Safety, Tolerability, and Potential Clinical Activity of a Glucocorticoid-Induced TNF Receptor–Related Protein Agonist Alone or in Combination With Nivolumab for Patients With Advanced Solid Tumors

Heinhuis, Kimberley M.; Carlino, Matteo S.; Joerger, Markus; Nicola, Massimo Di; Meniawy, Tarek; Rottey, Sylvie; Moreno, Víctor; Gazzah, Anas; Delord, Jean Pierre; Paz‐Ares, Luis; Britschgi, Christian; Schilder, Russell J.; O’Byrne, Kenneth J.; Curigliano, Giuseppe; Romano, Emanuela; Patah, Poliana; Wang, Rui; Liu, Yali; Bajaj, Gaurav; Siu, Lillian L.

doi:10.1001/jamaoncol.2019.3848

Cited by 77 publications

(82 citation statements)

References 31 publications

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“…Similarly, a lack of clinical benefit was reported for a number of GITR agonistic antibodies such as TRX518 38 , AMG228 45 , BMS-986156 46 and MK-1248 47 . Thus…”

Section: Discussionmentioning

confidence: 77%

Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels

Mock

Rascon

Stringhini

et al. 2020

Preprint

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Preclinical evidence has suggested that the Glucocorticoid-Induced TNFR-related protein (GITR) may be valuable a target for the development of anticancer therapeutics, but clinical studies with GITR ligand (GITRL) have been disappointing. Here, we report the development of a fusion protein featuring GITR ligand (GITRL) fused to the F8 antibody which targets the alternatively-spliced EDA domain of fibronectin, a tumor-associated antigen often found around the tumor neovasculature. Five different formats for F8-GITRL fusion proteins were cloned and characterized, but quantitative biodistribution studies failed to evidence a preferential accumulation at the tumor site. The in vivo tumor targeting properties of F8-GITRL could be substantially improved by enzymatic deglycosylation or site-directed mutagenesis of the N-glycosylation consensus sequence. However, therapy studies in a murine model of cancer with the glycoengineered F8-GITRL N74S and N157T variant failed to elicit a durable anti-tumor response, both in monotherapy and in combination with PD-1 blockade.HIGHLIGHTSDifferent formats of fusion proteins featuring Glucocorticoid-induced TNFR-related protein ligand (GITRL) fused to a tumor-targeting antibody were produced.The tumor uptake of the fusion proteins could be increased by enzymatic deglycosylation of the fusion protein or by site-directed mutagenesis of the N-glycosylation consensus sequences.The fusion protein developed in this study failed to show any anti-tumor activity either alone or in combination with PD-1 inhibition.

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“…Similarly, a lack of clinical benefit was reported for a number of GITR agonistic antibodies such as TRX518 38 , AMG228 45 , BMS-986156 46 and MK-1248 47 . Thus…”

Section: Discussionmentioning

confidence: 77%

Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels

Mock

Rascon

Stringhini

et al. 2020

Preprint

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“…Evaluation of immune cell populations in peripheral blood specimens from the treated patients showed that TRX518 preferentially increased the cell death of the highly active GITR + Foxp3 + Tregs. 43 18 In the same study, BMS-986156 exhibited linear pharmacokinetics (NCT02598960). 18 4 | TARGETING ONCOGENES…”

Section: Targeting Glucocorticoid-induced Tumor Necrosis Factor Recmentioning

confidence: 83%

“…43 18 In the same study, BMS-986156 exhibited linear pharmacokinetics (NCT02598960). 18 4 | TARGETING ONCOGENES…”

Section: Targeting Glucocorticoid-induced Tumor Necrosis Factor Recmentioning

confidence: 83%

“…Those include tackling glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) 18 ; cytotoxic T-lymphocyte associated antigen 4 (CTL-A4) 19,20 ; the murine double minute 2 (MDM2) oncogene 21 ; RAS signaling 22 ; beta-gamma IL-2 receptor complex 23 ; CD166 (ALCAM) 24 ; hematopoietic progenitor kinase 1 (HPK-1) 25,26 ; and branched-chain amino acid transaminase 1 (BCAT1). 27 This is in addition to utilizing the vascular disruptor CKD-516.…”

mentioning

confidence: 99%

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Revolutionizing the landscape of colorectal cancer treatment: The potential role of immune checkpoint inhibitors

Tolba

2020

Intl Journal of Cancer

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Colorectal cancer (CRC) represents the third cause of cancer-related mortalities worldwide. The progression of CRC to the metastatic phase significantly compromises the overall survival rates. Despite the advances in the therapeutic protocols, CRC treatment is still challenging. Cancer immunotherapy joined the ranks of surgery, chemotherapy, radiotherapy and targeted therapy as the fifth pillar in the foundation of cancer therapeutics. Interruption of the immunosuppressive signals within the tumor microenvironment and reactivation of antitumor immunity via targeting the molecular immune checkpoints generated promising therapeutic outcomes in several types of hard-to-treat cancers. The year 2017 witnessed the first US Food and Drug Administration (FDA) approval of immune checkpoint inhibitor (ICI) immunotherapy for the management of CRC. The approval was granted to pembrolizumab (anti-PD-1) for the treatment of patients with advanced/metastatic solid malignancies with mismatch-repair deficiency including CRCs. Such natively immunogenic tumors constitute only a minor percentage of all CRCs. Therefore, it is imperative to utilize novel combinatorial regimens to enhance the response of a wider range of CRC tumors to cancer immunotherapy and help in extending the survival rates in patients with advanced/metastatic disease. This review highlights the novel approaches under clinical development to overcome the resistance of CRCs to immunotherapy and improve the therapeutic outcomes. K E Y W O R D S clinical trials, colon cancer, immune checkpoint inhibitors, immunotherapy 1 | INTRODUCTION Colorectal cancer (CRC) is ranked as the third cause of cancer death worldwide. 1 The progression to the metastatic stage cuts down the overall survival rate to 10%. 2 Advances in treatment options for the metastatic stage of the disease only extended the median overall survival from 18 to 30 months. 2,3 Therefore, it is imperative to find better therapeutic strategies for patients with advanced/metastatic CRC. Cancer Immunotherapy is considered the fifth pillar for cancer therapy that proved effectiveness in the management of several types of hard-to-treat cancers. 4,5 Clinical testing of programmed cell death receptor (PD)-1 mAb in patients with metastatic CRC demonstrated promising outcomes with progression-free survival rates of 78% and 11% in mismatch-repair-deficient (dMMR) vs mismatch-repairproficient (pMMR) tumors. 6,7 It is noteworthy that dMMR or microsatellite unstable (MSI) CRC tumors represent only a small percentage

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“…A great deal of clinical practice has indicated that monotherapy of cancer reaches a ceiling, including immunotherapy. Recently, some novel combinational immunotherapies exhibit excellent curative effects (53)(54)(55)(56). These results suggest that multiple immune stimulations have the capability of eliciting immune response to erase malignant tumors.…”

Section: Discussionmentioning

confidence: 99%

Administration of fusion cytokines induces tumor regression and systemic antitumor immunity

Zhang¹,

Zhao

2020

Preprint

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One Sentence Summary: Fusion cytokines can induce tumor regression in mice.Abstract: The curative effects of cancer immunotherapy are hard to be improved in solid tumors. Cytokines, as powerful immune regulators, show potential in awaking host antitumor immunity. We have previously found that administration of certain cytokine combinations induced complete tumor clearance. Here we constructed the cognate fusion cytokines and evaluated their antitumor effects in various mouse tumor models. In situ induced expression of the fusion cytokine IL12IL2GMCSF led to tumor eradication, even those in high advanced stage. An immune memory against other irrelated syngeneic tumors was elicited. Flow cytometry analysis revealed that tumor infiltrating CD3+ cells greatly increased, accompanied with an elevation of CD8+/CD4+ ratio. The fusion protein exhibited superior immune activating capability to cytokine mixtures in vitro, and induced tumor regression in various immune competent tumor models by intratumoral injection. To improve translational potential, an immunocytokine IL12IL2DiaNFGMCSF for systemic administration was constructed by inserting tumor targeting diabody. The protein also displayed good activities in vitro. Intravenous infusion of IL12IL2DiaNFGMCSF induced a tumor infiltrating immune cell alteration like IL12IL2GMCSF, with moderate serum IFNγ increment. Therapeutic effects were observed in various tumor models after systemic administration of IL12IL2DiaNFGMCSF, with slight toxicity. These results provide the feasibility of developing a versatile cancer immunotherapy remedy.

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Safety, Tolerability, and Potential Clinical Activity of a Glucocorticoid-Induced TNF Receptor–Related Protein Agonist Alone or in Combination With Nivolumab for Patients With Advanced Solid Tumors

Cited by 77 publications

References 31 publications

Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels

Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels

Revolutionizing the landscape of colorectal cancer treatment: The potential role of immune checkpoint inhibitors

Administration of fusion cytokines induces tumor regression and systemic antitumor immunity

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