A Pilot Study of Denileukin Diftitox (DD) in Combination With High-dose Interleukin-2 (IL-2) for Patients With Metastatic Renal Cell Carcinoma (RCC)

Atchison, Elizabeth A.; Eklund, John; Martone, Brenda; Wang, Lili; Gidron, Adi; MacVicar, Gary R.; Rademaker, Alfred; Goolsby, Charles L.; Marszalek, Laura; Kozlowski, James M.; Smith, Norm D.; Kuzel, Timothy M.

doi:10.1097/cji.0b013e3181e4752e

Cited by 25 publications

(12 citation statements)

References 33 publications

(27 reference statements)

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“…To date, all of these approaches are focusing on targeting CD25. The IL-2/diphtheria toxin fusion protein, denileukin diftitox (Ontak®, Eisai Inc., Woodcliff Lake, NJ, USA), has been reported to diminish Treg numbers in the circulation in some studies [90-92], although this has not been observed in all trials [93]. Various doses and schedules are being pursued, and clinical regressions have been reported in melanoma [94].…”

Section: Reviewmentioning

confidence: 99%

Rational combinations of immunotherapeutics that target discrete pathways

Spranger¹,

Gajewski²

2013

j. immunotherapy cancer

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An effective anti-tumor immune response requires the coordinated action of the innate and adaptive phases of the immune system. Critical processes include the activation of dendritic cells to present antigens, produce cytokines including type I interferons, and express multiple costimulatory ligands; induction of a productive T cell response within lymph nodes; migration of activated T cells to the tumor microenvironment in response to chemokines and homing receptor expression; and having effector T cells gain access to antigen-expressing tumor cells and maintain sufficient functionality to destroy them. However, tumors can become adept at escaping the immune response, developing multiple mechanisms to disrupt key processes. In general, tumors can be assigned into two different, major groups depending on whether the tumor there is an ‘inflamed’ or ‘non-inflamed’ tumor microenvironment. Improvements in our understanding of the interactions between the immune system and cancer have resulted in the development of various strategies to improve the immune-mediated control of tumors in both sub-groups. Categories of major immunotherapeutic intervention include methods to increase the frequency of tumor antigen-specific effector T cells in the circulation, strategies to block or uncouple a range of immune suppressive mechanisms within the tumor microenvironment, and tactics to induce de novo immune inflammation within the tumor microenvironment. The latter may be particularly important for eliciting immune recognition of non-inflamed tumor phenotypes. The premise put forth in this review is that synergistic therapeutic effects in vivo may be derived from combination therapies taken from distinct “bins” based on these mechanisms of action. Early data in both preclinical and some clinical studies provide support for this model. We also suggest that optimal application of these combinations may be aided by appropriate patient selection based on predictive biomarkers.

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Section: Reviewmentioning

confidence: 99%

Rational combinations of immunotherapeutics that target discrete pathways

Spranger¹,

Gajewski²

2013

j. immunotherapy cancer

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“…The only unusual AE was the development in a single patient of transient acantholytic dermatosis (Grover disease) concurrent with CLS, which was related to the IL-2 treatment [14]. Cardiac events (atrial fibrillation, infarction) occurred only in the study group (11 and 6 % respectively), as well as for malignant pleural effusion (6 %).…”

Section: Off-label Experiencementioning

confidence: 96%

“…Among 207 reports in the FAERS database, the most frequent events were CLS (28), pain (22), pyrexia (18), nausea/vomiting (17/18), hypotension (16), and dyspnea (14), and 3 cases of CRS.…”

Section: Postmarketing Surveillancementioning

confidence: 99%

Denileukin-Diftitox

Tridente¹

2013

Adverse Events With Biomedicines

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“…Ontak has been used to treat CD25 + cutaneous T cell lymphoma ( 186 ). Ontak has also been tested with relatively positive results in peripheral T-cell lymphoma, metastatic renal cell carcinoma, and unresectable stage IV melanoma ( 187 – 189 ). Other studies of Ontak administration to melanoma patients, together with a DC vaccine reported no peripheral Treg depletion; yet, this result may be due to the use of a very low dose ( 190 ).…”

Section: Targeting Tregs As a Cure Research Strategymentioning

confidence: 99%

Regulatory T Cells As Potential Targets for HIV Cure Research

et al. 2018

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T regulatory cells (Tregs) are a key component of the immune system, which maintain a delicate balance between overactive responses and immunosuppression. As such, Treg deficiencies are linked to autoimmune disorders and alter the immune control of pathogens. In HIV infection, Tregs play major roles, both beneficial and detrimental. They regulate the immune system such that inflammation and spread of virus through activated T cells is suppressed. However, suppression of immune activation also limits viral clearance and promotes reservoir formation. Tregs can be directly targeted by HIV, thereby harboring a fraction of the viral reservoir. The vital role of Tregs in the pathogenesis and control of HIV makes them a subject of interest for manipulation in the search of an HIV cure. Here, we discuss the origin and generation, homeostasis, and functions of Tregs, particularly their roles and effects in HIV infection. We also present various Treg manipulation strategies, including Treg depletion techniques and interventions that alter Treg function, which may be used in different cure strategies, to simultaneously boost HIV-specific immune responses and induce reactivation of the latent virus.

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A Pilot Study of Denileukin Diftitox (DD) in Combination With High-dose Interleukin-2 (IL-2) for Patients With Metastatic Renal Cell Carcinoma (RCC)

Cited by 25 publications

References 33 publications

Rational combinations of immunotherapeutics that target discrete pathways

Rational combinations of immunotherapeutics that target discrete pathways

Denileukin-Diftitox

Regulatory T Cells As Potential Targets for HIV Cure Research

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