A Viral Vaccine Encoding Prostate-Specific Antigen Induces Antigen Spreading to a Common Set of Self-Proteins in Prostate Cancer Patients

Trev & Joyce Deeley Research Centre, BC Cancer Agency-Vancouver Island Centre, 2410 Lee Avenue, Victoria, British Columbia, Canada.
Clinical Cancer Research (Impact Factor: 8.72). 08/2010; 16(15):4046-56. DOI: 10.1158/1078-0432.CCR-10-0948
Source: PubMed


We previously reported a randomized phase II clinical trial combining a poxvirus-based vaccine encoding prostate-specific antigen (PSA) with radiotherapy in patients with localized prostate cancer. Here, we investigate whether vaccination against PSA induced immune responses to additional tumor-associated antigens and how this influenced clinical outcome.
Pretreatment and posttreatment serum samples from patients treated with vaccine + external beam radiation therapy (EBRT) versus EBRT alone were evaluated by Western blot and serologic screening of a prostate cancer cDNA expression library (SEREX) to assess the development of treatment-associated autoantibody responses.
Western blotting revealed treatment-associated autoantibody responses in 15 of 33 (45.5%) patients treated with vaccine + EBRT versus 1 of 8 (12.5%) treated with EBRT alone. SEREX screening identified 18 antigens, which were assembled on an antigen array with 16 previously identified antigens. Antigen array screening revealed that 7 of 33 patients (21.2%) treated with vaccine + EBRT showed a vaccine-associated autoantibody response to four ubiquitously expressed self-antigens: DIRC2, NDUFS1, MRFAP1, and MATN2. These responses were not seen in patients treated with EBRT alone, or other control groups. Patients with autoantibody responses to this panel of antigens had a trend toward decreased biochemical-free survival.
Vaccine + EBRT induced antigen spreading in a large proportion of patients. A subset of patients developed autoantibodies to a panel of four self-antigens and showed a trend toward inferior outcomes. Thus, cancer vaccines directed against tumor-specific antigens can trigger autoantibody responses to self-proteins, which may influence the efficacy of vaccination.

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Available from: Kwong-Yok Tsang, Jan 29, 2014
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    • "They could show that vaccination against PSA, combined with external beam radiation therapy, induced immune responses to additional tumor-associated antigens. The epitope spreading was observed in a large number of patients treated with vaccine and radiation [20]. Similar results were obtained by Gully and colleagues in a phase II clinical trial. "
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    ABSTRACT: The eradication of large, established tumors by active immunotherapy is a major challenge because of the numerous cancer evasion mechanisms that exist. This study aimed to establish a novel combination therapy consisting of messenger RNA (mRNA)-based cancer vaccines and radiation, which would facilitate the effective treatment of established tumors with aggressive growth kinetics. The combination of a tumor-specific mRNA-based vaccination with radiation was tested in two syngeneic tumor models, a highly immunogenic E.G7-OVA and a low immunogenic Lewis lung cancer (LLC). The molecular mechanism induced by the combination therapy was evaluated via gene expression arrays as well as flow cytometry analyses of tumor infiltrating cells. In both tumor models we demonstrated that a combination of mRNA-based immunotherapy with radiation results in a strong synergistic anti-tumor effect. This was manifested as either complete tumor eradication or delay in tumor growth. Gene expression analysis of mouse tumors revealed a variety of substantial changes at the tumor site following radiation. Genes associated with antigen presentation, infiltration of immune cells, adhesion, and activation of the innate immune system were upregulated. A combination of radiation and immunotherapy induced significant downregulation of tumor associated factors and upregulation of tumor suppressors. Moreover, combination therapy significantly increased CD4+, CD8+ and NKT cell infiltration of mouse tumors. Our data provide a scientific rationale for combining immunotherapy with radiation and provide a basis for the development of more potent anti-cancer therapies.
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    • "The potential value of this effect in prostate cancer was demonstrated in a clinical trial that combined vaccine with definitive radiation therapy in 30 patients with newly diagnosed disease. Patients treated with vaccine plus radiation had a significantly enhanced prostate cancer-specific immune response compared with those who received standard radiation alone.6061 An interim analysis of a radiation combination trial using the radioisotope samarium-153 (Sm-153) combined with PSA-TRICOM showed prolonged TTP compared to treatment with Sm-153 alone. "
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    ABSTRACT: In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleucel-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical benefit.
    Asian Journal of Andrology 01/2014; 16(3). DOI:10.4103/1008-682X.122585 · 2.60 Impact Factor
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    • "Additionally as Nesslinger states, castration alone is capable of inducing antibodies against tumor in both, animal models and in humans as a result of efficient presentation of tumor antigens obtained from apoptotic bodies. (Nesslinger et al, 2010). "
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