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Poleszczuk J.T.,H. Lee Moffitt Cancer Center and Research Institute | Luddy K.A.,H. Lee Moffitt Cancer Center and Research Institute | Prokopiou S.,H. Lee Moffitt Cancer Center and Research Institute | Robertson-Tessi M.,H. Lee Moffitt Cancer Center and Research Institute | And 5 more authors.
Cancer Research | Year: 2016

It remains unclear how localized radiotherapy for cancer metastases can occasionally elicit a systemic antitumor effect, known as the abscopal effect, but historically, it has been speculated to reflect the generation of a host immunotherapeutic response. The ability to purposefully and reliably induce abscopal effects in metastatic tumors could meet many unmet clinical needs. Here, we describe a mathematical model that incorporates physiologic information about T-cell trafficking to estimate the distribution of focal therapy-activated T cells between metastatic lesions. We integrated a dynamic model of tumor-immune interactions with systemic T-cell trafficking patterns to simulate the development of metastases. In virtual case studies, we found that the dissemination of activated T cells among multiple metastatic sites is complex and not intuitively predictable. Furthermore, we show that not all metastatic sites participate in systemic immune surveillance equally, and therefore the success in triggering the abscopal effect depends, at least in part, on which metastatic site is selected for localized therapy. Moreover, simulations revealed that seeding new metastatic sites may accelerate the growth of the primary tumor, because T-cell responses are partially diverted to the developing metastases, but the removal of the primary tumor can also favor the rapid growth of preexisting metastatic lesions. Collectively, our work provides the framework to prospectively identify anatomically defined focal therapy targets that are most likely to trigger an immune-mediated abscopal response and therefore may inform personalized treatment strategies in patients with metastatic disease. © 2016 American Association for Cancer Research. Source


Shah C.,Summa Health System | Vicini F.A.,Michigan Healthcare Professionals 21st Century Oncology | Berry S.,Summa Health System | Julian T.B.,Allegheny General Hospital | And 5 more authors.
American Journal of Clinical Oncology: Cancer Clinical Trials | Year: 2015

Ductal carcinoma in situ of the breast has rapidly increased in incidence over the past several decades secondary to an increased use of screening mammography. Local treatment options for women diagnosed with ductal carcinoma in situ include mastectomy or breastconserving therapy. Although several randomized trials have confirmed a >50% reduction in the risk of local recurrence with the administration of radiation therapy (RT) compared with breast-conserving surgery alone, controversy persists regarding whether or not RT is needed in selected "low-risk" patients. Over the past two decades, two prospective single-arm studies and one randomized trial have been performed and confirm that the omission of RT after surgery is associated with higher rates of local recurrence even after selecting patients with optimal clinical and pathologic features. Importantly, these trials have failed to consistently and reproducibly identify a low-risk cohort of patients (based on clinical and pathologic features) that does not benefit from RT. As a result, adjuvant RT is still advocated in the majority of patients, even in low-risk cases. Future research is moving beyond traditional clinical and pathologic risk factors and instead focusing on approaches such as multigene assays and biomarkers with the hopes of identifying truly low-risk patients who may not require RT. However, recent studies confirm that even low-risk patients identified from multigene assays have higher rates of local recurrence with local excision alone than would be expected with the addition of RT. Copyright © 2013 Wolters Kluwer Health, Inc. Source


Marsh J.C.,Century Oncology Translational Research Consortium | Goldfarb J.,Sonoran Hematology and Oncology | Shafman T.D.,21st Century Oncology Translational Research Consortium | Diaz A.Z.,Rush University Medical Center
Cancer Control | Year: 2013

Background: Despite improvements in surgical technique, radiation therapy delivery, and options for systemic cytotoxic therapy, the median survival for patients with newly diagnosed glioblastoma multiforme remains poor at 15 months with trimodality therapy. Multiple immunologic approaches are being tested to enhance the response of these tumors to existing therapy and/or to stimulate innate immune responses. Methods: We review the existing data that support the continued development of immunologic therapy in the treatment armamentarium against glioblastoma multiforme, with a focus on clinical data documenting outcomes. Results: In phase I and phase II trials, antitumor vaccines (dendritic and formalin-fixed) have demonstrated clinical efficacy with mild toxicity, suggesting that innate immune responses can be amplified and directed against these tumors. Suicide gene therapy (gene-mediated cytotoxic therapy) using a number of viral vectors and molecular pathways has also shown efficacy in completed phase I and ongoing phase II trials. In addition, neural stem cells are being investigated as vectors in this approach. Conclusions: Although phase III data are needed before immunologic therapies can be widely implemented into clinical practice, the existing phase I and phase II data suggest that these therapies can produce meaningful and sometimes durable responses in patients with glioblastoma multiforme with mild toxicity compared with other existing therapies. Source


Shore N.D.,Urologic | Mantz C.A.,21st Century Oncology Translational Research Consortium | Dosoretz D.E.,21st Century Oncology Translational Research Consortium | McCoy C.,Dendreon | Fishman M.N.,H. Lee Moffitt Cancer Center and Research Institute
Cancer Control | Year: 2013

Background: Sipuleucel-T is an autologous cellular immunotherapy approved by the US Food and Drug Administration for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. Its mechanism of action is based on stimulation of the patient's own immune system to target prostate cancer. Peripheral blood mononuclear cells, including antigen-presenting cells and T cells, are obtained from patients via leukapheresis and treated ex vivo with PA2024, a fusion protein consisting of prostatic acid phosphatase/granulocyte-macrophage colony-stimulating factor antigen. Methods: Data relating to the potential pharmacodynamic biomarkers associated with sipuleucel-T activity are reviewed, as well as considerations for patient selection and for sequencing sipuleucel-T with other prostate cancer treatments. Possible directions for future development are also discussed, including treatment of less advanced prostate cancer populations, combination treatment, and immune modulation. Results: Data from three randomized, double-blind, placebo-controlled phase III clinical trials of sipuleucel-T in patients with metastatic castration-rresistant prostate cancer have shown improvement in overall survival vs control. Here, we review its developing role in prostate cancer therapy and future directions for development. Conclusions: There is potential to build on sipuleucel-T to further advance immunotherapy of prostate cancer. Source


Finkelstein S.E.,21st Century Oncology Translational Research Consortium TRC | Salenius S.,21st Century Oncology Translational Research Consortium | Mantz C.A.,21st Century Oncology Translational Research Consortium | Shore N.D.,Urologic | And 7 more authors.
Clinical Genitourinary Cancer | Year: 2015

Radiotherapy has conventionally been viewed as immunosuppressive, which has precluded its use in combination with immunotherapy for prostate and other cancers. However, the relationship between ionizing radiation and immune reactivity is now known to be more complex than was previously thought, and data on the use of radiotherapy and immunotherapy are accumulating. Herein, we review this topic in the light of recently available data in the prostate cancer setting. Recent research has shown no significant lymphopenia in patients undergoing radiotherapy for high-risk adenocarcinoma of the prostate. In addition, emerging evidence suggests that radiotherapy can have immunostimulatory effects, and that tumor cell death, coupled with related changes in antigen availability and inflammatory signals, can affect lymphocyte and dendritic cell activation. Initial studies have focused on combinations of tumor irradiation and immunotherapy, such as the autologous cellular immunotherapy sipuleucel-T and the monoclonal antibody ipilimumab, in metastatic castration-resistant prostate cancer. These combinations appear to have clinical promise, and further investigation of the potentially synergistic combination of radiotherapy and immunotherapy is continuing in clinical trials. © 2015 The Authors. All rights reserved. Source

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