Immunotherapy of prostate cancer using novel synthetic DNA vaccines targeting multiple tumor antigens

The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed.

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Prognostic impact of post-prostatectomy PSA slope determined with a novel, nucleic acid detection immunoassay (NADiA ProsVue) for total PSA.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.47 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 47-47 ◽

Cited By ~ 1

Author(s):

J. W. Moul ◽

O. J. Semmes ◽

R. Vessella ◽

J. E. McDermed ◽

H. Lilja

Keyword(s):

Prostate Cancer ◽

Nucleic Acid Detection ◽

Prognostic Impact ◽

Decision Threshold ◽

New Paradigm ◽

Serum Samples ◽

Pilot Studies ◽

Synthetic Dna ◽

Total Psa

47 Background: ProsVue is an investigational PSA immunoassay whose reporter antibody is labeled with a synthetic DNA sequence. RT-PCR detects the DNA signal indicating the PSA concentration. Pilot studies showed ProsVue slope (least-squares linear slope of 3 post-RP PSA values) to correctly classify prostate cancer (PC) patients (pts) with no evidence of disease (NED) and clinical progression (CP) using a 2 pg/mL/month (mo) decision threshold. In a retrospective, multicenter clinical trial, we evaluated potential prognostic value of ProsVue slope at this decision threshold. Methods: 392 PC pts having RPs 11/1991 to 8/2001 were studied. Eligibility required first post-RP PSA <100 pg/mL, full pathologic and radiographic data and 3 frozen serum samples drawn 6 weeks to 19.4 mo post-RP. Adjuvant radiotherapy (RT) and/or hormone therapy (HT) was not allowed. CP was documented by positive imaging, biopsy results or PC-related death. Efficacy of ProsVue slope as a prognostic test for NED/CP at a 2 pg/mL/month decision threshold was determined and also examined with regards to Gleason score (GS), pre-RP PSA and final pathology stage. Results: Median (range) of pre-RP PSA was 6.3 (0-60.6) ng/mL and post-RP GS was 7.0 (4-10). 73 pts received neoadjuvant HT. Pathologic stage was pT0-2 (228), pT3 (147), pT4 (17); 116 pts had positive margins and 8 had positive lymph nodes. The 3 PSA values were drawn after a median of 4.9, 8.6 and 12.8 mo and showed median values of 10.7, 23.0 and 50.7 pg/mL, respectively. Calculated sensitivity, specificity, PPV and NPV for a 2 pg/mL/mo ProsVue slope were 75.0%, 96.6%, 81.4% and 95.2%, respectively. Median follow-up (f/u) was 10.5 years. There were 40 deaths (14 from PC). Conclusions: ProsVue provides information previously unknown in post-RP pts. ProsVue slope ≤2pg/mL/mo in the first year is highly associated with NED over long-term f/u. Potential clinical utility may include predicting pts not requiring long-term oncologic f/u and predicting a need for post-RP adjuvant RT. ProsVue slope may become a new paradigm for identifying those patients at reduced risk for recurrence of prostate cancer post-RP. Further studies are planned to address these questions. [Table: see text]

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Sulforaphane treatment in men with recurrent prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.5017 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 5017-5017 ◽

Cited By ~ 1

Author(s):

Joshi J. Alumkal ◽

Rachel Slottke ◽

Motomi Mori ◽

Jacob Schwartzman ◽

Julie Nicole Graff ◽

...

Keyword(s):

Prostate Cancer ◽

Doubling Time ◽

Mononuclear Cells ◽

Prostate Cancer Risk ◽

Multiple Tumor ◽

Psa Doubling Time ◽

Psa Response ◽

Psa Recurrence ◽

Time Changes ◽

Grade One

5017 Background: Diets high in cruciferous vegetables are strongly associated with lower prostate cancer risk. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on pre-clinical evidence in multiple tumor models. Our own work demonstrates that sulforaphane inhibits HDAC function and suppresses AR signaling in prostate cancer cells (Gibbs, et al PNAS 2009). However, the anti-tumor efficacy and safety of sulforaphane in men with prostate cancer was unknown. Methods: In this single arm study, we treated patients with biochemical (PSA)-recurrence of prostate cancer with 200 µmol of sulforaphane extracts for up to 20 weeks. The primary endpoint was PSA response rate (>50% decline in PSA). Other efficacy endpoints included: maximal PSA decline and percent change in PSA from baseline to end of study. We also analyzed PSA doubling time changes using a mixed effects model. Genotyping for GSTM1 that contributes to sulforaphane metabolism, sulforaphane pharmacokinetics (PK), and pharmacodynamic (PD) measurements of HDAC inhibition in mononuclear cells (MCs) were also performed. Results: Twenty patients were enrolled, and 16/20 (80%) completed the pre-planned 20 weeks of treatment. One patient experienced a PSA decline >50%. Thirty-five percent of patients had lesser PSA declines (3% to 20%), and 15% of patients had a final PSA lower than baseline. There was a significant reduction in PSA doubling time (6 months pre-study vs. 9.4 months on-study, p=.013). Of note, testosterone levels remained non-castrate in all subjects. PK analysis demonstrated that GSTM1 null genotype correlated with longer sulforaphane T1/2 (half-life) (2.6 hours for GSTM1 null vs. 2.1 hours for GSTM1 intact, p=0.04). Sulforaphane treatment also increased histone acetylation in PD assays in MCs. Finally, no grade three adverse events were seen, and only one patient discontinued study treatment for toxicity (grade one GI discomfort). Conclusions: Treatment with 200 µmol per day of sulforaphane is feasible, safe, and inhibits HDAC function. This combined with the preliminary observation of PSA modulation, which may indicate biologic activity, provides the basis for dose escalation studies of sulforaphane in men with prostate cancer. Clinical trial information: NCT01228084.

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Induction of autophagy across multiple tumor types through irreversible HER tyrosine kinase blockade.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e13517 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e13517-e13517

Author(s):

William Rayford Gwin ◽

Leihua Liu ◽

Sumin Zhao ◽

Wenle Xia ◽

Neil Spector

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Tyrosine Kinase ◽

Tyrosine Kinases ◽

Cellular Proliferation ◽

Kinase Inhibitor ◽

Significant Inhibition ◽

Wild Type ◽

Multiple Tumor ◽

Mtorc1 Signaling

e13517 Background: Human epidermal growth factor receptor (HER) receptor tyrosine kinases play a key role in solid tumor oncogenesis. Despite broad expression of HER receptors in solid tumors, HER targeted therapies have not shown significant improvement in survival, calling into question the value of wild-type HER receptors as therapeutic targets. Here we found that an irreversible pan-HER tyrosine kinase inhibitor (TKI), neratinib, but not similar HER TKIs, induced morphologic changes in ovarian, TNBC, and prostate cancer cell lines consistent with induction of autophagy. Methods: SKOV3 (ovarian), OVCAR8 (ovarian), HBL-100 (TNBC), and LAPC4 (prostate) cancer cells were treated with lapatinib, gefitinib, CI-1033, afatinib, and neratinib (0.5mM-2.5mM). The activation state of HER2, EGFR, HER3, Akt, Erk, p70S6, 4EBP1, and Ulk1 was determined by Western blot analysis (WB) at various time points of neratinib treatment. LC3 was analyzed by immunofluorescence (IF) microscopy and WB. Analysis of proliferation, apoptosis, and cell cycle were performed using WST-1, annexin V, and PI staining, respectively. Results: Neratinib, but not similar HER TKIs, induced marked cytoplasmic vacuolization in tumors. The conversion of LC3-I to LC3-II in neratinib-treated cells was consistent with induction of autophagy. Moreover, PI3K/Akt, MAPK/Erk1/2 and mTORC1 signaling cascades were inhibited in neratinib-treated cells, and were associated with the inhibition of phospho-Ulk1, a key step in autophagy initiation. Treatment with neratinib alone resulted in G1 cell cycle arrest. Importantly, the combination of neratinib and chloroquine, an autophagy inhibitor, induced a statistically significant inhibition of cellular proliferation (p <0.01) and increased apoptosis compared to treatment with either drug alone. Conclusions: Our data suggest that more effective inhibition of wild-type HER receptors, can lead to mTORC1 inhibition, which in turn triggers autophagy. Here, autophagy appears to protect cells rather than inducing apoptosis. Consequently, targeting both HER receptors and autophagy represents an attractive therapeutic strategy to treat tumors expressing wild-type HER receptors.

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Randomized phase II study of the safety, efficacy, and immune response of GVAX pancreas (with cyclophosphamide) and CRS-207 with or without nivolumab in patients with previously treated metastatic pancreatic adenocarcinoma (STELLAR).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.tps486 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. TPS486-TPS486 ◽

Cited By ~ 3

Author(s):

Dung T. Le ◽

Todd S. Crocenzi ◽

Jennifer N. Uram ◽

Eric R. Lutz ◽

Dan Laheru ◽

...

Keyword(s):

T Cells ◽

Pancreatic Adenocarcinoma ◽

Tumor Antigens ◽

Vaccination Strategy ◽

Progression Free Survival ◽

Primary Objective ◽

Multiple Tumor ◽

Immunological Responses ◽

Gm Csf ◽

Pancreatic Cancer Cells

TPS486 Background: A heterologous prime-boost vaccination strategy using GVAX pancreas and CRS-207 is showing promise in patients with pancreatic adenocarcinoma (PDA) (Le, JCO 2015). Furthermore, blockade of the immune checkpoint programmed death-1 (PD-1) is active in some cancers. Combinatorial strategies aimed at priming tumor antigen-specific T cells while simultaneously blocking negative checkpoints may be necessary to improve outcomes in PDA. GVAX is composed of allogeneic pancreatic cancer cells modified to express GM-CSF and induces a broad response against multiple tumor antigens. GVAX is given with low-dose cyclophosphamide (CY) to inhibit regulatory T cells. CRS-207 is live-attenuated Listeria monocytogenes engineered to express the tumor-associated antigen mesothelin. CRS-207 boosts responses against mesothelin and is unique in its capacity to stimulate both innate and adaptive immunity by activating T cells and NK cells. Nivolumab is an antibody against PD-1. Methods: This is a phase 2 study comparing CY/GVAX and CRS-207 with or without nivolumab in subjects with PDA who failed only one chemotherapy regimen for metastatic disease. Subjects are randomized in a 1:1 ratio to receive either 2 doses of CY/nivolumab/GVAX and 4 doses of nivolumab/CRS-207 (Arm A) or 2 doses of CY/GVAX and 4 doses of CRS-207 (Arm B). The primary objective is to compare OS between Arms A and B. Secondary/exploratory objectives include: assessment of safety and clinical responses (tumor assessments and CA19-9 levels) and correlation of Lm- and mesothelin-specific T cell and other immunological responses with OS, progression-free survival and best overall response. Clinical trial information: NCT02243371.

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Multiple Tumor Marker Elevation in Androgen Ablation-Refractory Prostate Cancer with Long-Term Response to Metronomic Chemotherapy: A Case Report

The International Journal of Biological Markers ◽

10.5301/jbm.2010.6109 ◽

2010 ◽

Vol 25 (4) ◽

pp. 243-247 ◽

Cited By ~ 3

Author(s):

Mariangela Massaccesi ◽

Franca Forni ◽

Pasquale Spagnuolo ◽

Gabriella Macchia ◽

Samantha Mignogna ◽

...

Keyword(s):

Prostate Cancer ◽

Colon Adenocarcinoma ◽

Metronomic Chemotherapy ◽

Serum Levels ◽

Hormone Refractory Prostate Cancer ◽

Multiple Tumor ◽

Androgen Ablation ◽

Antiangiogenic Therapies ◽

Specific Tumor ◽

Hormone Refractory

Outcomes in hormone-refractory prostate cancer are very poor. The time from progression to death is only 12–19 months. We present the case of a 69-year-old man with hormone-refractory prostate cancer and bone metastases treated with metronomic chemotherapy (cyclophosphamide based). He had had a colon adenocarcinoma ten years before. The atypical features of this case were an unusually long-lasting response to metronomic chemotherapy and an increase in serum levels of some non-prostate-specific tumor markers (CEA and CA 19–9) that was not related to a relapse of colon cancer. We hypothesize a potential role of hypoxia inducing CA 19–9 and CEA expression in tumor cells, which may predict the development of progressive resistance to antiangiogenic therapies.

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