Interim results of an ongoing Phase I, dose escalation study of MGA271 (Fc-optimized humanized anti-B7-H3 monoclonal antibody) in patients with refractory B7-H3-expressing neoplasms or neoplasms whose vasculature expresses B7-H3

Powderly, John D.; Coté, Gregory M.; Flaherty, Keith T.; Szmulewitz, Russell Z.; Ribas, Antoni; Weber, Jeffrey S.; Loo, Deryk; Baughman, Jan; Chen, Francine; Moore, Paul A.; Bonvini, Ezio; Vasselli, James R.; Wigginton, Jon M.; Cohen, Roger B.; Burris, Howard A.; Chmielowski, Bartosz

doi:10.1186/2051-1426-3-s2-o8

Cited by 87 publications

(69 citation statements)

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“…B7-H3 is thought to down-modulate T-cell responses (68), and may also impede NK-mediated cell lysis (62). Initial phase I results with an anti-B7-H3 monoclonal antibody showed antitumor activity in several solid tumor types and a favorable safety profile (NCT02628535) (69), and studies combining B7-H3 with anti-CTLA-4 are also underway (NCT02381314).…”

Section: Discussionmentioning

confidence: 99%

Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors

Danilova

Wang

Sunshine

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

151

120

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Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade has led to remarkable and durable objective responses in a number of different tumor types. A better understanding of factors associated with the PD-1/PD-L axis expression is desirable, as it informs their potential role as prognostic and predictive biomarkers and may suggest rational treatment combinations. In the current study, we analyzedPD-L1,PD-L2,PD-1, and cytolytic activity (CYT) expression, as well as mutational density from melanoma and eight other solid tumor types using The Cancer Genome Atlas database. We found that in some tumor types,PD-L2expression is more closely linked toTh1/IFNGexpression and PD-1 and CD8 signaling thanPD-L1. In contrast, mutational load was not correlated with aTh1/IFNGgene signature in any tumor type.PD-L1,PD-L2,PD-1,CYTexpression, and mutational density are all positive prognostic features in melanoma, and conditional inference modeling revealedPD-1/CYTexpression (i.e., an inflamed tumor microenvironment) as the most impactful feature, followed by mutational density. This study elucidates the highly interdependent nature of these parameters, and also indicates that future biomarkers for anti–PD-1/PD-L1 will benefit from tumor-type–specific, integrated, mRNA, protein, and genomic approaches.

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Section: Discussionmentioning

confidence: 99%

Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors

Danilova

Wang

Sunshine

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

151

120

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“…While drug development to target B7-H4 is ongoing (27), an anti B7-H3 monoclonal antibody, MGA271 (Enoblituzumab)(20), has been shown to be tolerable in a phase I study in solid tumors(19). Currently multiple phase I/II studies are ongoing to assess its safety and efficacy as a single agent and in combination with PD-1/PD-L1 or CTLA-4 axis blockers.…”

Section: Discussionmentioning

confidence: 99%

“…In NSCLC, B7-H3 protein expression has been associated with a negative impact in prognosis(17, 18). A humanized, Fc-optimized monoclonal antibody that targets B7-H3, Enoblituzumab (also referred to as MGA271) was shown to produce antitumor responses in a fraction of heavily pre-treated solid tumors and was well tolerated at dose levels in a Phase 1 study (19). Currently, clinical activity of Enoblituzumab is under investigation as a monotherapy and in combination with either CTLA-4 or PD-L1 targeting monoclonal antibodies (19, 20).…”

Section: Introductionmentioning

confidence: 99%

“…A humanized, Fc-optimized monoclonal antibody that targets B7-H3, Enoblituzumab (also referred to as MGA271) was shown to produce antitumor responses in a fraction of heavily pre-treated solid tumors and was well tolerated at dose levels in a Phase 1 study (19). Currently, clinical activity of Enoblituzumab is under investigation as a monotherapy and in combination with either CTLA-4 or PD-L1 targeting monoclonal antibodies (19, 20). The biologic significance of co-expression of B7 immunoregulatory molecules, their interaction in the tumor microenvironment, and their role in primary and acquired resistance to PD-1 axis inhibitors are unclear.…”

Section: Introductionmentioning

confidence: 99%

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B7-H3 Expression in NSCLC and Its Association with B7-H4, PD-L1 and Tumor-Infiltrating Lymphocytes

Altan

Pelekanou

Schalper

et al. 2017

Clinical Cancer Research

104

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Background and Purpose The immune checkpoint PD-1 and its receptor B7-H1 (PD-L1) are successful therapeutic targets in cancer but less is known about other B7 family members. Here, we determined the expression level of B7-H3 protein in non-small cell lung cancer (NSCLC) and evaluated its association with tumor infiltrating lymphocytes (TILs), PD-L1, B7-H4 and major clinico-pathological characteristics is in 3 NSCLC cohorts. Experimental design We used multiplexed automated quantitative immunofluorescence (QIF) to assess the levels of B7-H3, PD-L1, B7-H4 and TILs in 634 NSCLC cases with validated antibodies. Associations between the marker levels, major clinico-pathological variables and survival were analyzed. Results Expression of B7-H3 protein was found in 80.4% (510/634) of the cases. High B7-H3 protein level (top 10 percentile) was associated with poor overall survival (p <0.05). Elevated B7-H3 was consistently associated with smoking history across the 3 cohorts, but not with sex, age, clinical stage and histology. Co-expression of B7-H3 and PD-L1 was found in 17.6% of the cases (112/634) and with B7-H4 in 10% (63/634). B7-H4 and PD-L1 were simultaneously detected only in 1.8% of NSCLCs (12/634). The expression of B7-H3 was not associated with the levels of CD3, CD8 and CD20 positive TILs. Conclusion B7-H3 protein is expressed in the majority of NSCLCs and is associated with smoking history. High levels of B7-H3 protein has a negative prognostic impact in lung carcinomas. Co-expression of B7-H3 with PD-L1 and B7-H4 is relatively low, suggesting a non-redundant biological role of these targets.

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“…The anti-B7-H3 monoclonal antibody Enoblituzumab (MGA271) was shown to reduce growth of renal cell and bladder carcinoma xenografts in mice [57]. It is currently being tested as a monotherapy in a phase I dose-escalation study in patients with refractory cancers (NCT01391143), and interim results show that it is well tolerated and has antitumor activity [58]. It is also being evaluated in combination with ipilimumab (anti-CTLA-4 mAb) or pembrolizumab (anti-PD-1 mAb) in safety studies of refractory cancers (trial NCT02381314 and NCI201501495).…”

Section: New Immune Checkpoints B7-h3 B7x and Hhla2mentioning

confidence: 99%

The expanding repertoire of targets for immune checkpoint inhibition in bladder cancer: What lies beneath the tip of the iceberg, PD-L1

Sankin

Narasimhulu

John

et al. 2018

Urologic Oncology: Seminars and Original Investigations

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Over the last decade, a new understanding of tumor-immune system interplay has been ushered in, lead in large part by the discovery of immune checkpoints mediated through B7-CD28 family interactions. Therapeutic blockade of the PD-L1 immune checkpoint pathway has already shown great success as a cancer immunotherapy for advanced urothelial carcinoma, leading to durable clinical remissions in an otherwise incurable disease. There are newly described members of the B7-CD28 family including B7-H3, B7x, and HHLA2. These ligands are thought to play an essential role in suppressing T-cell response, leading to immune tolerance of tumors. This feature makes them attractive targets for novel immunotherapy treatment paradigms. Here, we review the literature of current strategies and future directions of immune checkpoint blockade therapy for bladder cancer.

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Interim results of an ongoing Phase I, dose escalation study of MGA271 (Fc-optimized humanized anti-B7-H3 monoclonal antibody) in patients with refractory B7-H3-expressing neoplasms or neoplasms whose vasculature expresses B7-H3

Cited by 87 publications

References 0 publications

Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors

Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors

B7-H3 Expression in NSCLC and Its Association with B7-H4, PD-L1 and Tumor-Infiltrating Lymphocytes

The expanding repertoire of targets for immune checkpoint inhibition in bladder cancer: What lies beneath the tip of the iceberg, PD-L1

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