A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study

Monk, Bradley J.; Brady, Mark F.; Aghajanian, Carol; Lankes, Heather A.; Rizack, Tina; Leach, Joseph W.; Fowler, Jeffrey; Higgins, Robert V.; Hanjani, Parviz; Morgan, Mark A.; Edwards, Robert P.; Bradley, William H.; Kolevska, Tatjana; Foukas, Periklis; Swisher, E.; Anderson, Karen S.; Gottardo, Raphaël; Bryan, James Kyle; Newkirk, Mona; Manjarrez, Kristi L.; Mannel, Robert S.; Hershberg, Robert M.; Coukos, George

doi:10.1093/annonc/mdx049

Cited by 72 publications

(51 citation statements)

References 26 publications

(31 reference statements)

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“…However, consistent with literature reports, we have found motolimod has weak activity on TLR7 in addition to its agonistic activity over TLR8 indicating it is in fact 5 a TLR7/8 dual agonist though it predominantly targets TLR8 (35). Motolimod is administered subcutaneously, a systemic dosing route (36,37). However, the clinical doses used for motolimod were relatively low and its efficacy appeared to be limited suggesting motolimod had a narrow therapeutic index (36,37).…”

Section: Introductionsupporting

confidence: 88%

“…Motolimod is administered subcutaneously, a systemic dosing route (36,37). However, the clinical doses used for motolimod were relatively low and its efficacy appeared to be limited suggesting motolimod had a narrow therapeutic index (36,37). Nevertheless, unlike other TLR7/8 dual agonists, motolimod can be dosed systemically suggesting its weaker activity on TLR7 relative to other TLR7/8 dual agonists might contribute to its improved tolerability.…”

Section: Introductionmentioning

confidence: 99%

“…As described above, motolimod, a known TLR8 agonist, is in fact a TLR7/8 dual agonist albeit its TLR7 activity is much weaker than its activity on TLR8 based on in vitro cell-based assays (35). Motolimod is currently in phase 1/2 clinical development for cancer indications (34,(36)(37)(38)(39)(40)(41) Therefore, there is an urgent need for a truly selective TLR8 agonist that would distinguish itself from all other TLR agonists. Through structure-based drug design, we discovered a novel, highly potent and selective small molecule TLR8 agonist with no activity on TLR7, namely DN052 for cancer indications.…”

Section: Introductionmentioning

confidence: 99%

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Development of A Novel Highly Selective TLR8 Agonist for Cancer Immunotherapy

Wang¹,

Yang²,

H³

et al. 2020

Preprint

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Toll-like receptors (TLRs) are a family of proteins that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while also involved in facilitating adaptive immune responses. Different TLRs exert distinct functions by activating varied immune cascades. Several TLRs are being pursued as cancer drug targets. We discovered a novel, highly potent and selective small molecule TLR8 agonist DN052. DN052 exhibited strong in vitro cellular activity with EC50 at 6.7 nM and was highly selective for TLR8 over other TLRs including TLR4, 7 and 9. The selectivity profile distinguished DN052 from all other TLR agonists currently in clinical development. DN052 displayed excellent in vitro ADMET and in vivo PK profiles. DN052 potently inhibited tumor growth as a single agent. Moreover, combination of DN052 with the immune checkpoint inhibitor, selected targeted therapeutics or chemotherapeutic drugs further enhanced efficacy of single agents. Mechanistically, treatment with DN052 resulted in strong induction of pro-inflammatory cytokines in ex vivo human PBMC assay and in vivo monkey study. GLP toxicity studies in rats and monkeys demonstrated favorable safety profile. This led to the advancement of DN052 into phase I clinical trials.

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Section: Introductionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of A Novel Highly Selective TLR8 Agonist for Cancer Immunotherapy

Wang¹,

Yang²,

H³

et al. 2020

Preprint

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“…A phase II randomized double‐blind, placebo‐controlled trial was performed in patients with recurrent or persistent ovarian cancer. Although motolimod in combination with PLD did not improve clinical outcomes compared to placebo, the overall survival was significantly different between the two groups .…”

Section: Tlr8mentioning

confidence: 75%

Therapeutic potential of toll‐like receptors in treatment of gynecological cancers

et al. 2019

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Toll‐like receptors (TLRs) play an important role in the innate and adaptive immune system. They are expressed in various regions of the female reproductive tract, and their regulation may be involved in the pathogenesis of gynecological lesions. There is growing evidence that ligands for several TLRs are potentially anticancer agents, some of which have already been approved by the FDA, and these compounds are now undergoing clinical evaluation. There is a rationale for using these ligands as adjuvants in the treatment or prevention of gynecological cancer. Some TLR agonists that are of potential interest in the treatment of gynecological lesions include imiquimod, motolimod, cervarix, and CpG‐oligodeoxynucleotides (ODNs). In this review, we outline the different functions of TLRs in gynecological cancer with particular emphasis on the value of TLR agonists as a potential therapeutic target in the treatment of gynecological cancer. © 2019 IUBMB Life, 71(5):549–564, 2019

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“…In a Phase II randomized, double-blind trial, 297 subjects with recurrent epithelial ovarian carcinoma were treated with PLD (for inducing immunogenic tumor cell death) in combination with either VTX-2337 or placebo for 28-day cycles until disease progression. [164]. It was shown that PLD and VTX-2337 combination did not significantly improve the PFS [4.8 versus 5.2 months in the PLD plus placebo; log rank one-sided P=0.943, HR=1.21] and OS [18.1 versus 18.9 months in PLD plus placebo; log rank one-sided P=0.923, HR=1.22] of the treated subjects.…”

Section: Bdca-1+ and Bdca-3+ Blood Dcs And Targeting Them With Tlr8 mentioning

confidence: 99%

In vivo cancer vaccination: Which dendritic cells to target and how?

Chiang¹,

Kandalaft²

2018

Cancer Treatment Reviews

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The field of cancer immunotherapy has been revolutionized with the use of immune checkpoint blockade antibodies such as anti-programmed cell death 1 protein (PD-1) and chimeric antigen receptor T cells. Significant clinical benefits are observed in different cancer types with these treatments. While considerable efforts are made in augmenting tumor-specific T cell responses with these therapies, other immunotherapies that actively stimulate endogenous anti-tumor T cells and generating long-term memory have received less attention. Given the high cost of cancer immunotherapies especially with chimeric antigen receptor T cells, not many patients will have access to such treatments. The next-generation of cancer immunotherapy could entail in vivo cancer vaccination to activate both the innate and adaptive anti-tumor responses. This could potentially be achieved via in vivo targeting of dendritic cells which are an indispensable link between the innate and adaptive immunities. Dendritic cells highly expressed toll-like receptors for recognizing and eliminating pathogens. Synthetic toll-like receptors agonists could be synthesized at a low cost and have shown promise in preclinical and clinical trials. As different subsets of human dendritic cells exist in the immune system, activation with different toll-like receptor agonists could exert profound effects on the quality and magnitude of anti-tumor T cell responses. Here, we reviewed the different subsets of human dendritic cells. Using published preclinical and clinical cancers studies available on PubMed, we discussed the use of clinically approved and emerging toll-like receptor agonists to activate dendritic cells in vivo for cancer immunotherapy. Finally, we searched www.clinicaltrials.gov and summarized the active cancer trials evaluating toll-like receptor agonists as an adjuvant.

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A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study

Cited by 72 publications

References 26 publications

Development of A Novel Highly Selective TLR8 Agonist for Cancer Immunotherapy

Development of A Novel Highly Selective TLR8 Agonist for Cancer Immunotherapy

Therapeutic potential of toll‐like receptors in treatment of gynecological cancers

In vivo cancer vaccination: Which dendritic cells to target and how?

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