Combined immunotherapy with Listeria monocytogenes-based PSA vaccine and radiation therapy leads to a therapeutic response in a murine model of prostate cancer

Abstract

Radiation therapy (RT) is an integral part of prostate cancer treatment across all stages and risk groups. Immunotherapy using a live, attenuated, Listeria monocytogenes-based vaccines have been shown previously to be highly efficient in stimulating anti-tumor responses to impact on the growth of established tumors in different tumor models. Here, we evaluated the combination of RT and immunotherapy using Listeria monocytogenes-based vaccine (ADXS31-142) in a mouse model of prostate cancer. Mice bearing PSA-expressing TPSA23 tumor were divided to 5 groups receiving no treatment, ADXS31-142, RT (10 Gy), control Listeria vector and combination of ADXS31-142 and RT. Tumor growth curve was generated by measuring the tumor volume biweekly. Tumor tissue, spleen, and sera were harvested from each group for IFN-γ ELISpot, intracellular cytokine assay, tetramer analysis, and immunofluorescence staining. There was a significant tumor growth delay in mice that received combined ADXS31-142 and RT treatment as compared with mice of other cohorts and this combined treatment causes complete regression of their established tumors in 60 % of the mice. ELISpot and immunohistochemistry of CD8+ cytotoxic T Lymphocytes (CTL) showed a significant increase in IFN-γ production in mice with combined treatment. Tetramer analysis showed a fourfold and a greater than 16-fold increase in PSA-specific CTLs in animals receiving ADXS31-142 alone and combination treatment, respectively. A similar increase in infiltration of CTLs was observed in the tumor tissues. Combination therapy with RT and Listeria PSA vaccine causes significant tumor regression by augmenting PSA-specific immune response and it could serve as a potential treatment regimen for prostate cancer.

Radiation therapy combined withListeria monocytogenes-based cancer vaccine synergize to enhance tumor control in the B16 melanoma model

“…To our knowledge, our report is only the second preclinical study investigating the therapeutic potential of combining RT and a Lm -based vaccine 39 . By focusing on evaluating the local tumor microenvironment, our data extend the earlier finding by Hannan et al that a similar combinatorial strategy results in additive effects on systemic immune responses 39 …”

Key role for neutrophils in radiation-induced antitumor immune responses: Potentiation with G-CSF

“…Although many studies have shown that RT induces tumorspecific immune responses (26)(27)(28)(29)46), our study demonstrates that the generation of tumor-specific CTLs (CD8 + OVA-tetramer + cells) is increased by the combination of RT and G-CSF. In addition, we demonstrated that ROS produced by G-CSF-stimulated RT-Ns are involved in the amplification of tumor-specific CTLs.…”

Listeria monocytogenes

“…17 In preclinical studies using a murine prostate tumor model, it has furthermore been shown that the combination of Lm-based PSA (prostate specific antigen) immunotherapy and radiation therapy was more effective for the treatment of established tumors than either of the 2 treatment modalities used alone, with the combinatorial treatment demonstrating a multifold increase in PSA-specific cytotoxic T lymphocytes (CTLs) as well as a significant increase in CTL infiltration of tumor tissues. 18 The immunotherapeutic efficacy of Lm-based vectors has been further improved when combined with anti-PD-1 antibodies. 19 In a metastatic model of hepatic colorectal cancer, an AH1 peptide-expressing Lm strain elicited potent cytotoxic tumorspecific CD8 + T cell responses that could cure mice of hepatic metastasis and subsequently protect from tumor re-challenge.…”