VTCN1 underexpression

This study identified immunoregulatory protein expression according to HER3 status in breast cancer patients. As tumor with HER3 expression have more immunogenic microenvironment, investigating combination treatment of HER3 targeting agent and immunotherapy in HER3 expressing breast cancer may be promising.

VDR has a clear correlation with ADORA2A, BTLA, CD160, CD244, CD274, CD96, CSF1R, CTLA4, HAVCR2, IL10, IDO1, LAG3, LGALS9, PDCD1, PDCD1LG2, PVRL2, TGFB1, TGFBR1, TIGIT and VTCN1.The expression of VDR is associated with immune infiltration in patients with COAD. VDR may be a new candidate biomarker for determining the level of immune infiltration and predicting immune checkpoint inhibitor therapy.

The management of GIST was revolutionized by the introduction of imatinib, a KIT inhibitor, which has become the standard first-line treatment for metastatic GIST...B7-H3 is expressed at a particularly high rate in GISTs. This suggests that B7-H3 might operate as part of an immune checkpoint in GISTs.

Interestingly, the distance from B7-H4+ cells to the nearest CD8+ cells was significantly farther in patients dying from cancer after surgery or immune checkpoint inhibitors compared to cancer survivors; thus, high B7-H4 expression in tumor cells may inhibit CD8 infiltration into the tumor space and that B7-H4-positive cells form a specific spatial niche. In summary, we performed a comprehensive evaluation of B7 family member expression and found that the spatial distribution of B7-H4 suggests the potentially useful role of combination blockade with both B7-H4 and the current anti-PD-1/PD-L1 axis in the treatment of UC.

High expression of B7H4 is associated with a poorer prognosis in patients with solid cancers. B7H4 is a promising prognostic biomarker and immunotherapeutic target for various solid cancers because of its activity in cancer immunity and tumourigenesis.

Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1...This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.

Significant differences in GA and immune biomarkers are noted between IDH1/2+ and IDHwt iCCA. IDH1-/2-mutated tumors appear immunologically cold without gLOH. These immunogenomic data provide insight for precision targeting of iCCA with IDH alterations.

The clinical outcome of patients with CRC was negatively related to the high expression of B7H4 in cancer cells or low expression of CD8 in the microenvironment. Therefore, B7H4 is a biomarker of poor prognosis in CRC patients, and interference with the IFN-γ/IRF1/B7H4 axis might be a novel immunotherapeutic method to restore the cytotoxic killing of CRC cells.

Also, B7-H4 was significantly associated with clinico-pathological parameters. Our findings highlight B7-H4 as potential therapeutic target for treatment of UCB patients in future after further validation.

Precision drug development is focusing on targeting tumor cell surface proteins for therapeutic delivery, maximizing biomarker identified on-target damage to the tumor while minimizing toxicity. A recent article demonstrated high expression of B7-H4 antigen on resistant ovarian cancer cells and described preclinical activity of B7-H4-directed antibody-drug conjugate.

Both temporal and spatial heterogeneity is present between the primary tumor and brain metastases of NCSLC. Brain metastases lesions exhibit a more immunosuppressive tumor immune microenvironment. B7-H4 and CD68 TAMs may have potential therapeutic value for lung adenocarcinoma brain metastases patients.

In human breast cancer, SOX9 and B7x expression are correlated and associated with reduced CD8 T cell infiltration. This study, using mouse models, cell lines, and patient samples, identifies a dedifferentiation-associated immunosuppression mechanism and demonstrates the therapeutic potential of targeting the SOX9-B7x pathway in basal-like breast cancer.

Our comparative study revealed distinct patterns of B7-H4 expression according to SGC histology, which has potential therapeutic implications. B7-H4 expression was particularly high in solid ACC and was an independent prognostic marker in this disease but not in the other SGC assessed.

The new 64 Cu-B7-H4-mAb radiotracer showed preferential tumor accumulation. In vivo B7-H4 blocking and Mф depletion reduced the tumor accumulation of the new radiotracer; however, a statistically significant difference was only observed between the control and the blocked group at 48 hours. *Clinical Relevance/Application: The new B7-H4 immunoPET probe is a clinically translatable imaging biomarker that could inform clinical trial design immediately.

P1, N=30, Terminated, Pfizer | Trial completion date: Jan 2024 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2024 --> Oct 2023; Pfizer has made an internal business decision to not continue further development of PF-07260437. This decision was not due to major safety concerns or requests from any regulatory authorities.

The recent approvals and data of pembrolizumab (anti-PD-1 inhibitor) in combination with chemotherapy in advanced-metastatic and early high-risk TNBC, and sacituzumab govitecan (an ADC that targets the tumor cell surface antigen TROP2 coupled with the irinotecan metabolite SN-38) in metastatic TNBC, has shed light on some of the immune and cancer signaling associated with TNBC. This preliminary analysis confirmed that only a limited number of early TNBC highly expressed PD-L1 and that a different immune suppressive landscape for PD-L1± and TROP2± tumors exists. In addition, our data suggest that early TNBC cases lacking PD-L1 might escape immune surveillance by virtue of the upregulation of key alternate signaling. Ongoing efforts investigating the expression of such markers on stroma/epithelial tumor components will help to clarify their biological, clinical, and potential therapeutic role in TNBC.

Our study illuminates the novel role of renouncing B7-H4 in breast cancer cells through immune escape, which contributes to EMT processes and provides new insights for breast cancer treatments.

These data support B7-H4 as an attractive ADC target for treatment of drug-resistant HGSOC and provide evidence for activity of an ADC with a DNA-damaging payload in this population.

Our result suggests that B7-H4 expression might be a useful prognostic factor in endometrial cancer.

The immune checkpoint ligand B7-H4 is a promising molecular target expressed by multiple solid tumors. SGN-B7H4V demonstrates robust antitumor activity in preclinical models through multiple potential mechanisms. Altogether, these preclinical data support the evaluation of SGN-B7H4V as a monotherapy in the ongoing phase 1 study of SGN-B7H4V in advanced solid tumors (NCT05194072) and potential future clinical combinations with immunotherapies.

We found that HR+ breast cancer cell lines treated with the selective estrogen-degrader fulvestrant, displayed increased B7-H4 levels and combination treatment of EVOLVE-106 with fulvestrant increases EC50 of tumor killing by 5–8 fold. Conclusions These data support the potential positioning of EVOLVE-106 as a first-in-category immunotherapeutic approach for patients with Her2 receptor low breast cancers, and both estrogen receptor positive and negative tumors, including TNBC.

Conclusions B7H4 and 4–1BB expression in cancer cells, PBMC and solid tumors, together with robust B7H4-dependent single agent activity of CLN-418 in preclinical tumor models, support the development of CLN-418 in patients with difficult-to-treat solid cancers. A Phase 1 dose-escalation trial of CLN-418 is ongoing (NCT05306444).

P1, N=25, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=100 --> 25 | Trial completion date: Sep 2025 --> Jan 2024 | Trial primary completion date: Sep 2025 --> Jan 2024

These results suggest that considering the TIL pattern and TLS and identifying the expression of PD-L1 and the basal-like type are useful for estimating B7-H4 expression. In addition, luminal androgen receptor (LAR)-type is frequently deficient in B7-H4 expression. In non-LAR types, B7-H4 and IDO1 expression are exclusive.

We demonstrate increased expression of markers tumor cell proliferation, stemness, hypoxia, and an immune evasive environment in young breast cancer patients. Hence, tumors of young breast cancer patients may have a unique biology that may open for new clinical opportunities stratifying treatment by age.

Responses were observed at all tested dose levels and across various tumor types. Dose expansion in select tumor types is planned.

No abstract available

Thus, the tumor suppressive function of aging-like DNA hypomethylation is severely impaired in hDNAmad+ tumors, likely due to enhanced expression of DNMT3A/3B and dysregulated aging regulators. Our findings not only enrich biological knowledge of EC pathogenesis but also help improve EC risk stratification and precision ICI immunotherapy.

In a panel of 28 breast cancer patient-derived xenografts (PDX), XMT-1660 demonstrated activity that correlated with B7-H4 expression. XMT-1660 has recently entered clinical development in a Phase 1 study (NCT05377996) in cancer patients.

Spatial analysis revealed that ACC subtypes have distinct TMEs, with enrichment of ACC-I immune cells that are restricted to the stroma. B7-H4 is highly expressed in poor-prognosis ACC-I subtype and is a potential therapeutic target.

In summary, these results suggested that ECA inhibits B7-H4 expression via STAT3 inhibition, leading to SPC/TGF-β1-induced EMT. Therefore, ECA might be an immune oncological drug for B7-H4-positive cancer, especially lung cancer.

XMT-1660 is a B7-H4-directed Dolasynthen antibody drug conjugate designed with a precise, optimized drug-to-antibody ratio and a DolaLock microtubule inhibitor payload with controlled bystander effect. NCT05377996. Clinical trial information: NCT05377996.

Overall, our data showcase that B7-H4 and PD-L1 expression was higher in T cells of UBC patients compared to healthy controls in peripheral blood. Upon stratifying patients with muscle invasive and non- muscle invasive bladder cancer their expression was increasing with disease severity and might be suggesting that cancer cells are constantly trying to escape the immune evasion by CD8 T cells. This maiden study highlights B7-H4 as a novel target showing a trend similar to PD-L1.

The comparison between biomarker levels at the baseline and in the first radiological assessment under ICI-based treatment showed a significant decrease in EV-PD-L1 and an increase in EV-B7H3 in patients in the disease response to ICIs. Our study shows that sPD-L1, sB7-H3 and sB7-H4 levels are emerging prognostic markers in patients with advanced NSCLC treated with ICIs and suggests potential EV involvement in the disease response to ICIs.

The expression of B7H4 was more frequent in microsatellite stable tumours, and was negatively associated with TILs. B7H4 is positively correlated with antitumour immunosuppressive iTME, thus contributing to the immunosuppressive environment in CRC.

VTCN1 and HHLA2 are frequently co-expressed in PD-L1-negative NSCLC, especially EGFR-mutant LUAD rich in CD8+ T-cells and can serve as potential novel immunotherapeutic targets.

Importantly, immune response genes related to ICD were increased following B7H4-MMAE treatment compared to DM1, DM4, and exatecan conjugates. Together, these data suggest that treatment with vedotin ADCs results in robust immunomodulatory changes in vivo that are distinct from other clinical ADC payloads.

To further exploit the DNA damage elicited by the specific delivery of the TOP1i warhead, the combination of AZD8205 with a novel poly-ADP ribose polymerase 1 (PARP1) selective inhibitor, AZD5305, was investigated. These data demonstrate that AZD8205 is a promising therapeutic candidate for the treatment of B7-H4 positive solid tumors. A first in human phase I/IIa study in patients with advanced solid tumors is currently ongoing (NCT05123482).

B7-H3 and B7-H4 expression inversely correlated with latency of ER+ MC and may represent targets for immune checkpoint antibodies and their drug conjugates. HCB, an inhibitor of OXPHOS and EET biosynthesis, reduced intratumoral hypoxia, increased CD8+ TIL and reduced the Treg:CD8+ ratio, potentially supporting ICB therapy of ER+ MC by turning cold tumors hot.

These data support B7-H4 as an attractive ADC target for treatment of drug-resistant HGSOC.

This study proposes a novel epigenetic alteration exerted by TNBC cells mainly by inducing the expression of MALAT-1 lncRNA. MALAT-1 mediates innate and adaptive immune suppression events partially via targeting miR-34a/MICA/B and miR-175p/PD-L1/B7-H4 axes in TNBC patients and cell lines.

P1, N=100, Recruiting, Pfizer | Trial completion date: Mar 2025 --> Sep 2025 | Trial primary completion date: Mar 2025 --> Sep 2025