Tumor B7-H3 Expression Research Articles

Diet restriction enhances the effect of immune checkpoint block by inhibiting the intratumoralmTORC1/B7-H3 axis.

Immune checkpoint blockade therapy has demonstrated significant therapeutic efficacy in certain cancer types; however, the impact of dietary restriction remains scarcely reported in this context. This study aimed to investigate the influence of dietary restriction on anti-PDL-1 therapy and the interplay of immune cells within this context. Using an anti-PDL-1 regimen combined with dietary restrictions, tumor progression was assessed in LLC-bearing mice. Flow cytometry was employed to analyze immune cell infiltration and differentiation levels within the tumor microenvironment. The expression of mTORC1/B7-H3 in tumors subjected to dietary restriction was also examined. LLC tumors with elevated B7-H3 expression were validated in mice to determine its inhibitory effect on immune cell proliferation and differentiation. A CD3/B7-H3 chimeric antibody was developed for therapeutic intervention in B7-H3 overexpressing tumors, with subsequent T cell responses assessed through flow cytometry. Dietary restriction potentiated the effect of anti-PDL1 therapy by suppressing the intratumorally mTORC1/B7-H3 axis. In vivo experiments demonstrated that elevated B7-H3 expression in tumors reduced infiltration and activation of CD8 + T cells within the tumor, while it did not affect tumor-infiltrating Tregs. In vitro studies revealed that high B7-H3 expression influenced the proliferation and activation of CD8 + T cells within a Coculture system. The constructed CD3/B7-H3 chimeric antibody prominently activated TCR within B7-H3 overexpressing tumors and impeded tumor progression. The findings suggest that dietary restriction enhances the efficacy of immune checkpoint blockade by modulating the intratumoral mTORC1/B7-H3 axis.

B7-H3/CD276 Inhibitors: Is There Room for the Treatment of Metastatic Non-Small Cell Lung Cancer?

The striking clinical outcomes of antibody-based immunotherapy, through the inhibitors of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and the programmed cell death protein-1 (PD-1) and its ligand (PD-L1) axis, have driven research aimed at identifying further clinically relevant tumor antigens that can serve as targets in solid tumors. B7 homolog 3 protein (B7-H3, also known as CD276) is a member of the B7 family overexpressed in tumor tissues, including non-small cell lung cancer (NSCLC), while showing limited expression in normal tissues, becoming an attractive and promising target for cancer immunotherapy. B7-H3 expression in tumors has been demonstrated to be associated with poor prognosis. In addition to its role in immune modulation, B7-H3 also promotes pro-tumorigenic functions such as tumor migration, invasion, metastases, resistance, and metabolism. In this review, we will provide an overview of this newly characterized immune checkpoint molecule and its development in the management of metastatic NSCLC.

Molecular correlates of high B7-H3-expressing metastatic castrate-resistant prostate cancers (mCRPC) via exome, transcriptome, and epigenome analyses.

5045 Background: mCRPC is a lethal condition with limited effective treatment options. B7-H3, a transmembrane protein of the B7 checkpoint superfamily is overexpressed in prostate cancer (PC) and is associated with poor prognosis. While several novel approaches target B7-H3 in prostate cancer, lack of knowledge about the molecular features and regulatory mechanisms of B7-H3 expression in mCRPC prevents the optimal design of these interventions. We aimed to characterize B7-H3 in mCRPC with the purpose to reveal the roles of B7-H3 in mCRPC pathogenesis, and stratify the patient population optimal for B7-H3–targeted therapies. Methods: We conducted bioinformatic interrogations at genome-scale on whole-exome and whole-transcriptome sequencing (WES, WTS) data from SU2C/PCF (n = 209, mCRPC), SUWC (n = 101, mCRPC) and GTEx (n = 246, benign prostate tissue). We developed and utilized novel machine learning (ML) algorithms to examine the association of B7-H3 with other key PC pathways. We examined the genetic and epigenetic regulation of B7-H3 by CHIP-seq. We also performed single-cell mRNA sequencing (scRNA-seq) analysis on one patient before and after treatment with the AR inhibitor, enzalutamide. We utilized both Gene Set Enrichment Analysis (GSEA) and our ML approaches to identify enriched signaling pathways in high B7-H3–expressing mCRPC. Results: Expression of B7-H3 was significantly elevated in mCRPC compared to benign prostate tissues, and was distinctive from other B7 family members. High B7-H3 expression was significantly associated with ERG fusions, AR-V7 variant, and increased FOXA1 and androgen receptor (AR) mRNA expression. At gene-level analysis, our ML algorithm suggested that B7-H3 shared similar gene networks as AR and its co-regulators, HOXB13, and FOXA1. CHIP-seq analysis revealed that the distal enhancers of B7-H3 in mCRPC were hyperactive (based on enhanced H3K27Ac marks) relative to primary tumors. Notably, these B7-H3 enhancers were bound by HOXB13, FOXA1 and AR in mCRPC samples. Our scRNA-seq analysis of one patient resistant to enzalutamide showed increased number of B7-H3-expressing cells. Based on integrated GSEA and ML analyses on WTS data, B7-H3 was positively associated with TGF-beta signaling, an enzalutamide resistance pathway. Conclusions: In mCRPC, we found B7-H3 overexpression as compared to other B7 family members. The association of B7-H3-high expression and certain genomic alterations may stratify mCRPC patients for B7-H3–targeted therapy. Further, B7-H3 exhibited regulation by AR, HOXB13 and FOXA1, at the B7-H3 enhancers. The activating epigenetic modification at the distal enhancers represents another potential marker to examine B7-H3 expression in tumors. Altogether, our study indicates that B7-H3 is a critical target in mCRPC patients, including those resistant to enzalutamide.

B7-H3: An Attractive Target for Antibody-based Immunotherapy.

The recent impressive clinical responses to antibody-based immunotherapy have prompted the identification of clinically relevant tumor antigens that can serve as targets in solid tumors. Among them, B7-H3, a member of the B7 ligand family, represents an attractive target for antibody-based immunotherapy, it is overexpressed on differentiated malignant cells and cancer-initiating cells, with limited heterogeneity, and high frequency (60% of 25,000 tumor samples) in many different cancer types, but has a limited expression at low level in normal tissues. In nonmalignant tissues, B7-H3 has a predominantly inhibitory role in adaptive immunity, suppressing T-cell activation and proliferation. In malignant tissues, B7-H3 inhibits tumor antigen-specific immune responses, leading to a protumorigenic effect. B7-H3 also has nonimmunologic protumorigenic functions, such as promoting migration and invasion, angiogenesis, chemoresistance, and endothelial-to-mesenchymal transition, as well as affecting tumor cell metabolism. As a result, B7-H3 expression in tumors is associated with poor prognosis. Although experimental B7-H3 silencing reduces cancer cell malignant potential, there has been limited emphasis on the development of B7-H3-blocking antibodies, most likely because the B7-H3 receptor remains unknown. Instead, many antibody-based strategies utilizing distinct effector mechanisms to target B7-H3-expressing cancer cells have been developed. These strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Ongoing clinical trials are assessing their safety and efficacy in patients. Identification of the B7-H3 receptor will improve our understanding of its role in tumor immunity, and will suggest rational strategies to develop blocking antibodies, which may enhance the therapeutic efficacy of tumor immunity.

Tumor B7-H3 expression in diagnostic biopsy specimens and survival in patients with metastatic prostate cancer.

Prostate cancer spans a broad spectrum from indolent to deadly disease. In the management of prostate cancer, diagnostic biopsy specimens are important sources of data that inform the selection of treatment. B7-H3 (CD276), an immune checkpoint molecule, has emerged as a promising immunotherapy target. B7-H3 expression is related to adverse clinical outcomes in various types of cancer; however, little is known concerning the association between tumor B7-H3 expression in diagnostic biopsy specimens and clinical outcome in patients with metastatic prostate cancer. We evaluated tumor B7-H3 expression levels in diagnostic biopsy specimens from 135 patients with metastatic prostate cancer and 113 patients with localized prostate cancer. High B7-H3 expression was more frequently observed in patients with metastatic cancer than in those with localized cancer (31 vs. 12%; p = 0.0003). In patients with localized cancer, the B7-H3 expression status was not associated with biochemical recurrence-free survival. However, among patients with metastatic cancer, high B7-H3 expression was independently associated with high disease-specific mortality (multivariable hazard ratio [HR] = 2.72; p = 0.047) and overall mortality rates (multivariable HR = 2.04; p = 0.025). Tumor B7-H3 expression in diagnostic biopsy specimens may be a useful biomarker for identifying highly aggressive metastatic prostate cancer. Given the potential utility of anti-B7-H3 immunotherapy, this information may aid in stratifying prostate cancer based on its responsiveness to B7-H3-targeted treatment.

B7-H3 expression in upper tract urothelial carcinoma associates with adverse clinicopathological features and poor survival

B7-H3, a member of the B7 superfamily, is an immune checkpoint molecule. An association between B7-H3 expression and poor survival has been reported in many types of cancer. However, its prognostic value in patients with upper tract urothelial carcinoma (UTUC) has not yet been reported. The aim of this study was to examine the clinical significance of tumor B7-H3 expression in UTUC. B7-H3 positivity was observed in 36 of 271 cases (13 %) by immunohistochemistry and was significantly associated with several adverse clinicopathological features such as tumor grade, tumor stage, and lymph node metastasis. In addition, B7-H3 positivity was significantly associated with shorter metastasis-free survival and cancer-specific survival. We also found that B7-H3/programmed cell death ligand-1 (PD-L1) co-positivity was significantly associated with worse prognosis. These results suggest the utility of B7-H3 positivity and B7-H3/PD-L1 co-positivity as novel prognostic biomarkers in UTUC, and the potential usefulness of B7-H3 targeted therapy for patients with UTUC, the effect of which may be enhanced by combination with programmed cell death-1 /PD-L1 blockade.

Intraventricular radioimmunotherapy targeting B7H3 for CNS malignancies.

e13592 Background: Tumors metastasizing to the central nervous system (CNS) are associated with significant mortality. We tested the toxicity and dosimetry of intraventricular 131I-labeled monoclonal antibody 8H9 targeting surface glycoprotein B7-H3 in patients with primary or metastatic CNS tumors. Methods: Tumor B7-H3 expression was assessed by immunohistochemistry. CSF flow was determined by 111Indium-DTPA cisternography. 131 patients received 2 mCi tracer of intra-Ommaya 124I- or 131I-8H9 for nuclear imaging followed by a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments for phase I patients; expanded cohort 50 mCi/injection) 131I-8H9. Pharmacokinetics were studied by serial CSF and blood samplings over 48 hours. Dosimetry was based on pharmacokinetics and region of interest analyses on serial PET. Toxicity was defined by the CTCAE v.3.0. 8H9 dosimetry and therapy injections were repeated after 1 month if no serious adverse events or progressive disease ensued. Tumor response was determined by clinical, radiographic, cytologic criteria; overall survival was noted. Results: 57 patients (ages 2 – 54 years, median age 11.7 years) received 158 injections Primary CNS diagnoses included medulloblastoma (n = 23), ependymoma (N = 8), chordoma (n = 1), rhabdoid tumor (n = 1), choroid plexus carcinoma (n = 3), ETMR (n = 3), glioblastoma multiforme (n = 1) , PXA (n = 1); metastatic tumors included sarcoma (n = 9), melanoma (n = 4), retinoblastoma (n = 2), and ovarian carcinoma (n = 1). Injections were well tolerated and routinely administered in the outpatient setting. Rare self-limited adverse events included grade 1 or 2 fever, headache, vomiting; 3 injections were associated with grade 3 toxicities requiring discontinuation of therapy including chemical meningitis (n = 2),and increasing communicating hydrocephalus (n = 1), Although not a dose limiting toxicity, myelosuppression occurred in patients who had received craniospinal radiation and at dose levels 6 and higher (≥60 mCi). 16 patients remain alive including patients with high-risk malignancies including choroid plexus carcinoma, ETMR, recurrent ependymoma and recurrent medulloblastoma. Conclusions: We conclude that intraventricular 131I-8H9 is safe, has favorable dosimetry to CSF, and may have clinical utility in the treatment of primary and metastatic CNS tumors. Clinical trial information: NCT00089245.

Tumor B7-H3 (CD276) Expression and Survival in Pancreatic Cancer.

B7-H3 (CD276), a member of the family of immune modulators, orchestrates antitumor immunity. To date, only small-sized studies have examined the association of B7-H3 expression with survival in pancreatic cancer, yielding inconclusive results. We evaluated tumor B7-H3 expression in 150 consecutive patients with pancreatic ductal adenocarcinoma using immunohistochemistry. B7-H3 expression was positive (≥10% tumor cells) in 99 of 150 (66%) cases of pancreatic cancer. We classified the tumors into four groups depending on B7-H3 expression (negative, low, intermediate, and high) and found that higher B7-H3 expression was independently associated with lower disease-free survival (DFS; for high vs. negative B7-H3 expression: multivariable hazard ratio (HR) = 3.12; 95% confidence interval (CI) = 1.48–6.15; Ptrend = 0.0026). Furthermore, the association of B7-H3 expression with survival differed according to the pathological stage (p-stage) (Pinteraction = 0.048, between p-stages I–II and III–IV). The association of B7-H3 positivity with lower DFS was stronger in tumors with p-stage I–II (multivariable HR = 3.10, 95% CI = 1.75–5.69; P < 0.0001) than in those with p-stage III–IV (multivariable HR = 1.20, 95% CI = 0.67–2.28; P = 0.55). We demonstrated that tumor high B7-H3 expression is independently associated with poor survival in patients with pancreatic cancer and that this association is stronger in tumors with p-stage I–II than in those with p-stage III–IV. B7-H3 expression may be a useful prognostic biomarker for identifying aggressive early-stage pancreatic cancer.

Abstract 4562: Tumor B7-H3 (CD276) expression and survival of patients with pancreatic cancer

Abstract Background: B7-H3 (CD276) belongs to a family of immune modulators that includes PD-L1 (B7-H1 or CD274), and has been associated with tumor immunosuppression. Although several studies have reported the association of B7-H3 expression with prognosis in pancreatic cancer, the results are conflicting and inconclusive. We therefore examined the association of tumor B7-H3 expression with prognosis of pancreatic cancer. Methods: Using tissue microarrays of 150 consecutive cases of pancreatic cancer, we evaluated tumor B7-H3 expression by immunohistochemistry. We examined the prognostic association of B7-H3 expression, using the log-rank test. We also used Cox proportional hazards regression models to compute the mortality hazard ratio (HR), adjusted for covariates including pathological-stage, tumor differentiation, preoperative levels of CEA and CA19-9, and adjuvant chemotherapy. Results: Tumor B7-H3 positivity (10% of tumor cells) was observed in 99 (66%) of 150 cases of pancreatic cancer. In a log-rank test, B7-H3 positivity was associated with higher pancreatic cancer-specific mortality (P = 0.0005). In a multivariable analysis, B7-H3 positivity was independently associated with higher pancreatic cancer-specific mortality (multivariable HR = 1.82; 95% confidence interval [CI] = 1.25-2.71; P = 0.0016). When we divided immunoreactivity of B7-H3 into four scores; i.e., score 0, negative; score 1, weak; score 2, moderate; score 3, strong, the immunoreactivity scores of B7-H3 were 51 (34%), 67 (45%), 20 (13%), 12 (8%) for score 0, 1, 2, 3, respectively. In a log-rank test, higher score of B7-H3 immunoreactivity was associated with higher pancreatic cancer-specific mortality (P = 0.0014). In a multivariable analysis, higher B7-H3 immunoreactivity was independently associated with higher pancreatic cancer-specific mortality (comparing score 3 versus score 0: multivariable HR = 2.78; 95% CI = 1.38-5.25; P for trend = 0.0011). Conclusion: Tumor B7-H3 positivity and higher B7-H3 immunoreactivity are both independently associated with higher mortality of pancreatic cancer. Citation Format: Kentaro Inamura, Yusuke Yokouchi, Maki Kobayashi, Yosuke Inoue, Akio Saiura, Yutaka Takazawa, Yuichi Ishikawa. Tumor B7-H3 (CD276) expression and survival of patients with pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4562.

PD-L1, B7-H3, and PD-1 expression in immunocompetent vs. immunosuppressed patients with cutaneous squamous cell carcinoma.

To characterize the expression of co-signaling molecules PD-L1, PD-1, and B7-H3 in cutaneous squamous cell carcinoma (cSCC) by immune status. We retrospectively analyzed 66 cases of cSCC treated with surgical resection from 2012 to 2015. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 (Tum-PD-L1%), B7-H3 (Tum-B7-H3%), density of peri and intratumoral CD8 T cells (CD8 density), proportion of CD8 T cells expressing PD-1 (CD8-PD-1%) and of tumor-infiltrating immune cells (TII) expressing PD-L1 (TII-PD-L1%). Of 66 cases, 42 were immunocompetent, 24 immunosuppressed (13 organ transplant, 8 HIV+, 3 other). Defining positive expression at > 5%, 26% of tumors were positive for PD-L1, 85% for B7-H3, 80% had CD8 T cells that expressed PD-1 and 55% had TII that expressed PD-L1. Tum-B7-H3% was significantly higher (median 60 vs. 28%, p = 0.025) in immunocompetent vs. immunosuppressed patients, including when factoring in cause of immunosuppression. No significant difference in Tum-PD-L1%, TII-PD-L1%, CD8 density, or CD8-PD-1% was observed. Tumors from HIV+ patients lacked PD-L1 expression, and had lower B7-H3% (median 2.5 vs. 60%, p = 0.007), and higher CD8 density (median 75% vs. 40%, p = 0.04) compared to immunocompetent patients. Higher tumor grade (Rs = 0.34, p = 0.006) and LVI (Rs = 0.61, p < 0.001) were both associated with higher Tum-PD-L1%. cSCC showed expression of PD-L1 on tumor in 26% of cases, and high tumor B7-H3 expression (85%) and PD-1 expression on CD8 TILs (80%). Tumor B7-H3 expression was significantly higher in immunocompetent vs. immunosuppressed patients, largely driven by very low expression in HIV+ patients.

Expression of B7-H3 (CD276) in surgically resected esophageal squamous cell carcinoma.

70 Background: B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274), which has been reported to be expressed in many carcinomas and associated with poor prognosis. In this study, we explored the relationship between B7-H3 expression and clinical background and prognosis of esophageal squamous cell carcinoma (ESCC) patients treated with surgery alone. Methods: The subjects of this study was the ESCC patients who received curative surgery between January 2009 and December 2014 without prior treatment, excluding T4 and M1 disease. We evaluated tumor B7-H3 expression by immunohistochemistry, which was scored to 0 (absent) if &lt; 10% of cancer cells were stained, and 1 (weak), 2 (moderate), or 3 (strong) according to the intensity in stained cancer cells (&gt; 10%). The B7-H3 expression of score 2 and 3 was regarded as positive. We compared the clinical characteristics and prognosis between B7-H3 positive and negative patients using log rank test and Cox proportional hazards regression analysis for adjusting the backgrounds. Results: 33 (45%) of 74 patients were positive for expression of B7-H3. Between H7-H3 (+) and (-) groups, there were difference in pathological T stage (pT1/pT2/pT3: 9/0/24 vs. 23/4/14, p &lt; 0.01) and lymph vessel invasion (+/-: 7/26 vs. 17/24, p=0.08). There was no association between sex, age, N factor, and vascular invasion. B7-H3 (+) patients showed trend of poor recurrence free survival (RFS) and overall survival, not significant, (HR=1.41[95%CI:0.63-3.14] p=0.41 for RFS, HR=1.34[ 95%CI:0.52-3.48] p=0.55 for OS). However B7-H3 status was not a prognostic factor in multivariate analysis (HR=0.78[95% CI: 0.33-1.85] for RFS, HR=0.73 [ 95%CI:0.26-2.02] for OS). Conclusions: The expression ratio of B7-H3 was observed in 45% of the esophageal cancer, which was related with T stage and lymphatic vessel invasion but not with clinical outcomes such as RFS and OS.

Molecular imaging of T cell co-regulator factor B7-H3 with 89Zr-DS-5573a.

B7-H3 is a transmembrane protein widely expressed in a variety of cancers and has been shown to play a role in anti-tumor immunity. This study aims to develop a molecular imaging probe to identify B7-H3 expression in tumors and to develop 89Zr-DS-5573a as a theranostic that could aid patient selection in clinical Phase I studies.Methods: The anti-B7-H3 humanised monoclonal antibody DS-5573a was labeled with zirconium-89 (89Zr-), and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen binding affinity (Scatchard analysis), and serum stability in vitro. In vivo biodistribution and imaging studies were performed with positron emission tomography and magnetic resonance imaging (PET/MRI) studies to identify and quantitate 89Zr-DS-5573a tumor uptake in a B7-H3-positive breast cancer model (MDA-MB-231) and a B7-H3-negative murine colon cancer model (CT26). Imaging and biodistribution studies were also performed in MDA-MB-231 tumor-bearing SCID mice in the absence and presence of therapeutic DS-5573a antibody dose (3 mg/kg DS-5573a).Results: 89Zr-DS-5573a showed high and specific binding to B7-H3-expressing MDA-MB-231 cells (immunoreactivity on day 0, 75.0 ± 2.9%), and low binding to B7-H3-negative CT26 cells (immunoreactivity on day 0, 10.85 ± 0.11%) in vitro. 89Zr-DS-5573a demonstrated good serum stability in vitro with 57.2 ± 2.0% of immunoreactivity remaining on day 7. In vivo biodistribution studies showed high uptake of 89Zr-DS-5573a in B7-H3-expressing MDA-MB-231 tumor-bearing mice, achieving 32.32 ± 6.55 %ID/g on day 7 post injection in BALB/c nu/nu mice and 25.76 ± 1.79 %ID/g in SCID mice, with minimal evidence of non-specific uptake in normal tissues, and excellent tumor localization on PET/MRI. In a combined imaging/therapy study, receptor saturation was demonstrated in tumors responding to therapy.Conclusion: 89Zr-DS-5573a demonstrates specific and prolonged targeting of B7-H3-expressing tumors in vivo. Saturation of binding sites was demonstrated in tumors responding to DS-5573a therapy. These results indicate that 89Zr-DS-5573a has potential to target B7-H3-expressing tumors in cancer patients. Furthermore 89Zr-DS-5573a has the potential to provide important insights into T cell biology through its specific binding to B7-H3.

SCDT-38. SAFETY AND EFFICACY OF INTRAVENTRICULAR 131I-LABELED MONOCLONAL ANTIBODY 8H9 TARGETING THE SURFACE GLYCOPROTEIN B7-H3 IN PATIENTS WITH CNS/LM DISEASE

AbstractTumors metastasizing to the central nervous system (CNS) are associated with significant mortality. We tested the toxicity and dosimetry of intraventricular I-labeled monoclonal antibody 8H9 targeting surface glycoprotein B7-H3 in patients with CNS. Tumor B7-H3 expression was assessed by immunohistochemistry. CSF flow was determined by Indium-DTPA cisternography. 131 patients received 2 mCi tracer of intra-Ommaya I- or I-8H9 for nuclear imaging followed by a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments for phase I patients; expanded cohort 50 mCi/injection) I-8H9. Pharmacokinetics were studied by serial CSF and blood samplings over 48 hours. Dosimetry was based on pharmacokinetics and region of interest analyses on serial PET. Toxicity was defined by the CTCAE v.3.0. 8H9 dosimetry and therapy injections were repeated after 1 month if no serious adverse events or progressive disease ensued. Tumor response was determined by clinical, radiographic, cytologic criteria; overall survival was noted. 129 patients with primary or metastatic CNS tumors received 383 injections [median age 5.4 years (1.2- 53.6 years)] Injections were well tolerated and routinely administered in the outpatient setting. Rare self-limited adverse events included grade 1 or 2 fever, headache, vomiting, biochemical elevations in AST or ALT and 1 injection with grade 3 ALT elevation (dose level 3). Although not a dose limiting toxicity, myelosuppression occurred in patients who had received craniospinal radiation and at dose levels 6 and higher (>60 mCi). Of 93 patients treated for metastatic CNS neuroblastoma, an improved overall survival was noted compared to survival reported with conventional therapies. Interpatient variability for total absorbed dose to the CSF and blood was observed; mean absorbed CSF dose was 104.9 cGy/mCi by CSF sampling, and 2.6 cGy/mCi to the blood. We conclude that intraventricular I-8H9 is safe, has favorable dosimetry to CSF, and has clinical utility.

Expression and significance of B7-H3 and Tie-2 in the tumor vasculature of clear cell renal carcinoma

Tumor angiogenesis is required for tumor growth and metastasis, and the Ang/Tie-2 axis plays a pivotal role in angiogenesis. B7-H3, a new member of the B7 family of costimulatory molecules, has a critical function in the T-cell-mediated antitumor immune response, and abnormal tumor B7-H3 expression is frequently associated with a poor prognosis. However, the relationship between B7-H3 and angiogenesis in clear cell renal carcinoma (ccRCC) remains unclear. In this study, we used immunohistochemical methods to detect tumor vascular expression of B7-H3 and Tie-2 in tissue microarrays of 82 ccRCC patient samples. According to the results, B7-H3 is highly expressed in the tumor vascular endothelium of ccRCC and is associated with the ccRCC grade and tumor-node-metastasis (TNM) stage. Although vascular Tie-2 expression was also correlated with T stage and lymph node metastasis, it was not related to ccRCC grade or distant metastasis. The microvessel density (MVD) labeled by CD34 was correlated with tumor grade and TNM stage. Expression of B7-H3 and Tie-2 was positively correlated, and the levels were positively associated with the MVD. Additionally, immunofluorescence staining revealed coexpression of B7-H3 and Tie-2 in the vascular endothelia of ccRCC. Collectively, our findings suggest that expression of B7-H3 and Tie-2 in ccRCC tumor vasculature is closely related to the progression and prognosis of the disease. Furthermore, B7-H3 possibly promotes ccRCC angiogenesis through the Tie-2 pathway. Thus, B7-H3 might serve as an effective endothelial marker for ccRCC prognosis and become a promising target for ccRCC anti-angiogenic-targeted therapy.

Tumor B7-H3 (CD276) expression and smoking history in relation to lung adenocarcinoma prognosis

ObjectivesCompared with non-smoking counterparts, smoking-associated lung cancers have a higher mutational load, resulting in the creation of more tumor neoantigens and increased immunogenicity. B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274). Considering the evidence that PD-L1 inhibitors have been shown to be more effective against lung cancer in smokers, we herein examined the prognostic interaction of tumor B7-H3 expression level with smoking history in lung adenocarcinoma patients. Materials and methodsUsing tissue microarrays comprising 270 consecutive cases of lung adenocarcinoma, we evaluated tumor B7-H3 expression by immunohistochemistry. We examined the prognostic association between B7-H3 expression levels and smoking history, using Cox proportional hazards regression analysis and the log-rank test. Additionally, we used logistic regression analysis to examine the correlations between B7-H3 expression levels and clinicopathological/molecular features of lung adenocarcinoma. ResultsThe association of B7-H3 expression with survival differed by smoking history (Pinteraction=0.014); high B7-H3 expression was associated with decreased lung cancer-specific survival in moderate/heavy-smoking patients (smoking index [SI]≥400) (hazard ratio [HR]=3.07, 95% confidence interval [CI]=1.74–5.49, P=0.0001; log-rank: P<0.0001), but not in non/light-smoking patients (SI<400) (HR=1.14, 95% CI=0.63–1.96, P=0.64; log-rank: P=0.64). Interestingly, in moderate/heavy-smoking patients, high B7-H3 expression was associated with decreased survival in stage I cancer (log-rank; P=0.0005), whereas it showed no significant difference of survival in stage II–IV cancer (P=0.37). High B7-H3 expression was associated with smokers (univariable odds ratio [OR]=2.63, 95% CI=1.51–4.65; P=0.0005) and independently associated with EGFR wild-type status (multivariable OR=2.80, 95% CI=1.38–5.84; P=0.0042). ConclusionsWe demonstrated that the prognostic association of B7-H3 expression indeed differed according to smoking history. Our study also showed the significant association of high B7-H3 expression with EGFR wild-type and smoking patients, indicating the potential effectiveness of anti-B7-H3 therapy for EGFR wild-type or smokers’ lung adenocarcinoma.

B7-H3 is Overexpressed in Patients Suffering Osteosarcoma and Associated with Tumor Aggressiveness and Metastasis

B7-H3 is a member of the B7-family of co-stimulatory molecules, which has been shown to be broadly expressed in various tumor tissues, and which plays an important role in adaptive immune responses. The role of B7-H3 in osteosarcoma, however, remains unknown. In this study we used immunohistochemistry to analyze B7-H3 expression in 61 primary osteosarcoma tissues with case-matched adjacent normal tissues, and 37 osteochondroma and 20 bone fibrous dysplasia tissues. B7-H3 expression was expressed in 91.8% (56/61) of the osteosarcoma lesions, and the intensity of B7-H3 expression in osteosarcoma was significantly increased compared with adjacent normal tissues, osteochondroma and bone fibrous dysplasia tissues (p<0.001). Patients with high tumor B7-H3 levels had a significantly shorter survival time and recurrence time than patients with low tumor B7-H3 levels (p<0.001). Moreover, tumor B7-H3 expression inversely correlated with the number of tumor-infiltrating CD8+ T cells (p<0.05). In vitro, increasing expression of B7-H3 promotes osteosarcoma cell invasion, at least in part by upregulating matrix metalloproteinase-2 (MMP-2). In conclusion, our study provides the first evidence of B7-H3 expression in osteosarcoma cells as a potential mechanism controlling tumor immunity and invasive malignancy, and which is correlated with patients’ survival and metastasis.

Effect of Pemetrexed on Innate Immune Killer Cells and Adaptive Immune T Cells in Subjects With Adenocarcinoma of the Pancreas

Baseline levels of innate and adaptive immune cell functions were studied in patients with pancreatic cancer. The effects of pemetrexed were measured at 7 and 14 days after initial therapy then 14 days after combination therapy with gemcitabine. Pretherapy levels of absolute numbers of natural killer (NK) cells positively correlated with survival. Cytolytic units of NK activity correlated positively with NK cell numbers. Pemetrexed decreased NK cytolytic units to significance when combined with gemcitabine. Pemetrexed increased intracellular accumulation of interferon gamma (IFNγ) in NK cells that correlated negatively with survival. Addition of gemcitabine decreased IFNγ-producing NK cells to baseline. Memory (CD45RO*) T cells enumerated at baseline correlated negatively with survival but were decreased by pemetrexed therapy. Memory T cells were increased in subjects with greater B7-H3 expression in tumor tissue, whereas OX40*-activated total T cells and helper T-cell subset were decreased. FoxP3*, CD8* T cells correlated positively with progression-free interval and survival. In conclusion, innate NK-cell immunity and FoxP3*, CD8* T cells seemed beneficial to pancreatic cancer patients. Higher levels of B7-H3 expression in pancreatic tumors were detrimental to effective immunity. Although pemetrexed therapy increased activation of a subset of NK cells to produce IFNγ, addition of gemcitabine abated those responses, decreasing IFNγ-producing NK cells, whereas NK cells producing interleukin-2 without IFNγ at this timepoint positively correlated with survival. Innate immunity and adaptive immunity thus are important in defense against pancreatic cancer. Progression-free interval and survival were longer than observed in a phase III trial where gemcitabine preceded pemetrexed suggesting that a larger trial of pemetrexed preceding gemcitabine is warranted.

Expression of the costimulatory molecule B7-H3 is associated with prolonged survival in human pancreatic cancer

BackgroundCostimulatory signaling has been implicated as a potential regulator of antitumor immunity in various human cancers. In contrast to the negative prognostic value of aberrant B7-H1 expression by pancreatic cancer cells, the role of B7-H3 is still unknown. Therefore, we investigated the expression pattern and clinical significance of B7-H3 expression in human pancreatic cancer.MethodsB7-H3 expression was evaluated by immunohistochemistry in 68 patients with pancreatic cancer who underwent surgical tumor resection. Expression data was correlated with clinicopathologic features and with the number of tumor-infiltrating T cells.ResultsB7-H3 expression was significantly upregulated in pancreatic cancer compared to normal pancreas (p < 0.05). In 60 of 68 examined tumors B7-H3 protein was detectable in pancreatic cancer cells. Patients with high tumor B7-H3 levels had a significantly better postoperative prognosis than patients with low tumor B7-H3 levels (p = 0.0067). Furthermore, tumor B7-H3 expression significantly correlated with the number of tumor-infiltrating CD8+ T cells (p = 0.018).ConclusionWe demonstrate for the first time that B7-H3 is abundantly expressed in pancreatic cancer and that tumor-associated B7-H3 expression significantly correlates with prolonged postoperative survival. Our findings suggest that B7-H3 might play an important role as a potential stimulator of antitumor immune response in pancreatic cancer.