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Aldesleukin

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Marc S. Ernstoff – One of the best experts on this subject based on the ideXlab platform.

  • Safety and activity of hydroxychloroquine and Aldesleukin in metastatic renal cell carcinoma: A cytokine working group phase II study.
    Journal of Clinical Oncology, 2018
    Co-Authors: Leonard Joseph Appleman, Jodi K. Maranchie, Theodore F. Logan, Daniel P. Normolle, Marc S. Ernstoff, Rahul A. Parikh, David F. Mcdermott, Paul Monk, Thomas Olencki, David M. Friedland
    Abstract:

    4573Background: Aldesleukin (recombinant human interleukin-2, IL-2) has been an FDA-approved treatment for mRCC since 1992 with a 5-10% rate of durable complete response. Hydroxychloroquine (HCQ) i…

  • Targeting autophagy and immunotherapy with hydroxychloroquine and interleukin 2 in patients with metastatic renal cell carcinoma (mRCC): A Cytokine Working Group study.
    Journal of Clinical Oncology, 2018
    Co-Authors: Leonard Joseph Appleman, Theodore F. Logan, Daniel P. Normolle, Marc S. Ernstoff, Rahul A. Parikh, David F. Mcdermott, Paul Monk, Thomas Olencki, David M. Friedland, Jodi K. Maranchie
    Abstract:

    106Background: We performed a Phase II study of the combination of the autophagy inhibitor, hydroxychloroquine (HCQ), along with high dose IL-2 in patients with advanced renal cancer. 31 patients were entered on this Cytokine Working Group Study conducted at six member institutions;NCT01550367. This combination in murine models was associated with diminished toxicity and increased efficacy, and, in preliminary studies, diminished high mobility group box 1 (HMGB1) protein, consistent with its established role in serving as a Damage Associated Molecular Pattern (DAMP) molecule and inducer of autophagy. Methods: The Study Design involved initiating oral Hydroxychloroquine 300 mg P.O bid. Aldesleukin (600,000 IU/kg) was administered q8hrs in courses consisting of two cycles separated by 7-14 days and constituting a single course. For patients with stable or responsive disease, additional courses were administered every approximately 85-90 days. Serum, plasma, Paxgene tubes, and peripheral blood mononuclear ce…

  • Safety and preliminary activity of hydroxychloroquine and Aldesleukin in metastatic renal cell carcinoma (mRCC): A cytokine working group study.
    Journal of Clinical Oncology, 2017
    Co-Authors: Leonard Joseph Appleman, Theodore F. Logan, Daniel P. Normolle, Marc S. Ernstoff, Rahul A. Parikh, David F. Mcdermott, Paul Monk, Thomas Olencki, David M. Friedland, Jodi K. Maranchie
    Abstract:

    440Background: Aldesleukin (recombinant human interleukin-2) has been an FDA-approved treatment for mRCC since 1992, based on a 5-10% rate of durable complete remissions. Autophagy is a protective mechanism that enables cells to survive the metabolic stress of cancer therapy. Hydroxychloroquine (HCQ) inhibits cellular autophagy and has shown synergy with interleukin-2 in animal tumor models. We hypothesized that this combination would be tolerable and active in patients with mRCC. Methods: The Cytokine Working Group initiated a study of high-dose Aldesleukin in combination with oral HCQ for patients with mRCC. Subjects receive up to 6 cycles of aldeskleukin, 600,000 International Units per kg, on a standard schedule. HCQ is administered orally starting 2 weeks prior to the first dose of Aldesleukin and continuing up to one year. The initial HCQ dose was 600 mg daily, with a planned dose escalation to 1200 mg daily after safety was demonstrated in five subjects. Subjects were monitored for safety and toler…

David F. Mcdermott – One of the best experts on this subject based on the ideXlab platform.

  • Safety and activity of hydroxychloroquine and Aldesleukin in metastatic renal cell carcinoma: A cytokine working group phase II study.
    Journal of Clinical Oncology, 2018
    Co-Authors: Leonard Joseph Appleman, Jodi K. Maranchie, Theodore F. Logan, Daniel P. Normolle, Marc S. Ernstoff, Rahul A. Parikh, David F. Mcdermott, Paul Monk, Thomas Olencki, David M. Friedland
    Abstract:

    4573Background: Aldesleukin (recombinant human interleukin-2, IL-2) has been an FDA-approved treatment for mRCC since 1992 with a 5-10% rate of durable complete response. Hydroxychloroquine (HCQ) i…

  • Targeting autophagy and immunotherapy with hydroxychloroquine and interleukin 2 in patients with metastatic renal cell carcinoma (mRCC): A Cytokine Working Group study.
    Journal of Clinical Oncology, 2018
    Co-Authors: Leonard Joseph Appleman, Theodore F. Logan, Daniel P. Normolle, Marc S. Ernstoff, Rahul A. Parikh, David F. Mcdermott, Paul Monk, Thomas Olencki, David M. Friedland, Jodi K. Maranchie
    Abstract:

    106Background: We performed a Phase II study of the combination of the autophagy inhibitor, hydroxychloroquine (HCQ), along with high dose IL-2 in patients with advanced renal cancer. 31 patients were entered on this Cytokine Working Group Study conducted at six member institutions;NCT01550367. This combination in murine models was associated with diminished toxicity and increased efficacy, and, in preliminary studies, diminished high mobility group box 1 (HMGB1) protein, consistent with its established role in serving as a Damage Associated Molecular Pattern (DAMP) molecule and inducer of autophagy. Methods: The Study Design involved initiating oral Hydroxychloroquine 300 mg P.O bid. Aldesleukin (600,000 IU/kg) was administered q8hrs in courses consisting of two cycles separated by 7-14 days and constituting a single course. For patients with stable or responsive disease, additional courses were administered every approximately 85-90 days. Serum, plasma, Paxgene tubes, and peripheral blood mononuclear ce…

  • Safety and preliminary activity of hydroxychloroquine and Aldesleukin in metastatic renal cell carcinoma (mRCC): A cytokine working group study.
    Journal of Clinical Oncology, 2017
    Co-Authors: Leonard Joseph Appleman, Theodore F. Logan, Daniel P. Normolle, Marc S. Ernstoff, Rahul A. Parikh, David F. Mcdermott, Paul Monk, Thomas Olencki, David M. Friedland, Jodi K. Maranchie
    Abstract:

    440Background: Aldesleukin (recombinant human interleukin-2) has been an FDA-approved treatment for mRCC since 1992, based on a 5-10% rate of durable complete remissions. Autophagy is a protective mechanism that enables cells to survive the metabolic stress of cancer therapy. Hydroxychloroquine (HCQ) inhibits cellular autophagy and has shown synergy with interleukin-2 in animal tumor models. We hypothesized that this combination would be tolerable and active in patients with mRCC. Methods: The Cytokine Working Group initiated a study of high-dose Aldesleukin in combination with oral HCQ for patients with mRCC. Subjects receive up to 6 cycles of aldeskleukin, 600,000 International Units per kg, on a standard schedule. HCQ is administered orally starting 2 weeks prior to the first dose of Aldesleukin and continuing up to one year. The initial HCQ dose was 600 mg daily, with a planned dose escalation to 1200 mg daily after safety was demonstrated in five subjects. Subjects were monitored for safety and toler…

Michael B. Atkins – One of the best experts on this subject based on the ideXlab platform.

  • High dose interleukin-2 (Aldesleukin) – expert consensus on best management practices-2014
    Journal for immunotherapy of cancer, 2014
    Co-Authors: Janice P. Dutcher, Douglas J. Schwartzentruber, Howard L. Kaufman, Sanjiv S. Agarwala, Ahmad A. Tarhini, James N. Lowder, Michael B. Atkins
    Abstract:

    Interleukin-2 (IL-2) was historically one of the few treatments for adults with stage IV solid tumors that could produce complete responses (CRs) that were often durable for decades without further therapy. The majority of complete responders with metastatic renal cell carcinoma (mRCC) and metastatic melanoma (mM) could probably be classified as “cures”. Recent publications have suggested improved efficacy, perhaps due to improved patient selection based on a better understanding of clinical features predicting outcomes. Guidelines for clinical management were established from experience at the National Cancer Institute (NCI) and an affiliation of institutions known as the Cytokine Working Group (CWG), who were among the first to utilize HD IL-2 treatment outside of the NCI. As new centers have opened, further management variations have emerged based upon center-specific experience, to optimize administration of IL-2 and provide high quality care for patients at each individual site. Twenty years of evolution in differing environments has led to a plethora of clinical experience and effective management approaches. The goal of this review is to summarize the spectrum of HD IL-2 treatment approaches, describing various effective strategies that incorporate newer adjunctive treatments for managing the side effects of IL-2 in patients with mRCC and mM. The goal for IL-2 therapy is typically to administer the maximum number of doses of IL-2 without putting the patient at unacceptable risk for severe, irreversible toxicity. This review is based upon a consensus meeting and includes guidelines on pre-treatment screening, criteria for administration and withholding doses, and defines consensus criteria for safe administration and toxicity management. The somewhat heterogeneous best practices of 2014 will be compared and contrasted with the guidelines provided in 2001 and the package inserts from 1992 and 1998.

  • The high-dose Aldesleukin (HD IL-2) “SELECT” trial in patients with metastatic renal cell carcinoma (mRCC).
    Journal of Clinical Oncology, 2010
    Co-Authors: David F. Mcdermott, Janice P. Dutcher, Musie Ghebremichael, Sabina Signoretti, K. Margolin, J. Clark, J. A. Sosman, T. Logan, Robert A. Figlin, Michael B. Atkins
    Abstract:

    4514 Background: HD IL-2 received FDA approval for mRCC in 1992, producing a 14% major response (CR + PR) rate and durable remissions in phase II trials. The Cytokine Working Group conducted the present trial to identify patients (pts) likely to respond to treatment in order to improve the therapeutic index of HD IL-2. Methods: In this multicenter, prospective study pts with histologically confirmed RCC that was metastatic or unresectable, measurable disease, age ≥ 18 years, ECOG PS 0-1 and adequate organ function received HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 (maximum 28 doses) every 12 weeks. The primary endpoint of the study was to determine the major response rate (RR) of pts with “favorable” predictive features. All pts were consented to provide archived tumor tissue that would be used for pathology risk classification, carbonic anhydrase IX (CAIX) staining and in creation of a tissue microarray. Results: One hundred twenty eligible pts enrolled betwe…

  • Cytokine Working Group Study of Lymphodepleting Chemotherapy, Interleukin-2, and Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Metastatic Melanoma: Clinical Outcomes and Peripheral-Blood Cell Recovery
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2010
    Co-Authors: Krishna S. Gunturu, David F. Mcdermott, Kim Margolin, Michael B. Atkins, Kenneth R. Meehan, Todd A. Mackenzie, Todd S. Crocenzi, Edward J. Usherwood, Nancy A. Crosby, Mary Jo Turk
    Abstract:

    Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m(2), day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 microg/m(2)/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8(+) cells was observed in one of four HLA-A2-positive patients. Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose Aldesleukin alone.