were Th1 type, and cytolytic T-cell responses were specifically elicited in HLA-A2-expressing subjects [58]. Approximately 1/3 of individuals were observed to have at least a 100% increase in PSA doubling time, and this was associated with the detection of long-term PAP-specific IFNγ-secreting immune responses detectable at multiple times during the follow up period (up to 1 year after immunization).…”

“…Approximately 1/3 of individuals were observed to have at least a 100% increase in PSA doubling time, and this was associated with the detection of long-term PAP-specific IFNγ-secreting immune responses detectable at multiple times during the follow up period (up to 1 year after immunization). PAP-specific CD8+ T-cell immune responses were detected at each dose level, and one patient treated at the lowest (100 μg) dose was subsequently re-immunized at this dose with evidence of immune response, making the 100 μg dose the dose chosen for further trials [58]. Given the safety, immunological efficacy, and prolongation of PSA doubling time observed in some individuals, a randomized phase II clinical trial is currently underway to evaluate the 2-year metastasis-free rate in high-risk individuals (PSA doubling time less than 12 months) in patients treated with this vaccine or GM-CSF adjuvant alone (NCT01341652).…”