Heterologous vaccination targeting prostatic acid phosphatase (PAP) using DNA andListeriavaccines elicits superior anti-tumor immunity dependent on CD4+ T cells elicited by DNA priming

Abstract

. Sipuleucel T, an autologous cell-based vaccine targeting prostatic acid phosphatase (PAP), has demonstrated efficacy for the treatment of advanced prostate cancer. DNA vaccines encoding PAP and live attenuated vaccines have entered clinical trials for patients with prostate cancer, and have advantages in terms of eliciting predominantly Th1-biased immunity. In this study, we investigated whether the immunogenicity and anti-tumor efficacy of a DNA and vaccine, each encoding PAP, could be enhanced by using them in a heterologous prime/boost approach. . Transgenic mice expressing HLA-A2.01 and HLA-DRB1*0101 were immunized alone or with a heterologous prime/boost strategy. Splenocytes were evaluated for MHC class I and II-restricted, PAP-specific immune responses by IFNγ ELISPOTs. Anti-tumor activity to a syngeneic, PAP-expressing tumor line was evaluated.. PAP-specific cellular immunity and anti-tumor activity were elicited in mice after immunization with DNA- or listeria-based vaccines. Greater CD4+ and CD8+ responses, and anti-tumor responses, were elicited when mice were immunized first with DNA and boosted with , but not when administered in the opposite order. This was found to be dependent on CD4+ T cells elicited with DNA priming, and was not due to inflammatory signals by itself or due to B cells serving as antigen-presenting cells for DNA during priming.. Heterologous prime/boost vaccination using DNA priming with boosting may provide better anti-tumor immunity, similar to many reports evaluating DNA priming with vaccines targeting foreign microbial antigens. These findings have implications for the design of future clinical trials.

Clinical Experience and Recent Advances in the Development of Listeria-Based Tumor Immunotherapies

“…Even with the use of these first generation constructs, promising clinical responses have been reported in several cancers including cervical cancer, malignant pleural mesothelioma, and canine osteosarcoma (74). As results from clinical and preclinical studies demonstrate, improvements to therapeutic efficacy may be realized utilizing Lm-based vaccines in heterologous prime boost regimens with other vectors and by combination with synergistic therapeutic strategies such as ACT and ICI (14,53,108,110,122,123,134). However, there still remain several challenges going forward to realize the full potential of Lm-based vaccines.…”

“…Heterologous prime boost involves the administration of the same antigens using different vaccine vector platforms to generate a more robust immune response than a homologous prime boost vaccine regimen (120,121). Lm-based vaccines are particularly effective at generating robust responses when used as a booster or primer in combination with various vaccine vectors including viruses, DNA and peptides (122)(123)(124)(125). In a preclinical study that involved the use of a DNA vaccine encoding the prostate-specific antigen prostatic acid phosphatase (PAP) along with an attenuated Lm vaccine, LADD-PAP, greater antitumor efficacy was seen in the prime boost regimen as compared to the DNA vaccine only regimen or the LADD-PAP only regimen (122).…”

“…Lm-based vaccines are particularly effective at generating robust responses when used as a booster or primer in combination with various vaccine vectors including viruses, DNA and peptides (122)(123)(124)(125). In a preclinical study that involved the use of a DNA vaccine encoding the prostate-specific antigen prostatic acid phosphatase (PAP) along with an attenuated Lm vaccine, LADD-PAP, greater antitumor efficacy was seen in the prime boost regimen as compared to the DNA vaccine only regimen or the LADD-PAP only regimen (122). This heterologous vaccination schedule interestingly led to the induction of more CD4 + T cells, which may have played a role in the enhanced antitumor immune response.…”

Is There a Role for Immunotherapy in Prostate Cancer?

“…The rationale of LM vaccines relies on the stimulation of immune response avoiding the pathogenic features of this bacterium, using LM-Listeriolysin O (LLO) therapies [ 92 ]. Among these therapies, the listeria attenuated vaccine ADXS31-142 targeting PSA has shown promising results in terms of antitumor efficacy in PC preclinical murine models since previous reports regarding the combination of ADXS31-142 and anti-PD-1 agents have resulted in prolonged survival in treated mice [ 93 , 94 ]. An ongoing phase I trial is currently testing the role of ADXS31-142 as single-agent and combined with pembrolizumab in mCRPC patients (NCT02325557); preliminary results of this study have highlighted that the 14% of patients treated with single-agent vaccine and the 43% of subjects receiving combination therapy have shown a decreased PSA post-baseline [ 95 ].…”

Nanomedicine and Onco-Immunotherapy: From the Bench to Bedside to Biomarkers

“…APCs absorb genetic material and translate peptide and proteins as cancer-specific antigens, stimulating the immune response [ 107 ]. Currently, there are some DNA vaccines include mammaglobin-A for breast cancer, PAP for prostate cancer, and gp100 and gp75 DNA for melanoma [ 136 , 137 , 138 , 139 ]. Disadvantages may be the method of DNA/RNA delivery and the efficiency of absorption, which may limit transcription and antigenic presentation by APCs [ 107 ].…”