A phase 1 study of enoblituzumab in combination with pembrolizumab in patients with advanced B7-H3-expressing cancers.

Rizvi, Naiyer A.; Loo, Deryk; Baughman, Jan; Soyoung, Yun; Chen, Francine; Moore, Paul A.; Bonvini, Ezio; Vasselli, James R.; Wigginton, Jon M.; Cohen, Roger B.; Aggarwal, Charu; Tolcher, Anthony W.

doi:10.1200/jco.2016.34.15_suppl.tps3104

Cited by 17 publications

(14 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…High frequency of PD-L1, IDO, and B7-H3 expression on TILs and TAMs may play an important role in immunosuppression in the TME, which could be targeted for inhibition. Combination of PD-L1 inhibition with either IDO inhibitors or B7-H3targeted therapy is already in early clinical trials for other solid cancers (35)(36)(37). Although it will be important to interrogate larger tumor cohorts to confirm our findings, the upregulation of multiple immune checkpoints in our cohort provides a basis for investigating immune-checkpoint blockade as a novel therapeutic strategy for patients with FLC.…”

Section: Discussionmentioning

confidence: 99%

Multiple Immune-Suppressive Mechanisms in Fibrolamellar Carcinoma

Kim

Gani

Layman

et al. 2019

Cancer Immunology Research

View full text Add to dashboard Cite

Fibrolamellar carcinoma (FLC) is a rare type of liver cancer that affects adolescents and young adults. The most effective treatment for FLC is surgical resection, but no standardized systemic therapy exists for patients with recurrent or unresectable FLC. As a first step to understand the immune microenvironment of FLC, we investigated targetable immune-checkpoint pathways, PD-1, PD-L1, B7-H3, IDO-1, and LAG3, in relation to CD8 þ cytotoxic T-lymphocyte density. Thirty-two FLC tumor specimens were analyzed using IHC staining for PD-L1, CD8, PD-1, IDO, LAG3, and B7-H3. Sixty-three percent of FLC cases demonstrated membranous PD-L1 expression on tumor cells, and almost 70% of cases demonstrated PD-L1 þ tumor-infiltrating lymphocytes and tumor-associated macrophages (TIL/TAM). Myeloid-derived cells appeared to be a major component of PD-L1 þ tumor-infiltrating immune cells. Forty percent of the cases showed B7-H3 expression in the tumor zone, with 91% cases showing B7-H3 expression in TILs and TAMs. IDO and PD-1 expression was highest in the tumor interface zone. B7-H3 or IDO expression on tumor cells significantly correlated with higher CD8 þ T-cell density. In conclusion, a high proportion of FLC cases showed robust expression of PD-1, PD-L1, B7-H3, and IDO in an adaptive immune-resistance pattern. Our findings provide further basis for targeting these different immune-checkpoint axes in FLC.

show abstract

Section: Discussionmentioning

confidence: 99%

Multiple Immune-Suppressive Mechanisms in Fibrolamellar Carcinoma

Kim

Gani

Layman

et al. 2019

Cancer Immunology Research

View full text Add to dashboard Cite

show abstract

“…MGA271 (or enoblituzumab), is an Fc-enhanced humanized IgG1 anti-B7-H3 antibody developed by MacroGenics. Mutations were introduced in the IgG1 Fc domain to increase its affinity to FcγRIIIa but decrease the affinity to FcγRIIb (169). Enhanced ADCC against a wide arrange of B7-H3 positive tumor cell lines (including prostate, lung, breast, colon, bladder, renal cancers and melanoma) was observed across all the donors with different FcγRIIIa polymorphisms (low-affinity 158F homozygous, high-affinity 158V homozygous, and 158F/V heterozygous).…”

Section: Immune Checkpoint Molecules and Their Therapeutic Antibodiesmentioning

confidence: 99%

FcγR-Binding Is an Important Functional Attribute for Immune Checkpoint Antibodies in Cancer Immunotherapy

et al. 2019

View full text Add to dashboard Cite

T cells play critical roles in anti-tumor immunity. Up-regulation of immune checkpoint molecules (PD-1, PD-L1, CTLA-4, TIM-3, Lag-3, TIGIT, CD73, VISTA, B7-H3) in the tumor microenvironment is an important mechanism that restrains effector T cells from the anti-tumor activity. To date, immune checkpoint antibodies have demonstrated significant clinical benefits for cancer patients treated with mono- or combination immunotherapies. However, many tumors do not respond to the treatment well, and merely blocking the immune suppression pathways by checkpoint-regulatory antibodies may not render optimal tumor growth inhibition. Binding of the antibody Fc-hinge region to Fc gamma receptors (FcγRs) has been shown to exert a profound impact on antibody function and in vivo efficacy. Investigation of immune checkpoint antibodies regarding their effector functions and impact on therapeutic efficacy has gained more attention in recent years. In this review, we discuss Fc variants of antibodies against immune checkpoint targets and the potential mechanisms of how FcγR-binding could influence the anti-tumor activity of these antibodies.

show abstract

“…Another member of the B7 family of costimulatory ligands is B7‐H3, expressed on activated T cells, B cells, monocytes, dendritic cells (DCs), and some tumor cell lines as well . Importantly, the effect of an anti–B7‐H3 monoclonal antibody enoblituzumab on B7‐H3–expressing relapsed or refractory malignant solid tumors in young adults and children is under phase 1 clinical trial . Cleavage of membrane‐bound B7‐H3 on the cell surface of activated T cells and monocytes, by a matrix metalloprotease, results into the release of a soluble form of B7‐H3, the sB7‐H3 .…”

Section: Immune Checkpoint Molecules: Regulating the Immune Response mentioning

confidence: 99%

“…56 Importantly, the effect of an anti-B7-H3 monoclonal antibody enoblituzumab on B7-H3expressing relapsed or refractory malignant solid tumors in young adults and children is under phase 1 clinical trial. 57 Cleavage of membrane-bound B7-H3 on the cell surface of activated T cells and monocytes, by a matrix metalloprotease, results into the release of a soluble form of B7-H3, the sB7-H3. 56 The sB7-H3 was traceable in the serum/plasma of healthy donors, and elevated levels of this molecule indicated a poor prognosis in NSCLC.…”

Section: B7 Ligands In the Circulationmentioning

confidence: 99%

Soluble immune checkpoint molecules: Serum markers for cancer diagnosis and prognosis

2019

View full text Add to dashboard Cite

Background With the recent advances in the understanding of the interaction of the immune system with developing tumor, it has become imperative to consider the immunological parameters for both cancer diagnosis and disease prognosis. Additionally, in the era of emerging immunotherapeutic strategies in cancer, it is very important to follow the treatment outcome and also to predict the correct immunotherapeutic strategy in individual patients. There being enormous heterogeneity among tumors at different sites or between primary and metastatic tumors in the same individual, or interpatient heterogeneity, it is very important to study the tumor‐immune interaction in the tumor microenvironment and beyond. Importantly, molecular tools and markers identified for such studies must be suitable for monitoring in a noninvasive manner. Recent findings Recent studies have shown that the immune checkpoint molecules play a key role in the development and progression of tumors. In‐depth studies of these molecules have led to the development of most of the cancer immunotherapeutic reagents that are currently either in clinical use or under different phases of clinical trials. Interestingly, many of these cell surface molecules undergo alternative splicing to produce soluble isoforms, which can be tracked in the serum of patients. Conclusions Several studies demonstrate that the serum levels of these soluble isoforms could be used as noninvasive markers for cancer diagnosis and disease prognosis or to predict patient response to specific therapeutic strategies.

show abstract

A phase 1 study of enoblituzumab in combination with pembrolizumab in patients with advanced B7-H3-expressing cancers.

Cited by 17 publications

References 0 publications

Multiple Immune-Suppressive Mechanisms in Fibrolamellar Carcinoma

Multiple Immune-Suppressive Mechanisms in Fibrolamellar Carcinoma

FcγR-Binding Is an Important Functional Attribute for Immune Checkpoint Antibodies in Cancer Immunotherapy

Soluble immune checkpoint molecules: Serum markers for cancer diagnosis and prognosis

Contact Info

Product

Resources

About