Mayer Fishman

Moffitt Cancer Center, Tampa, Florida, United States

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Publications (37)243.49 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer patients who receive androgen deprivation therapy (ADT) often experience many physical and psychological side effects. ADT may be associated with increased risk for depression, but the relationship between ADT and depression is not fully understood. This study used a longitudinal design to assess depressive symptomatology in patients receiving ADT compared with two groups of matched controls.
    Psycho-Oncology 06/2014; · 3.51 Impact Factor
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    ABSTRACT: Functionally altered myeloid cells play an important role in immune suppression in cancer, in angiogenesis, and in tumor cells' invasion and metastases. Here, we report that inhibition of Notch signaling in hematopoietic progenitor cells (HPC), myeloid-derived suppressor cells (MDSC), and dendritic cells (DC) is directly involved in abnormal myeloid cell differentiation in cancer. Inhibition of Notch signaling was caused by the disruption of the interaction between Notch receptor and transcriptional repressor CSL, which is normally required for efficient transcription of target genes. This disruption was the result of serine phosphorylation of Notch. We demonstrated that increased activity of caseine kinase 2 (CK2) observed in HPC and in MDSC could be responsible for the phosphorylation of Notch and down-regulation of Notch signaling. Inhibition of CK2 by siRNA or by pharmacological inhibitor restored Notch signaling in myeloid cells and substantially improved their differentiation, both in vitro and in vivo. This study demonstrates a novel mechanism regulation of Notch signaling in cancer. This may suggest a new perspective for pharmacological regulation of differentiation of myeloid cells in cancer.
    Cancer Research 11/2013; · 9.28 Impact Factor
  • Mayer N Fishman
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    ABSTRACT: Therapy for metastatic kidney cancer is actively evolving, particularly in the results of registration drug trials that have led to the approval of vascular endothelial growth factor pathway drugs such as sorafenib, sunitinib, pazopanib, bevacizumab, and axitinib, with focus on patients with good- or intermediate-risk criteria and clear cell histology. Mammalian target of rapamycin (mTOR) drugs such as everolimus and temsirolimus pivotal trials emphasize experiences in the setting of prior treatment or high-risk features. Interferon and interleukin 2 also are part of the treatment algorithms. The results of pivotal trials and the underlying context for the development of a cogent, cohesive treatment plan for an individual are reviewed, touching on decision points such as nephrectomy, metastasectomy, and medical initiation and discontinuation time points. To the extent that these drug therapies are essential for achieving best outcomes for patients, these pivotal trial results and associated guidelines exist within a multidimensional, multidisciplinary context of many other disease features, comorbid features, and non-drug treatment decisions. Other dimensions include investigational targeted therapies, patient selection strategies, surgical strategies, and immunotherapies, some of which are in active development. Clinicians should work toward the best use of drug sequencing and selection strategies based on core data derived from prospective randomized trials. To address individual patient needs, they should also recognize and emphasize individualized goals, to the extent that these are different from issues that were directly addressed in the trials.
    Cancer control: journal of the Moffitt Cancer Center 07/2013; 20(3):222-32. · 3.59 Impact Factor
  • International Symposium on Supportive Care in Cancer, Berlin, Germany; 06/2013
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    ABSTRACT: Two major populations of myeloid-derived suppressor cells (MDSCs), monocytic MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs) regulate immune responses in cancer and other pathologic conditions. Under physiologic conditions, Ly6C(hi)Ly6G(-) inflammatory monocytes, which are the normal counterpart of M-MDSCs, differentiate into macrophages and dendritic cells. PMN-MDSCs are the predominant group of MDSCs that accumulates in cancer. Here we show that a large proportion of M-MDSCs in tumor-bearing mice acquired phenotypic, morphological and functional features of PMN-MDSCs. Acquisition of this phenotype, but not the functional attributes of PMN-MDSCs, was mediated by transcriptional silencing of the retinoblastoma gene through epigenetic modifications mediated by histone deacetylase 2 (HDAC-2). These data demonstrate a new regulatory mechanism of myeloid cells in cancer.
    Nature Immunology 01/2013; · 26.20 Impact Factor
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    ABSTRACT: 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. 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. 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. There is potential to build on sipuleucel-T to further advance immunotherapy of prostate cancer.
    Cancer control: journal of the Moffitt Cancer Center 01/2013; 20(1):7-16. · 3.59 Impact Factor
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    ABSTRACT: BACKGROUND: Research has shown that self-directed stress management training improves mental well-being in patients undergoing chemotherapy. The present study extends this work by evaluating separate and combined effects of stress management training and home-based exercise. METHOD: Following assessment of mental and physical well-being, depression, anxiety, exercise, and stress reduction activity before chemotherapy started, patients were randomized to stress management training (SM), exercise (EX), combined stress management and exercise (SMEX), or usual care only (UCO). Outcomes were reassessed 6 and 12 weeks after chemotherapy started. Significance testing of group-by-time interactions in 286 patients who completed all assessments was used to evaluate intervention efficacy. RESULTS: Interaction effects for mental and physical well-being scores were not significant. Depression scores yielded a linear interaction comparing UCO and SMEX (p = 0.019), with decreases in SMEX but not UCO. Anxiety scores yielded a quadratic interaction comparing UCO and SMEX (p = 0.049), with trends for changes in SMEX but not UCO. Additional analyses yielded quadratic interactions for exercise activity comparing UCO and SMEX (p = 0.022), with positive changes in SMEX but not UCO, and for stress management activity comparing UCO and SM (p < 0.001) and UCO and SMEX (p = 0.013), with positive changes in SM and SMEX but not UCO. CONCLUSION: Only the combined intervention yielded effects on quality of life outcomes, and these were limited to anxiety and depression. These findings are consistent with evidence that only the combined intervention yielded increases in both exercise and stress management activity. Future research should investigate ways to augment this intervention to enhance its benefits. Copyright © 2012 John Wiley & Sons, Ltd.
    Psycho-Oncology 06/2012; · 3.51 Impact Factor
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    ABSTRACT: Local radiotherapy plus intratumoral syngeneic dendritic cell injection can mediate apoptosis/cell death and immunological tumor eradication in murine models. A novel method of coordinated intraprostatic, autologous dendritic cell injection together with radiation therapy was prospectively evaluated in five HLA-A2(+) subjects with high-risk, localized prostate cancer, using androgen suppression, 45 Gy external beam radiation therapy in 25 fractions over 5 weeks, dendritic cell injections after fractions 5, 15 and 25 and then interstitial radioactive seed placement. Serial prostate biopsies before and during treatment showed increased apoptotic cells and parenchymal distribution of CD8(+) cells. CD8(+) T-cell responses to test peptides were assessed using an enzyme-linked immunosorbent spot IFN-γ production assay, demonstrating some prostate cancer-specific protein-derived peptides associated with increased titer. In conclusion, the technique was feasible and well-tolerated and specific immune responses were observable. Future trials could further test the utility of this approach and improve on temporal coordination of intratumoral dendritic cell introduction with particular timelines of therapy-induced apoptosis.
    Immunotherapy 04/2012; 4(4):373-82. · 2.39 Impact Factor
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    ABSTRACT: Soft tissue sarcomas are rare neoplasms, with approximately 9000 new cases in the USA every year. Unfortunately, during the past two decades, there has been little progress in the treatment of metastatic soft tissue sarcomas beyond the standard approaches of surgery, chemotherapy and radiation. Immunotherapy is a modality complementary to conventional therapy. It is appealing because functional antitumor activity could affect both local-regional and systemic disease, and act over a prolonged period of time. In this report, we review immunotherapeutic investigative strategies that are being developed, including several tumor vaccine, antigen vaccine and dendritic cell vaccine strategies.
    Immunotherapy 03/2012; 4(3):283-90. · 2.39 Impact Factor
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    Steven E Finkelstein, Mayer Fishman
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    ABSTRACT: Preclinical work in murine models suggests that local radiotherapy plus intratumoral syngeneic dendritic cells (DC) injection can mediate immunologic tumor eradication. Radiotherapy affects the immune response to cancer, besides the direct impact on the tumor cells, and other ways to coordinate immune modulation with radiotherapy have been explored. We review here the potential for immune-mediated anticancer activity of radiation on tumors. This can be mediated by differential antigen acquisition and presentation by DC, through changes of lymphocytes' activation, and changes of tumor susceptibility to immune clearance. Recent work has implemented the combination of external beam radiation therapy (EBRT) with intratumoral injection of DC. This included a pilot study of coordinated intraprostatic, autologous DC injection together with radiation therapy with five HLA-A2(+) subjects with high-risk, localized prostate cancer; the protocol used androgen suppression, EBRT (25 fractions, 45 Gy), DC injections after fractions 5, 15, and 25, and then interstitial radioactive implant. Another was a phase II trial using neo-adjuvant apoptosis-inducing EBRT plus intra-tumoral DC in soft tissue sarcoma, to test if this would increase immune activity toward soft tissue sarcoma associated antigens. In the future, radiation therapy approaches designed to optimize immune stimulation at the level of DC, lymphocytes, tumor and stroma effects could be evaluated specifically in clinical trials.
    Frontiers in Oncology 01/2012; 2:169.
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    ABSTRACT: ALT-801 is a bifunctional fusion protein comprising interleukin-2 (IL-2) linked to a soluble, single-chain T-cell receptor domain that recognizes a peptide epitope (aa264-272) of the human p53 antigen displayed on cancer cells in the context of HLA-A*0201 (p53+/HLA-A*0201). We evaluated the safety, pharmacokinetics, and pharmacodynamics of ALT-801 in p53+/HLA-A*0201 patients with metastatic malignancies. p53+/HLA-A*0201 patients were treated with ALT-801 on a schedule of four daily 15-minute intravenous infusions, then 10 days rest and four more daily infusions. Cohorts of patients were treated at 0.015, 0.040, and 0.080 mg/kg/dose. Four, 16, and 6 patients were treated at the 0.015, 0.04, and 0.08 mg/kg cohorts, respectively. Two dose-limiting toxicities (a grade 4 transient thrombocytopenia and a myocardial infarction) in the 0.08 mg/kg cohort established the maximum tolerated dose (MTD) at 0.04 mg/kg. Patients treated at the MTD experienced toxicities similar to those associated with high-dose IL-2 but of lesser severity. The serum half-life of ALT-801 was 4 hours and ALT-801 serum recovery was as expected based on the dose administered. ALT-801 treatment induced an increase of serum IFN-γ but not TNF-α. Response assessment showed 10 subjects with stable disease at at least 11 weeks, and in one who had melanoma metastasis, there is an ongoing complete absence of identifiable disease after resection of radiographically identified lesions. This first-in-man study defines an ALT-801 regimen that can be administered safely and is associated with immunologic changes of potential antitumor relevance.
    Clinical Cancer Research 12/2011; 17(24):7765-75. · 7.84 Impact Factor
  • Shilpa Gupta, Mayer Fishman
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    ABSTRACT: INTRODUCTION: Targets for drug development for the treatment of kidney cancer (renal cell carcinoma; RCC) include vascular endothelial growth factor (VEGF) and its receptors and mammalian target of rapamycin. Currently available oral multitargeted VEGF tyrosine kinase inhibitors (TKIs) that have been approved by the US Food and Drug Administration for advanced RCC, include sunitinib, sorafenib and pazopanib. Off-target TKI inhibition can potentially preclude full-dose combination with other targeted and chemotherapeutic agents. There is a need to develop more potent and selective targeted agents for RCC therapy, which are more effective and have minimal off-target effects. AREAS COVERED: This drug evaluation review addresses the ongoing development for the treatment of RCC with tivozanib: a potent, selective and long-half-life VEGF TKI. The testing for clinical efficacy alone or in combination with other therapies for RCC and for other tumor types, and the clinical and market relevance of introducing another RCC therapy are discussed. EXPERT OPINION: Tivozanib is distinguished by its high potency, selectivity, long-half-life and its potential to be effectively combined with other agents in RCC. This may offer more effective, yet well-tolerated treatment options. The relative clinical and market relevance remain to be seen, both for RCC therapy and other tumor types.
    Expert Opinion on Pharmacotherapy 12/2011; 12(18):2915-22. · 2.86 Impact Factor
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    ABSTRACT: Cancer diagnosis and treatment, particularly chemotherapy, has well-established adverse effects on individuals. Exercise has been found to confer benefits to patients, although the current evidence base is limited primarily to patients assessed during or after treatment. Although exercise has been a target of intervention efforts, its relationship to quality of life in patients about to begin chemotherapy has not fully been examined. To examine the relationship of pre-treatment exercise rates to patient's quality of life. One hundred ninety-two adults diagnosed with Stages I-IV cancer and Eastern Cooperative Oncology Group performance status ≤ 2, provided data on exercise, distress (anxiety and depression), and health-related quality of life prior to their initial chemotherapy infusion. As predicted, higher rates of exercise activity were associated with lower levels of anxiety and depression, and better overall mental and physical quality of life. These relationships were independent of demographic variables (i.e., body mass index and age) also associated with quality of life in the present analyses. These findings further highlight the importance of assessing exercise before the start of chemotherapy as part of broader efforts to link patients to appropriate interventions aimed at enhancing quality of life. Findings also raise the possibility that assessing exercise rates could be useful in matching patients to the type of intervention most likely to benefit them. Future research should use prospective longitudinal designs to further explore this association.
    Journal of pain and symptom management 02/2011; 41(5):859-69. · 2.42 Impact Factor
  • Mayer Fishman
    Clinical advances in hematology & oncology: H&O 01/2011; 9(1):67-9.
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    ABSTRACT: Sipuleucel-T is an autologous cell immunotherapy for castrate-refractory prostate cancer, with US Food and Drug Administration (FDA) approval in asymptomatic or minimally symptomatic prostate cancer. In this review we address the background of prostate cancer incidence and other available therapy onto which sipuleucel-T treatment has been added, with discussion of hormone-therapy, chemotherapy, and other investigational immunotherapies. The sipuleucel-T manufacturing process, toxicity and clinical benefit are reviewed, along with an examination of the issue of clinical benefit to survival, independent of apparent changes of prostate-specific antigen (PSA) levels. Sipuleucel-T therapy is appraised from clinician, patient and immunotherapeutic perspectives, with reference to the clinical data from the pivotal trial, the mechanism of action, and the treatment process.
    OncoTargets and Therapy 01/2011; 4:79-96. · 2.07 Impact Factor
  • Estrella Carballido, Mayer Fishman
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    ABSTRACT: Prostate cancer immunotherapy officially debuted with the recent FDA approval of Sipuleucel-T. The novel trend of cancer immunotherapy relies on the identification of particular tumor-associated antigens, like prostatic acid phosphatase (PAP). Sipuleucel-T consists of autologous dendritic cells activated in vitro with recombinant fusion protein PA2024, PAP-linked to granulocyte-macrophage colony-stimulating factor. Sipuleucel-T represents a prototype for the development of cancer vaccines. Preclinical and clinical data as well as landmark studies for the existing narrow chemotherapy alternatives and early immunotherapy trials will be discussed. The pivotal trial demonstrated a 4.1-month difference of median survival, but with no effect on time to progression in asymptomatic or minimally symptomatic metastatic castrate-resistant patients. Several immunologic effects were observed in the treated population, including antibody and T cell-specific activity to P2024 and PAP. With all new therapies the extent of clinical and objective benefits versus encountered limitations should be evaluated. This review highlights the events and decisions in the process of the development of Sipuleucel-T. We discuss how this successful immunotherapy outcome challenges us to use it as a starting point for variations to or try to amplify practical anticancer progress within the antitumor vaccine paradigm.
    Current Oncology Reports 01/2011; 13(2):112-9. · 3.33 Impact Factor
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    ABSTRACT: High-dose intravenous interleukin-2 (IL-2) therapy (14 doses/course, 2 courses/cycle) for metastatic melanoma or kidney cancer induces infrequent, although major responses. In this trial, we evaluated a new schedule (dose of 600,000 IU/kg, 8 h between doses, 5 doses/course, 4 courses at weekly intervals/cycle) of high-dose IL-2, in which we inserted more planned breaks while maintaining high cumulative dose delivery, and investigated the relationship between dendritic cells (DC) and response to treatment. Target dose delivery was attained: median IL-2 cumulative dose per patient was 11.4 and 10.8 million units/kg (cycles 1 and 2, respectively). Major responses were observed in patients with kidney cancer (n=20; 3 complete and 2 partial responses) and melanoma (n=16; 1 partial response). Adverse events appeared comparable with those typically associated with high-dose IL-2. From this data set, we introduce the hypothesis-generating observation that patients who had more favorable outcomes had high pretreatment DC-to-myeloid-derived suppressor cell (MDSC) ratios, similar to the ratio observed in healthy individuals. However, even in patients with the most favorable outcome, after treatment, there were IL-2-induced changes in the DC-to-MDSC ratio, specifically increases in MDSCs. This modified IL-2 schedule is a feasible option, with a more uniform dose delivery over the treatment cycle, a similar toxicity profile, and observed complete, durable response in patients with renal cancer. Pretreatment assessment of DC phenotypic or maturational status may be a starting point to predicting response to high-dose IL-2 cytokine immunotherapy in patients with melanoma and kidney cancer.
    Journal of immunotherapy (Hagerstown, Md.: 1997) 10/2010; 33(8):817-27. · 3.20 Impact Factor
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    Philippe E Spiess, Mayer N Fishman
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    ABSTRACT: Renal cell carcinoma (RCC) can be considered as two distinct entities: localized and metastatic disease. We conducted a review of the scientific literature published within the past decade pertaining to cytoreductive nephrectomy for metastatic RCC. Retrospective data and historical prospective series have demonstrated the survival benefit of debulking nephrectomy in well-selected RCC patients. New medical therapies, including vascular endothelial growth factor and mTOR pathway blocking drugs, are active biological agents, with survival improvement and potential regression of metastatic and primary tumors. Our current therapeutic challenge is the optimal integration of multimodal therapy consisting of systemic therapy and surgery including cytoreductive nephrectomy, debulking, and metastasectomy. Empiric data to guide this decision are limited. The decision concerning whether medical or surgical therapy should be the primary treatment approach selected must be made on an individual basis, taking into account patient performance status, clinical parameters, and physician expertise and recommendations, thus making each case a unique therapeutic challenge.
    Cancer control: journal of the Moffitt Cancer Center 10/2010; 17(4):269-78. · 3.59 Impact Factor
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    ABSTRACT: Dendritic cells (DCs), a type of professional antigen-presenting cells, are responsible for initiation and maintenance of immune responses. Here we report that a substantial proportion of DCs in tumor-bearing mice and people with cancer have high amounts of triglycerides as compared with DCs from tumor-free mice and healthy individuals. In our studies, lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to upregulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of major histocompatibility complex and co-stimulatory molecules. However, lipid-laden DCs had a reduced capacity to process antigens. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs.
    Nature medicine 08/2010; 16(8):880-6. · 27.14 Impact Factor
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    ABSTRACT: Myeloid-derived suppressor cells (MDSC) are one of the major factors responsible for immune suppression in cancer. Therefore, it would be important to identify effective therapeutic means to modulate these cells. We evaluated the effect of the synthetic triterpenoid C-28 methyl ester of 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid (CDDO-Me; bardoxolone methyl) in MC38 colon carcinoma, Lewis lung carcinoma, and EL-4 thymoma mouse tumor models, as well as blood samples from patients with renal cell cancer and soft tissue sarcoma. Samples were also analyzed from patients with pancreatic cancer treated with CDDO-Me in combination with gemcitabine. CDDO-Me at concentrations of 25 to 100 nmol/L completely abrogated immune suppressive activity of MDSC in vitro. CDDO-Me reduced reactive oxygen species in MDSCs but did not affect their viability or the levels of nitric oxide and arginase. Treatment of tumor-bearing mice with CDDO-Me did not affect the proportion of MDSCs in the spleens but eliminated their suppressive activity. This effect was independent of antitumor activity. CDDO-Me treatment decreased tumor growth in mice. Experiments with severe combined immunodeficient-beige mice indicated that this effect was largely mediated by the immune system. CDDO-Me substantially enhanced the antitumor effect of a cancer vaccines. Treatment of pancreatic cancer patients with CDDO-Me did not affect the number of MDSCs in peripheral blood but significantly improved the immune response. CDDO-Me abrogated the immune suppressive effect of MDSCs and improved immune responses in tumor-bearing mice and cancer patients. It may represent an attractive therapeutic option by enhancing the effect of cancer immunotherapy.
    Clinical Cancer Research 03/2010; 16(6):1812-23. · 7.84 Impact Factor

Publication Stats

664 Citations
243.49 Total Impact Points

Institutions

  • 2004–2014
    • Moffitt Cancer Center
      • • Department of Health Outcomes and Behavior (HOB)
      • • Department of Immunology
      Tampa, Florida, United States
  • 2012
    • 21st Century Oncology
      Redding, California, United States
  • 2011
    • Georgetown University
      Washington, Washington, D.C., United States
  • 2001–2008
    • University of South Florida
      Tampa, Florida, United States