PD-L1 expression in muscle invasive urothelial carcinoma: Comparison of SP142 and SP263 assay

Introduction: High-grade urothelial carcinoma has a different molecular pathway than superficial low grade urothelial carcinoma, and is characterized by genomic instability. The high tumor mutation burden leads to neoantigen formation, evoking an immune response. The immune response has been keenly studied in last two decades and programmed death ligand-1 (PDL-1) has emerged as acceptable immunohistochemical marker for assessment of response to therapy, prognostication and patient selection for immunotherapy. The targeting of PD-1 and PDL-1 by checkpoint inhibitors (CPIs) is an attractive strategy to unblock the inhibitor and induce cytotoxic cell death. However, the presence of complementary and companion diagnostic testing with multiple PDL-1 assays and platforms for various CPIs make a diagnostic quagmire. Thus, it is the need of hour to harmonize these assays. In this undertaken study we evaluated the concordance in PD-L1 expression between the two PD-L1 clones: SP263 and SP142, in treatment naïve muscle invasive bladder cancer (MIBC). Methods: We evaluated Ventana PD-L1 “SP263 and SP142” qualitative immunohistochemical assay using rabbit monoclonal anti-PD-L1 clones in evaluation of PDL-1 immunoexpression on Ventana autostainer platform. The study includes 30 muscle invasive urothelial carcinomas, with 10 of 30 having nodal metastasis. Results: SP263 assay was statistically more sensitive than SP142 for tumor cell (TC) scoring (P = 0.0009), whereas SP142 was more sensitive for immune cell (IC) scoring (P = 0.0067). There was no statistical significant discordance for TC or IC scoring between primary tumor and metastatic lymph node. Conclusion: PD-L1 testing status can be done on both primary tumor and metastatic site, however in metachronous metastatic setting, testing on recent metastatic site should be preferred. The harmonization of immunoexpression between 2 PD-L1 clones could not be achieved.

Leishmania donovani: Immune response and immune evasion with emphasis on PD-1/PDL-1 pathway and role of autophagy

Leishmania donovani is one of the causative agents of visceral leishmaniasis. The immune response against Leishmania depends on CD4+ T helper type 1 cells. The immune system is unable to combat Leishmania because the parasite can exert several immune suppressive mechanisms that facilitate escaping the immune responses. One of these mechanisms is the up-regulation of programmed death-1/programmed death ligand-1 pathway which causes T cells to undergo exhaustion. Autophagy is strongly linked to the immune response, with some research indicating that activating autophagy reduces the immune response to some intracellular pathogens, while others indicate that activating autophagy limits the growth of intracellular pathogens. Leishmania was found to subvert the host defense mechanisms for its own persistence, such as Leishmania-induced autophagy modulation. Leishmania was reported to activate autophagy in different studies, thus getting a dual benefit by evading the immune system and simultaneously utilizing the autophagy byproducts as nutrients. In this review, we introduced different immune evasion/suppressive mechanisms used by Leishmania, and different immunotherapies which were developed accordingly. We focused on the programmed death-1/programmed death ligand-1 pathway as well as autophagy with the potential interplay of both mechanisms.

Regulatory lymphocytes: the dice that resolve the tumor endgame

A large number of cancer patients relapse after chemotherapeutic treatment. The immune system is capable of identifying and destroying cancer cells, so recent studies have highlighted the growing importance of using combinatorial chemotherapy and immunotherapy. However, many patients have innate or acquired resistance to immunotherapies. Long-term follow-up in a pooled meta-analysis exhibited long-term survival in approximately 20% of patients treated with immune checkpoint inhibitors or the adoptive transfer of chimeric T cells. It has been reported that high levels of immunoregulatory cells in cancer patients contribute to immunotherapy resistance via immunosuppression. Among the most important regulatory cell subtypes are the CD4+ T-regulatory cells (Tregs), identified by their expression of the well-characterized, lineage-specific transcription factor FOXP3. In addition to CD4+ Tregs, other regulatory cells present in the tumor microenvironment, namely CD8+ Tregs and IL10-producing B-regulatory cells (Bregs) that also modulate the immune response in solid and lymphoid tumors. These cells together have detrimental effects on tumor immune surveillance and anti-tumor immunity. Therefore, targeting these regulatory lymphocytes will be crucial in improving treatment outcomes for immunotherapy.

Comparison of Efficacy of Pembrolizumab between Epstein-Barr Virus‒Positive and ‒Negative Relapsed or Refractory Non-Hodgkin Lymphomas / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Pembrolizumab, a programmed cell death protein 1 (PD1) inhibitor inhibits the interplay between PD1 of T-cell and programmed cell death ligand 1 (PDL1) on tumor cells. Although pembrolizumab has been tried to various subtypes of non-Hodgkin lymphoma (NHL), real-world data about the efficacy of pembrolizumab in NHL patients are limited. MATERIALS AND METHODS: We analyzed the outcome of 30 relapsed or refractory NHL patients treated with pembrolizumab, and compared the outcome between Epstein-Barr virus (EBV)‒positive and negative subtypes because EBV infection of tumor cells can upregulate PDL1 expression. RESULTS: Seven patients with EBV-positive NHL showed a response including NK/T-cell lymphoma (6/14, 44%) and primary mediastinal B-cell lymphoma (1/4, 25%) whereas EBV-negative subtypes did not respond such as diffuse large B-cell lymphoma and T-lymphoblastic lymphoma. We also evaluated PDL1 expression using tumor tissue of 76 patients. High PDL1 expression (positive staining of > 50% of tumor cells) was more frequent in NK/T-cell lymphoma and primary mediastinal B-cell lymphoma than other subtypes. Thus, PDL1 expression was significantly higher in EBV-positive (18/32, 56%) than EBV-negative NHL (4/38, 11%, p < 0.001). Furthermore, NK/T-cell lymphoma patients with high PDL1 expression showed a higher response (4/6, 67%) than those with low PDL1 expression (1/5, 20%). CONCLUSION: Pembrolizumab could be useful as a salvage treatment for relapsed or refractory EBV-positive NHL, especially NK/T-cell lymphoma. However, its efficacy in EBV-negative NHL with low or absent PDL1 expression is still not clear although pembrolizumab could be a potential treatment option for relapsed or refractory NHL.

Dynamics of Soluble Programmed Death-Ligand 1 (sPDL1) during Chemotherapy and Its Prognostic Implications in Cancer Patients: Biomarker Development in Immuno-oncology / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The soluble programmed death-ligand 1 (sPDL1) has immunosuppressive activity and is a candidate biomarker for immuno-oncology drug development. In this study, we measured sPDL1 at pre- and post-chemotherapy and at disease progression to uncover the dynamics of sPDL1 during treatment in biliary tract cancer (BTC) patients. MATERIALS AND METHODS: From 90 BTC patients (training cohort, 53; validation cohort, 37) who were candidates for palliative first-line chemotherapy, blood was collected at pre- and post-chemotherapy (at the time of best response) and at disease progression. The sPDL1 levels were measured using an enzyme-linked immunosorbent assay. Responses to chemotherapy, overall survival (OS), and other prognostic factors including the neutrophil-lymphocyte ratio (NLR) were analyzed. RESULTS: The OS of all patients was 11.5 months (confidence interval [CI], 9.7 to 16.2). The best response was complete response in seven (7.8%), partial response in 20 (22.2%), stable disease in 52 (57.8%), and disease progression (PD) in 11 patients (12.2%). Patients with high pre-chemotherapy sPDL1 (≥ 1.30 ng/mL) showed worse OS than patients with low prechemotherapy sPDL1 (9.1 months vs. 12.5 months, p=0.003). In multivariate analyses, high pre-chemotherapy sPDL1 (hazard ratio [HR], 1.96; 95% CI, 1.2 to 3.9; p=0.011) and high pre-chemotherapy NLR (HR, 1.82; 95% CI, 1.1 to 3.0; p=0.020) were independent poor prognostic factors for OS. At the time of PD, sPDL1 was increased significantly compared with pre-chemotherapy sPDL1 (1.59 ng/mL vs. 0.72 ng/mL, p=0.003). CONCLUSION: The sPDL1 at pre-chemotherapy confers the prognostic value for OS in BTC patients under palliative chemotherapy. The dynamics of sPDL1 during chemotherapy correlate with disease burden and have prognostic value.

Advances in immunotherapy of extranodal NK/T cell lymphoma / 中华耳鼻咽喉头颈外科杂志

Extranodal NK/T-cell lymphoma (ENKTCL) is a relatively rare group of highly aggressive non-Hodgkin′s lymphoma (NHL). The disease has rapid clinical progress, high degree of malignancy and poor prognosis. Traditional chemoradiotherapy regimens have not shown good efficacy. In recent years, the immunotherapy of tumors has developed rapidly. At present, it has shown strong therapeutic activity in the treatment of various solid tumors such as non-small cell lung cancer, prostate cancer, melanoma and kidney cancer. Multiple tumor immunotherapy drugs have been approved by the US Food and Drug Administration (FDA) for clinical use. This article reviews recent novel immunotherapeutic regimens of ENKTCL, hoping to change the treatment modality of this malignant disease.

Advances in targeted therapy of gastric cancer / 中国肿瘤临床

Progress in the treatment of gastric cancer(GC)is a major concern because GC is a common cancer worldwide.Recently,by studying the molecular mechanisms of GC,researchers learned that GC progression involved a series of changes at the molecular lev-el,including the activation of signaling pathways,abnormal expression and mutation of genes,and response to related targeted drugs used in clinics.However,many targeted drugs produce resistance in a short period of time because of complicated cellular,microenvi-ronmental,and genetic instabilities.Therefore,it is important to find new targets against GC.In this review,we present the current re-search status and progress with respect to GC targets.

The recent advances in the biological immunotherapy of pancreatic cancer / 中国肿瘤生物治疗杂志

@#[摘 要] 胰腺癌是恶性程度最高的消化系统肿瘤，免疫治疗在胰腺癌领域的研究取得较大进展。目前对免疫检查点的研究主 要集中在细胞毒T淋巴细胞抗原4(cytotoxic T lymphocyte antigen-4,CTLA-4)及程序性细胞死亡分子1 (programmed death-1，PD1)/程序性死亡蛋白配体1 (programmed death-ligand 1,PD-L1)等分子的研究。已有大量疫苗应用于胰腺癌：靶向KRas、MUC-1/ CEA、WT1 (Wilms tumor-1) 、热激蛋白、多肽疫苗以及VEGFR2 等，其中取得较好效果的有全肿瘤疫苗(如algenpantucel-L)、端粒 酶多肽疫苗(GV1001)、GVAX瘤苗和WT1疫苗等。T细胞也可以控制胰腺癌的进展，大多数免疫疗法在胰腺癌的临床前期实验 中依靠改进T细胞功能来提高疗效，但未来应用于临床还有待进一步深入研究。

Clinical research on immune checkpoint and head and neck squamous cell carcinoma / 中华耳鼻咽喉头颈外科杂志

T cell immune checkpoint pathways contribute to tumor immune escape. Many studies have shown that immune checkpoint is demonstrably correlated with tumor grade or prognosis in several types of malignancies and immune checkpoint has become a new biological index for tumor detection and prognosis. Immune checkpoint inhibitors have shown promising tumor outcomes in clinical trials for some advanced solid tumors and it will become a new target for cancer immunotherapy. In this review we will explore the correlation between expressions of immune checkpoint-associated genes and proteins in immune microenviroment and prognosis of head and neck squamous cell carcinoma, and specifically will discuss how this pathway can be manipulated with immune therapeutic drugs.