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

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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 usingListeria 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.

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Acknowledgments

This work was supported in part by the NIH grants, R01EB009040, RC2 AI087612 and U19AI091175 to CG.

Conflicts of interest

Dr. Anu Wallecha, Dr. Reshma Singh, and Dr. John Rothman are employed by Advaxis Inc and own stock in that company.

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Authors and Affiliations

  1. Department of Radiation Oncology, UT Southwestern Medical Center, 5801 Forest Park Rd., Dallas, TX, 75390-9183, USA

    Raquibul Hannan

  2. Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical Centre, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Huagang Zhang, Laibin Liu, Patrice Cohen, Alan Alfieri & Chandan Guha

  3. Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, USA

    Chandan Guha

  4. Advaxis Inc., 305 College Road East, Princeton, NJ, 08540, USA

    Anu Wallecha, Reshma Singh & John Rothman

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  1. Raquibul Hannan

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Correspondence toChandan Guha.

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262_2012_1257_MOESM1_ESM.tif

Supplemental Figure 1: Tumor response in representative mice on d34 from each of the cohorts: A) PSA Vaccine, B), PSA Vaccine +RT, C)RT Alone, D) No Treatment and E) Control Vaccine. (TIFF 3668 kb)

262_2012_1257_MOESM2_ESM.tif

Supplemental Figure 2: Representative wells after subjecting the splenocytes from each cohort to ELISpot analysis. A) Non-specific stimulation with PMA, B) Negative control stimulation with BSA, and C-G stimulation with PSA, C) PSA Vaccine, D), PSA Vaccine +RT, E)RT Alone, F) No Treatment and G) Control Vaccine. (TIFF 276 kb)

262_2012_1257_MOESM3_ESM.tif

Supplemental Figure 3: FACS analysis for IFN-γ in CD8+CD3+ cells.  A) PSA Vaccine, B), PSA Vaccine +RT, C)RT Alone, D) No Treatment and E) Control Vaccine. (TIFF 3480 kb)

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Hannan, R., Zhang, H., Wallecha, A.et al. Combined immunotherapy withListeria monocytogenes-based PSA vaccine and radiation therapy leads to a therapeutic response in a murine model of prostate cancer.Cancer Immunol Immunother61, 2227–2238 (2012). https://doi.org/10.1007/s00262-012-1257-x

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