Safety and Efficacy of PF-3512676 for the Treatment of Stage IV Renal Cell Carcinoma: An Open-Label, Multicenter Phase I/II Study

Thompson, John A.; Kuzel, Timothy M.; Drucker, Beverly J.; Urba, Walter J.; Bukowski, Ronald M.

doi:10.3816/cgc.2009.n.025

Cited by 44 publications

(21 citation statements)

References 15 publications

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“…Twenty-eight patients received up to 0.36 mg/kg of subcutaneous PF-3512676 and three complete responses (CR) were reported along with six PR. Finally, 39 patients with stage IV renal cell carcinoma receiving subcutaneous PF-3512676 at doses up to 0.81 mg/kg in a phase I/II study reported two PR [54].…”

Section: Toll-like Receptor 9 (Tlr-9) Agonists In Tumor Immunotherapymentioning

confidence: 97%

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MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

Wittig¹,

Schmidt

Scheithauer³

et al. 2015

Critical Reviews in Oncology/Hematology

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The adaptive immune system has been the main focus of immunological strategies in oncology with only more recent approaches targeting innate immunity. Endosomal toll-like receptors (TLR-7, TLR-9) activate innate immune responses by signaling damage-associated molecular patterns (DAMP) from decaying tumor cells. This has led to the development of DNA-based TLR-9 agonists, which induce antitumor activity through innate and subsequent adaptive immune responses. Early clinical trials with CpG-ODN as TLR-9 agonists were associated with unfavorable tolerability and narrow clinical efficacy, leading to failure in pivotal trials. dSLIM, the active ingredient of MGN1703, is a DNA-based, radically different molecular alternative to CpG-ODN, which results in genuine antitumor immunomodulation. Preclinical and clinical studies of MGN1703 have confirmed that this TLR-9 agonist has therapeutic potential in a variety of solid tumors, while long-term treatment with high doses was very well tolerated. A pivotal trial of first-line maintenance treatment with MGN1703 in patients with metastatic colorectal cancer is underway.

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Section: Toll-like Receptor 9 (Tlr-9) Agonists In Tumor Immunotherapymentioning

confidence: 97%

“…Investigation of PF-3512676 monotherapy in a variety of cancers has shown mixed results [47,[51][52][53][54][55]. In 41 patients with chronic lymphocytic leukemia no clinical response was reported following PF-3512676 given as an intravenous (i.v.)…”

Section: Toll-like Receptor 9 (Tlr-9) Agonists In Tumor Immunotherapymentioning

confidence: 98%

MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

Wittig¹,

Schmidt

Scheithauer³

et al. 2015

Critical Reviews in Oncology/Hematology

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“…In humans, the subcutaneous (more than the intravenous) administration of CpG-7909 activates both myeloid and plasmacytoid DCs, 190 resulting in a potent systemic Th1 response that can boost anticancer immunity 191 - 193 . During the last decade, the safety and anticancer potential of CpG-7909 (as a standalone agent or in combination with chemotherapy and/or vaccination approaches) have been investigated in a large number of Phase I/II clinical trials, including studies with leukemia, 194 lymphoma, 195 - 198 basal cell carcinoma, 199 melanoma, 199 - 202 esophageal squamous cell carcinoma, 203 NSCLC, 204 - 206 renal cell carcinoma, 207 and prostate cancer patients 208 . In a peculiar approach, CpG-7909 has been tested as an adjuvant for oncological indications in combination with MPL and QS-21, a water soluble saponin extracted from the South American tree Quillaja saponaria Molina 209 .…”

Section: Tlr9 Agonistsmentioning

confidence: 99%

Trial Watch

et al. 2012

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Toll-like receptors (TLRs) are prototypic pattern recognition receptors (PRRs) best known for their ability to activate the innate immune system in response to conserved microbial components such as lipopolysaccharide and double-stranded RNA. Accumulating evidence indicates that the function of TLRs is not restricted to the elicitation of innate immune responses against invading pathogens. TLRs have indeed been shown to participate in tissue repair and injury-induced regeneration as well as in adaptive immune responses against cancer. In particular, TLR4 signaling appears to be required for the efficient processing and cross-presentation of cell-associated tumor antigens by dendritic cells, which de facto underlie optimal therapeutic responses to some anticancer drugs. Thus, TLRs constitute prominent therapeutic targets for the activation/intensification of anticancer immune responses. In line with this notion, long-used preparations such as the Coley toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and the bacillus Calmette-Guérin (BCG, an attenuated strain of Mycobacterium bovis originally developed as a vaccine against tuberculosis), both of which have been associated with consistent anticancer responses, potently activate TLR2 and TLR4 signaling. Today, besides BCG, only one TLR agonist is FDA-approved for therapeutic use in cancer patients: imiquimod. In this Trial Watch, we will briefly present the role of TLRs in innate and cognate immunity and discuss the progress of clinical studies evaluating the safety and efficacy of experimental TLR agonists as immunostimulatory agents for oncological indications.

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“…Given the well-known role of other immunotherapies, such as cytokines [75] and bevacizumab [76], in the treatment of advanced renal cell carcinoma (RCC), PF-3512676 was tested on 39 patients affected by this disease in a phase I/II single arm trial [65]. PF-3512676 was administered subcutaneously every week with cohorts of patients given 0.08, 0.12, 0.16, 0.36, 0.54 and 0.81 mg/kg up to 24 weeks.…”

Section: Clinical Evidences For Tlr-9 Agonists Antitumor Activitymentioning

confidence: 99%

Toll-Like Receptor 9 Agonists for Cancer Therapy

et al. 2014

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The immune system has acquired increasing importance as a key player in cancer maintenance and growth. Thus, modulating anti-tumor immune mediators has become an attractive strategy for cancer treatment. Toll-like receptors (TLRs) have gradually emerged as potential targets of newer immunotherapies. TLR-9 is preferentially expressed on endosome membranes of B-cells and plasmacytoid dendritic cells (pDC) and is known for its ability to stimulate specific immune reactions through the activation of inflammation-like innate responses. Several synthetic CpG oligonucleotides (ODNs) have been developed as TLR-9 agonists with the aim of enhancing cancer immune surveillance. In many preclinical models, CpG ODNs were found to suppress tumor growth and proliferation both in monotherapy and in addition to chemotherapies or target therapies. TLR-9 agonists have been also tested in several clinical trials in patients with solid tumors. These agents showed good tolerability and usually met activity endpoints in early phase trials. However, they have not yet been demonstrated to significantly impact survival, neither as single agent treatments, nor in combination with chemotherapies or cancer vaccines. Further investigations in larger prospective studies are required.

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Safety and Efficacy of PF-3512676 for the Treatment of Stage IV Renal Cell Carcinoma: An Open-Label, Multicenter Phase I/II Study

Cited by 44 publications

References 15 publications

MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside

Trial Watch

Toll-Like Receptor 9 Agonists for Cancer Therapy

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