PD-L1 overexpression

P2, N=169, Active, not recruiting, Arcus Biosciences, Inc. | Phase classification: P3 --> P2 | Trial primary completion date: Aug 2024 --> May 2027

P1, N=55, Completed, Anaveon AG | Recruiting --> Completed | N=80 --> 55 | Trial completion date: Jan 2025 --> Jul 2024

Overexpression of KLF1 or PD-L1 reversed the immune-modulating effects of KIAA1429 knockdown. In conclusion, KIAA1429 facilitates immune evasion in NSCLC by stabilizing KLF1 mRNA and upregulating PD-L1 expression.

Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.

There is a correlation between CAF-PDPN and tumoral/stromal PD-L1 expression, and positive status for either CAF-PDPN or stromal PD-L1 expression could be an independent favorable prognostic factor in surgically resected HGNEC patients.

All examined ISMCs over-expressed PD-L1. ISMC showed higher PD-L1 expression than UEA and GEA and worse survival than UEA. PD-L1 over-expression was found to be a significant predictor for worse DFS and OS in patients with ISMC. Our data suggest that PD-L1 over-expression is associated with poor ISMC prognosis.

Thus, we initiated the administration of dexamethasone (3.3 mg/day). Pembrolizumab may be effective against G-CSF-producing NSCLC with high PD-L1 expression. Corticosteroids seemed to inhibit inflammation induced by the tumor, and exert the efficacy of pembrolizumab.

Ferroptosis inhibitor Fer-1 administration could reverse the beneficial effects caused by Rg3 treatment while ferroptosis inducer Erastin treatment enhanced the effects...Rg3 inactivated the circFOXP1-miR-4477a-PD-L1 signaling axis to activate the immune function of CD8+ T cells, thereby inducing ferroptosis and apoptosis in GBC cells. This research recognizes the mechanism of Rg3-mediated anti-cancer effect and offers evidence for the potentiality of Rg3 in clinical application for GBC therapy.

High TcellinfGEP status, but not PD-L1 or PD-L2 expression, was independently associated with longer survival in patients with LA HNSCC. Results may have implications for evaluating therapies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) in HNSCC.

There are individual differences in PD-L1 expression, which can also vary depending on the different clinical features. Specific molecular features correlate with differential PD-L1 expression and may influence the response to therapy.

SCLC TME is highly heterogeneous. Immune-hot tumors were associated with OS but not with molecular classification. PD1 expression and PD-L1 expression by immune cells may thus serve as a prognostic marker.

Immunotherapy has revolutionized TNBC treatment, especially with the FDA's approval of pembrolizumab (Keytruda) combined with chemotherapy for advanced cases, opening new avenues for treating this deadly disease...In this review, we provide a short background on TNBC and immunotherapy and explore the different types of immunotherapy strategies that are currently being evaluated in TNBC. Additionally, we review why combination strategies may be beneficial, provide an overview of the combination strategies, and discuss the novel immunotherapeutic opportunities that may be approved in the near future for TNBC.

In addition, compared with PD-L1-negative yolk sac tissue, dysgerminomas/seminomas with high PD-L1 expression are associated with more genetic alterations and a better prognosis. Our findings will contribute to the knowledge about the potential benefits of ovarian cancer immunotherapy in specific subsets of germ cell tumor patients and the risk factors for resistance mediated by tumor microenvironment cells.

Multiplexed immunofluorescence on 93 NSCLC samples identified higher intratumoral CD8+PD1+ T cells (p = 0.02) in tumors with PD-L1 TPS greater than or equal to 90% versus 50% to 89%. Pembrolizumab and cemiplimab were found to have long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS greater than or equal to 90% compared with TPS 50% to 89%.

The phase III IMpower110 trial differed in that regard, that it clinically evaluated both the PD-L1 TC and IC score as a predictive biomarker for Atezolizumab monotherapy in patients with metastasized or locally advanced NSCLC and gained market authorization for patients with high prevalence of PD-L1 on both tumor and/or immune cells: TC3 (≥50% TC/TPS score) and/or IC3 (≥10% IC score)...Furthermore, correlations to clinical important gene alterations will be presented. This shows that for appropriate treatment decisions by the treating physician according to different marketing authorizations it is of utmost importance that every NSCLC patient should be scored not only for PD-L1 TPS/TC but also for IC.

The expression of the PD-L1 and MET genes is remarkably associated with worse tumor clinicopathologic features and poor prognosis in patients with breast cancer. Further investigations using combination drug regimens targeting PD-L1 and MET are important, particularly in breast tumors expressing high levels of both proteins.

P1; Recruiting --> Suspended

The recent trends indicate that there are various monoclonal antibodies and peptide-based vaccines that can be utilized to overcome the immune evasion technique harbored by GBM cells. A strategic development of Immunotherapy considering these hallmarks of immune evasion may help in designing a therapy that may prove to be effective in killing the GBM cells thereby, improving the overall survival of GBM-affected patients.

The association between PD-L1 positivity and HPV positivity (78.57%) was confirmed by meta-analysis. The conclusion was that HPV-positive status has an impact on immunohistochemical expression of PD-L1 in OPSCC.

These results suggest that the high expression of miR-140-3p in LUAD is correlated with good patient prognosis and may contribute to the treatment of LUAD, especially by increasing responsiveness to docetaxel.

Although a rare occurrence and known to have a poor prognosis, B-Raf mutation positive programmed death ligand 1 overexpressed lung adenocarcinoma presenting with metastatic musculoskeletal lesions can respond favorably to a combination immune checkpoint inhibitor and BRAF inhibitor medication.

Combining CAR T-cell therapy with ICIs and Bruton tyrosine kinase (BTK) inhibitors and developing novel CAR constructs targeting multiple antigens are potential strategies to enhance treatment outcomes. Further prospective studies are essential to corroborate these strategies and improve the prognosis for this challenging lymphoma subtype.

Malignant transformation of NF1-PNST is characterized by an immunosuppressive microenvironment comprising of TAM with high expression of PD-L1, which are associated with inferior outcomes. These findings suggest a clinical potential of immune modulating therapeutics that can unleash an anti-tumor immune response.

Furthermore, the Biomeder strategy is successfully expanded to prevent ICI-induced type 1 diabetes. This Biomeder technique is a universal method for the treatment of various ICI-related adverse events.

These results showed that plasma fibrinogen, smoking history, and SUVmax are predictors of high PD-L1 expression, providing a basis for identifying patients expected to benefit from neoadjuvant ICI treatment.

In spite of PD-L1 overexpression, ISMC patients who treated with pembrolizumab showed no clinical responses. We confirmed that ISMC exhibits more aggressive behaviour than UEA and that all ISMCs displayed PD-L1 overexpression, which is significantly higher than that of UEA and GEA. Our data suggest that PD-L1 overexpression is associated with poor prognosis of ISMC.

SUV3 knockdown resulted in elevated PD-L1 expression (P<0.001), and overexpression of TREX1 in SUV3 knockdown cells decreased mtDNA levels in the cytoplasm and inhibited SUV3 knockdown, resulting in elevated PD-L1 expression, indicating that SUV3 knockdown induced PD-L1 expression by increasing cytoplasmic DNA levels. The SUV3 gene may play an oncogenic function in hepatocellular carcinoma cells.

In addition, an immune adjuvant of imiquimod (R837) is incorporated...Specifically, QUE inhibits the activation state of hepatic stellate cells and reduces highly expressed programmed death receptor ligand 1 (PD-L1) on tumor cells, meanwhile R837 exposes calreticulin on tumor cell surface as an "eat me" signal and leads to a large number of DCs maturing for enhanced antigen presentation. Consequently, the cooperative immune regulation results in a remodeled TME with high infiltration of cytotoxic T lymphocytes for enhanced HCC immunotherapy, which demonstrates an effective immunotherapy paradigm for dense ECM characterized solid tumors with high PD-L1 expression.

Our data suggest that HER2 is more frequently expressed in conventional UC than in divergent subtypes. Additionally, PD-L1 has a higher expression level in lower urinary tract UC compared to upper. However, PD-L1 and HER2 expression are not related to gender or tumor stage in UC.

With the presence of the ALK rearrangement, the patient was started on alectinib...The patient subsequently underwent three cycles of carboplatin/pemetrexed, and ultimately transitioned to hospice care and passed away fourteen months after initial diagnosis... Mucinous adenocarcinoma is an uncommon histological subtype of lung adenocarcinoma with a poor prognosis, with patients often presenting at a later disease stage with complications which may include malignant pleural effusions.

Atezolizumab and durvalumab, the most commonly used PD-L1 antibodies in cancer immunotherapy, were selected and compared in the development of the pretargeted PET imaging strategy. In conclusion, a pretargeted 18F-immuno-PET imaging technology was successfully established on atezolizumab. The high-contrast PET images of the A549-PDL1 tumor models demonstrate that the pretargeting strategy incorporating short-lived fluorine-18 is viable in identifying tumors with high PD-L1 expression, marking this strategy as a potential candidate for further clinical translation.

In addition, a high ratio of CD8+ cells to M2 macrophages was found to predict favorable outcomes in patients with PD-L1-expressing lung cancer after immune checkpoint inhibitor therapy. This study demonstrates that TCs and ICs have distinct spatial features within the tumor microenvironment that are related to tumor PD-L1 expression and IC infiltration.

However, there were no differences in tumor mutational burden (TMB) between CIMP-H and CIMP-L/0 tumors in MSI-H CRCs. In conclusion, CIMP-H is associated with abundant cytotoxic CD8 + TILs and PD-L1 overexpression independent of TMB in MSI-H CRCs, suggesting that CIMP-H tumors represent a typical immune-hot subtype and are optimal candidates for immunotherapy in MSI-H tumors.

PD-1 inhibitor combined with chemotherapy and bevacizumab did not show a clear advantage over PD-1 inhibitor combined with chemotherapy alone (mPFS, 6.2 vs. 4.4 months; P=0.681), although it resulted in an improved overall response rate (ORR) and disease control rate...Therefore, it is suggested that PD-1 inhibitor-based combinations should be a priority treatment option in selective populations, such as those with low ECOG-PS scores, T790M-negative status or high PD-L1 expression in EGFR-mutant NSCLC after TKI failure. The use of immunotherapy and chemotherapy in combination with antiangiogenic agents appears to be a promising combination therapy for such patients.

These findings suggest that PMF patients with a JAK2 mutation have a higher PD-L1 expression in megakaryocytes compared with the control group. We postulate that the combination of checkpoint and JAK2 inhibitors may be an active treatment option in JAK2 mutated PMF given the higher PD-L1 expression.

PD-L1 expression may differ between preoperative biopsy and surgery. CLINICAL IMPLICATIONS: When comparing the benefit of preoperative, postoperative or perioperative immunotherapy, the timing of PD-L1 expression assessment as a biomarker test for immunotherapy requires caution.

Characteristic Overall Training Set Testing Set N 348 279 69 sex (%) female 165 (47.69) 125 (45.13) 40 (57.97) male 181 (52.31) 152 (54.87 29 (42.03) age (%) old 188 (54.34) 158 (57.04) 30 (43.48) young 158 (45.66) 119 (42.96) 39 (56.52) Smoking (%) no 220 (86.96) 174 (86.57) 46 (88.46) yes 33 (13.04) 27 (13.43) 6 (11.54) Stage (%) I 71 (20.52) 48 (17.33) 23 (33.33) II 95 (27.46) 80 (28.88) 15 (21.74) III 168 (48.55) 139 (50.18) 29 (42.03) IV 12 (3.47) 10 (3.61) 2 (2.90) PD-L1_score (%) ≥ 50% 45 (12.93) 37 (13.26) 8 (11.59) < 1% 156 (44.83) 125 (44.80) 31 (44.93) 1-49% 147 (42.24) 117 (41.94) 30 (43.48) PD-L1_clone (%) 22C3 330 (94.83) 264 (94.62) 66 (95.65) SP142 17 (4.89) 14 (5.02) 3 (4.35) ZR3 1 (0.29) 1 (0.36) 0 (0.00) Pathology (%) LUAD 288 (83.48) 231 (83.70) 57 (82.61) LELC 9 (2.61) 4 (1.45) 5 (7.25) other 12 (3.48) 9 (3.26) 3 (4.35) LUSC 36 (10.43) 32 (11.59) 4 (5.80) Figure 1. Model Evaluation of Testing Set (A) and ROC of Two Sets (B).

Conclusions : SMARCA4 -deficient NSCLCs has a distinct tumor immune microenvironment characterized by increased myeloid cell and macrophage infiltration, potentially contributing to resistance to immune checkpoint inhibitors. Additional work is underway to profile and spatially analyze the tumor immune microenvironment and to characterize its relation to STK11 co-mutation status.

Patient demographic and clinical characteristics Patient case Patient 1 Patient 2 Patient 3 Sex Male Female Female Age at ICI initiation (years) 37 62 75 Histology Squamous cell carcinoma Lymphoepithelioma-like carcinoma Squamous cell carcinoma Staging cT4N2M1a, stage IVa pT4N3M1a, stage IVa cT4N2M1a, stage IVa ECOG performance status 0 0 1 Immunohistochemical assay DAKO 22C3 DAKO 22C3 Ventana SP263, DAKO 22C3 PD-L1 expression % 100% 55% 98% (both assays) Prior and subsequent treatments Cisplatin/gemcitabine → Cisplatin/docetaxel → Pembrolizumab Cisplatin/pemetrexed → Docetaxel → Paclitaxel → Pembrolizumab → Gemcitabine Cisplatin/gemcitabine → Pembrolizumab → Paclitaxel ICI treatment cycles 1 7 6 Clinical benefit Partial response Partial response Partial response Time to irMG onset after ICI initiation (days) 16 (Mar 25 th 2020 - Apr 10 th 2020) 253 (June 24 th 2020 - Mar 4 th 2021) 27 (May 17 th 2019 - June 13 th 2019) Diagnostic tests 1. 2021. Abbreviation: AChEI, acetylcholinesterase inhibitor; CT, computerized tomography; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; MRI, magnetic resonance imaging; PD-L1, programmed death-ligand 1; RNS, repetitive nerve stimulation

Treatment options are limited to Tebentafusp in patients with HLA-A*02:01 mutation with immunotherapy and chemotherapy yielding poor results...In a recent phase I trial of a PRMT5 inhibitor, PRT811, clinical activity was described in cases of CAUM. 676 CAUM and 9666 CASM patients underwent hybrid capture based CGP to evaluate genomic alterations (GA)... Although MTAP loss is less frequent in CAUM than in CASM, the recent evidence that this genomic alteration predicts responsiveness to PRMT5 inhibition is noteworthy. This highlights the importance of further investigating this biomarker for patients with this rare and clinically aggressive type of cancer.

Our study unveils differential immune-related RNA expression patterns in NSCLC by stage and underscores the potential utility of immune-signatures as predictive biomarkers of immune response even in patients with high PD-L1 expression levels.

NGEF expression is upregulated in LUAD and is significantly associated with tumor stages, OS probability, immune infiltration, immunotherapy response, and chemotherapy response. NGEF may be a potential diagnostic and prognostic biomarker and therapeutic target in LUAD.