A Cytomegalovirus-based Vaccine Expressing a Single Tumor-specific CD8+ T-cell Epitope Delays Tumor Growth in a Murine Model of Prostate Cancer

Abstract

Cytomegalovirus (CMV) is a highly immunogenic virus that results in a persistent, life-long infection in the host typically with no ill-effects. Certain unique features of CMV, including its capacity to actively replicate in the presence of strong host CMV-specific immunity, may give CMV an advantage compared to other virus-based vaccine delivery platforms. In the present study, we tested the utility of mouse CMV (mCMV)-based vaccines expressing human prostate-specific antigen (PSA) for prostate cancer immunotherapy in double-transgenic mice expressing PSA and HLA-DRB1*1501 (DR2b×PSA F1). We assessed the capacity of two mCMV-based vectors to induce PSA-specific CD8 T cell responses and affect the growth of PSA-expressing Transgenic Adenocarcinoma of the Mouse Prostate tumors (TRAMP-PSA). In the absence of tumor challenge, immunization with mCMV vectors expressing either a H2-Db-restricted epitope PSA65-73 (mCMV/PSA65-73) or the full length gene for PSA (mCMV/PSAFL) induced comparable levels of CD8 T cell responses that increased (inflated) with time. Upon challenge with TRAMP-PSA tumor cells, animals immunized with mCMV/PSA65-73 had delay of tumor growth and increased PSA-specific CD8 T cell responses, whereas animals immunized with mCMV/PSAFL showed progressive tumor growth and no increase in number of splenic PSA65-73-specific T cells. The data show that a prototype CMV-based prostate cancer vaccine can induce an effective anti-tumor immune response in a “humanized” double-transgenic mouse model. The observation that mCMV/PSAFL is not effective against TRAMP-PSA is consistent with our previous findings that HLA-DRB1*1501-restricted immune responses to PSA are associated with suppression of effective CD8 T cell responses to TRAMP-PSA tumors.

Cytomegalovirus Reinfections Stimulate CD8 T-Memory Inflation

“…Given that high titer primary infection and reinfection might contribute significantly to these phenomena, strategies to reduce primary or prevent reinfection might be desirable. In addition, there is growing interest in using CMV as a vaccine vector for other diseases [37, 78–81]. Given the widespread prevalence of CMV in the population, many of these vaccines would require reinfection of naturally infected hosts.…”

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

“…CMV-based vectors have shown promising results in diverse infectious and cancer models, but the success of these vaccines is considered T cell mediated (5,55,56). Recently, it has been shown that CMV vectors encoding additional antigens also can induce protective anti-melanoma or anti-tetanus toxin antibodies (8,9).…”

Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung

“…12, 14, 15, 16, 17, 18 Similar vectors have been evaluated for therapeutic utility against cancer leading to delayed growth or rejection of tumors and even for the purpose of immunocontraception in mice. 19, 20, 21 …”