Programmed Death Receptor Ligand Research Articles

Progress in the Management of Malignant PleuralMesothelioma in 2017.

Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed deathreceptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1-deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored.

The impact of PD-L1 on survival and value of the immune check point inhibitors in non-small-cell lung cancer; proposal, policies and perspective

BackgroundThe impact of programmed death receptor-ligand1 (PD-L1) on costs and value of the immune check point inhibitors (ICPI) has received minimal attention. Objectives: 1- Design a sliding scale to grade survival in 2nd-line non-small-cell lung cancer (NSCLC). 2- Compare costs and value of Nivolumab (Nivo), Atezolizumab (Atezo) and Pembrolizumab (Pembro) vs. Docetaxel (Doc).MethodsPreviously reported median overall survival (OS) and prices posted by parent company were utilized. The OS gains over controls in days were graded (gr) from A+ to D. Docetaxel costs were calculated for 6–12 cycles and the ICPI for 1 year. Adverse events treatment costs (AEsTC) were reported separately. The cost/life-year gain (C/LYG) was computed as drug yearly-cost/OS gain over control in days × 360 days. The relative value of the ICPI were expressed as $100,000/C/LYG.ResultsCosts of Doc 6 cycles were $23,868, OS/gr 87/C, AEs gr ¾ > 20%, AEsTC $1978 and 6- 12 cycle C/LYG $98,764 -$197,528. Nivo, Atezo and Pembro gr ¾ were < 20% at average costs of $1480. In non-squamous NSCLC, Nivo demonstrated OS/g 84/C and C/LYG $558,326 as compared with 264/A and $177,645 in PD-L1 > 10%. Atezolizumab OS/g were 87/B and C/LYG $551,407 improving in enriched PD-L1 to 162/A and $332,020 respectively. Pembrolizumab in PD-L1 > 1.0% demonstrated OS/g 57/C and C/LYG $659,059 improving in > 50% PD-L1 to 201/A and $186,897. PD-L1 enrichment increased RV of Nivo from 0.18 to 0.56, Atezo from 0.16 to 0.66 and Pembro from 0.15 to 0.53.ConclusionsSimplified methodology to grade OS and weigh value of anticancer drugs was proposed. In 2nd-line non-squamous NSCLC, value of Doc, Nivo, Atezo and Pembro regardless of PDL-1 expression were limited and modest. Enrichment of PD-L1 resulted in unprecedented OS, improved grades and enhanced value at seemingly justifiable costs.

The impact of PD-L1 on survival and values of nivolumab, atezolizumab, and pembrolizumab compared with docetaxel in second-line non-small cell lung cancer.

141 Background: The impact of programmed death receptor-ligand1 (PD-L1) on values of the immune check point inhibitors (ICPI) has received minimal attention. Objectives: Grade survival and weigh values of Nivolumab (Nivo), Atezolizumab (Atezo) and Pembrolizumab (Pembro) vs. Docetaxel (Doc) in 2nd-line non-squamous non-small-cell lung cancer (NSCLC). Methods: Previously reported median overall survival (OS), adverse events and prices posted by the parent companies were utilized. The OS gains in days over controls were graded (gr) from A to D. Docetaxel costs x 6 -12 cycles and ICPI x one year were calculated separately from adverse events treatment costs (AEsTC). Costs/life-year gain (C/LYG) were computed as drug C/OS gain x 360. Relative Values were expressed as $100,000/C/LYG. Results: Docetaxel costs of 9 cycles were $35,802, OS/gr 87/C, AEs gr ¾ &gt; 20%, AEsTC $4,940 and C/LYG $148,146. Nivo, Atezo and Pembro gr ¾ &lt; 20% were at $1,480 costs. In non-squamous NSCLC, Nivo OS/gr were 84/C and C/LYG $545,754. The results improved in PD-L1 &gt; 10% to 264/A and $177,645 respectively. Atezolizumab demonstrated OS/gr 99/C and C/LYG $551,407 improving in PD-L1 50% to 348/A and $151,193. Pembrolizumab in PD-L1 &gt; 1.0%, the OS/gr were 57/C and C/LYG $659,059 improving in &gt; 50% to 201/A and $186,897. PD-L1 enrichment increased relative values of Nivo from 0.19 to 0.56, Atezo from 0.19 to 0.66 and Pembro from 0.15 to 0.53. Conclusions: In 2nd-line non-squamous NSCLC, the OS of Doc, Nivo, Atezo and Pembro were limited. In PD-L1 enriched, the ICPI resulted in unprecedented OS, improved grades and enhanced values at justifiable costs.

Oral cavity squamous cell carcinoma and Waldeyer ring squamous cell carcinoma PDL-1 expression: A large, retrospective, single institution site series on head and neck squamous cell carcinoma, looking at the relationship with morphology, human papilloma virus and p16.

TPS119 Background: The most frequent type of epithelial malignancy in oral cavity and Waldeyer's ring (WR) is squamous cell carcinoma (SCC). Patients with Head and Neck SCC (HNSCC) show reduced levels of CD3+, CD4+, and CD8+ T cells compare to healthy controls. SCCs with a higher number of intra-tumoural CD4+ and CD8+ lymphocytes are associated with better prognosis. Programmed death receptor ligand (PD-L1 ) is present on the surface of neoplastic cells in SCC. T cells harbour inhibitory receptors (the so-called immune checkpoints) such as PD-1. Activation of this immune checkpoints results in T cell deactivation. The PD-1/PDL-1 interaction provokes an immunosuppressive effect which allows the tumour to evade immune destruction. However, WR SCCs present some diversities comparing to oral cavity SCC: younger age, frequent neck LN metastasis, often cystic, distinct morphology: often undifferentiated and solid (nonkeratinizing basal cell morphology), better prognosis, often HPV+, often p16+, an increased number of CD56+ cytotoxic NK. Methods: We have a series of 90 cases of epithelial malignancy in oral cavity and Waldeyer's ring (WR)Squamous cell Carcinoma, registered for Ethics IRAS number for Translational study with Immunohistochemistry; Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR); Fluorescence in Situ Hybridisation (FISH); Next Generation Sequencing; Digital Imaging scanning and visualising microscopy. The Study will show the relationship of PDL-1 expression with morphology, Human Papilloma Virus (HPV) infection and p16 expression, answering if the oral cavity SCC and Waldeyer's Ring SCC express PD-L1 in the same way.

In vitro-induced M2 type macrophages induces the resistance of prostate cancer cells to cytotoxic action of NK cells

Previous reports, including our experimental results, showed that macrophages migrate to prostate cancer (PCa) cells. We tested whether the migrated macrophages affect the susceptibility of castration-resistant PCa (CRPC) cells to cytotoxic actions of natural killer (NK) cells. We found treatment of tumor cells with the conditioned media (CM) of the PMA/IL-4 treated THP-1 cells (M2 type macrophages) (THP-1 CM) decreased the susceptibility of tumor cells to NK cell cytotoxicity, as a result of increased programmed death receptor ligand 1 (PD-L1) and decreased NK group 2D (NKG2D) ligands in CRPC cells. Meanwhile, the decreased susceptibility of tumor cells was also detected when NK cells were treated with THP-1 CM and used in NK cell cytotoxicity tests. Therefore, we observed higher resistance of CRPC cells when both tumor and NK cells were treated with THP-1 CM than when tumor cells or NK cells were individually treated. We further discovered that the PMA/IL-4 treated THP-1 cells secrete a high level of IL-6, so blocking the IL-6 action significantly decreased the PD-L1 level while recovering the NKG2D ligands, thus increasing the susceptibility of CRPC cells to NK cell action. Moreover, we discovered that JAK-Stat3 is the most critical IL-6 downstream signaling in triggering the THP-1 CM effect. Consequently, we found the susceptibility of CRPC cells to NK cells was increased when either JAK or Stat 3 inhibitor was added when tumor cells were treated with THP-1 CM, and that the best effect was observed when the JAK inhibitor and PD-L1 Ab were added together.

Inhibition of IL-6-JAK/Stat3 signaling in castration-resistant prostate cancer cells enhances the NK cell-mediated cytotoxicity via alteration of PD-L1/NKG2D ligand levels.

To investigate whether IL‐6 signaling affects the susceptibility of castration‐resistant prostate cancer (CRPC) cells to cytotoxic action of natural killer (NK) cells, CRPC cell lines (having different IL‐6 levels) were developed by lentiviral transduction. While observing no secreted IL‐6 level in parental C4‐2 and CWR22Rv1 cells, we found the IL‐6 expression/secretion in these cells was induced after the transduction process and the IL‐6 level difference in C4‐2siIL‐6/sc and CWR22siIL‐6/sc cell CRPC cell sets could be detected. We then found that IL‐6‐knockdown cells were more susceptible to NK cell cytotoxicity than control cells due to lowered programmed death receptor ligand 1 (PD‐L1) and increased NK group 2D (NKG2D) ligand levels. In animal studies, to concur with the in vitro results, we found that IL‐6‐expressing cell‐derived tumors were more resistant to NK cell action than the tumors of IL‐6‐knockdown cells. Further, we discovered that JAK‐Stat3 is the most critical IL‐6 downstream signaling that modulates PD‐L1/NKG2D ligand levels in CRPC cells. Furthermore, inhibition of the JAK or Stat3 signaling effectively increased the susceptibility of C4‐2sc and CWRsc cells to NK cell cytotoxicity. We observed the most effective cytotoxicity when the PD‐L1 Ab and JAK inhibitor (or Stat 3 inhibitor) were used together. These results suggest that the strategy of targeting IL‐6 signaling (or its downstream signaling) may enhance the NK cell‐mediated immune action to CRPC tumors, thus yielding clinical implications in developing future immunotherapeutics of exploiting this strategy to treat patients with CRPC.

Adipocytes affect castration-resistant prostate cancer cells to develop the resistance to cytotoxic action of NK cells with alterations of PD-L1/NKG2D ligand levels in tumor cells.

Obesity affects prostate cancer (PCa) progression, and the periprostatic adipose tissue adjacent to the prostate is considered a driving force of disease progression. Adipocytes are the main cell population in adipose tissues and their paracrine role contributes to PCa progression, however its implication in modulating immune reactions remains largely unknown. We investigated the adipocyte role in controlling the susceptibility of castration-resistant PCa (CRPC) cells to the cytotoxic action of natural killer (NK) cells. Using primary NK cells as the NK cell source, NK cell cytotoxicities to CRPC cells, either control media treated or adipocyte-conditioned media (CM) treated, were tested in lactate dehydrogenase (LDH) release-based assays. The levels of programmed death receptor ligand (PD-L1) and NK group 2D (NKG2D) ligands in adipocyte CM-treated CRPC cells were analyzed in qPCR analyses. Effects of blocking adipocyte action on altering PD-L1/NKG2D ligand levels and the susceptibility of CRPC cells to NK cell cytotoxicity were investigated. We found NK cell cytotoxicity to CRPC cells decreases when tumor cells are treated with adipocyte CM associated with PD-L1 and NKG2D ligand level alterations. Further, we discovered that the JAK/Stat3 signaling pathway was responsible for the adipocyte CM effect. Two adipokine molecules, IL-6 and leptin, were shown to be important in activation of the JAK/Stat3 signaling in CRPC cells to modulate the PD-L1/NKG2D ligand level alteration. Adding the inhibitors of JAK/Stat3 signaling or neutralizing antibodies of IL-6 or leptin increased the susceptibility of CRPC cells to NK cell action. Blocking the adipocyte effect by inhibiting the IL-6/leptin-JAK/Stat3 signaling axis may enhance NK cell mediated immunity to CRPC cells and this strategy may help to develop future therapeutics to treat obese PCa patients.

RETRACTED: FASN-TGF-β1-PD-L1 axis contributes to the development of resistance to NK cell cytotoxicity of cisplatin-resistant lung cancer cells

Cisplatin remains the most effective therapy for non-small cell lung cancer (NSCLC). We previously have found cisplatin-resistant lung cancer cells (A549CisR and H157CisR) were more resistant to natural killer (NK) cell-mediated cytotoxicity than parental cells. We also discovered that fatty acid synthase (FASN) levels in cisplatin-resistant cells were significantly higher than in parental cells. To reveal whether a link exists between the up-regulated FASN levels and higher resistance to NK cell cytotoxicity, we performed inhibition studies using a FASN inhibitor and applied the FASN knockdown approach. In both approaches, we found that the FASN inhibition/knockdown significantly increased the susceptibility of cisplatin-resistant cells to NK cell cytotoxicity. We further found such decreased susceptibility was associated with an increased programmed death receptor ligand (PD-L1) level in cisplatin-resistant cells. In mechanisms studies, TGF-β1 was found to be the FASN downstream signaling molecule that was responsible for modulating the PD-L1 levels in cisplatin-resistant cells. Accordingly, TGF-β1 inhibition resulted in significantly increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity. We suggest that the inhibition of FASN-TGFβ1-PD-L1 axis may improve the efficacy of immunotherapy in treating cisplatin-resistant lung cancer.

T-Cell Immunoglobulin Mucin 3 Expression on Tumor Infiltrating Lymphocytes as a Positive Prognosticator in Triple-Negative Breast Cancer.

PurposeT-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) is an emerging immune response molecule related to T-cell anergy. There has been tremendous interest in breast cancer targeting immune checkpoint molecules, especially in the triple-negative breast cancer (TNBC). This study was designed to investigate TIM-3 expression on tumor infiltrating lymphocytes (TILs), its relationships with clinicopathological para-meters and expression of programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 (PD-L1), and its prognostic role.MethodsImmunohistochemistry on tissue microarray blocks produced from 109 samples of invasive ductal carcinoma type TNBC was performed with antibodies toward TIM-3, PD-1, PD-L1 and breast cancer-related molecular markers. Associations between their expression and clinicopathological parameters as well as survival analyses were performed.ResultsTIM-3 was expressed in TILs from all 109 TNBCs, consisting of 17 cases (<5%), 31 cases (6%–25%), 48 cases (26%–50%), and 13 cases (>51%). High TIM-3 was significantly correlated with younger patients (p=0.0101), high TILs (p=0.0029), high tumor stage (p=0.0018), high PD-1 (p=0.0001) and high PD-L1 (p=0.0019), and tended to be associated with higher histologic grade, absence of extensive in situ components and microcalcification. High TIM-3 expression was significantly associated with a combinational immunophenotype group of high PD-L1 and high PD-1 (p<0.0001). High TIM-3 demonstrated a significantly better disease-free survival (DFS) (p<0.0001) and longer overall survival (OS) (p=0.0001), together with high TILs and high PD-1. In univariate survival analysis, high TIM-3 showed reduced relapse risk (p<0.0001) and longer OS (p=0.0003), together with high PD-1 expression. In multivariate analysis, high TIM-3 was statistically significant in predicting prognosis, showing better DFS (hazard ratio [HR], 0.0994; 95% confidence interval [CI], 0.0296–0.3337; p=0.0002) and longer OS (HR, 0.1109; 95% CI, 0.0314–0.3912; p=0.0006).ConclusionIn this study, we demonstrate that TIM-3 expression is an independent positive prognostic factor in TNBC, despite its association with poor clinical and pathologic features.

Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma

Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment. High-dose interleukin-2 (HDIL-2) therapy remains a reasonable treatment option in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and have minimal comorbid conditions. In the near future, these agents are likely to be surpassed by cabozantinib and by combination immune checkpoint inhibitor therapy with nivolumab and ipilimumab. Independent review has recently confirmed superiority of first-line cabozantinib over sunitinib in a phase 2 trial of 157 patients with intermediate or poor risk mccRCC (progression-free survival [PFS] 8.6 vs 5.3months, hazard ratio [HR] 0.48, p = 0.0008). In a separate study of 1096 patients treated with either upfront sunitinib or the combination of nivolumab and ipilimumab, those with intermediate and poor risk had significant improvement in both PFS (11.6 vs 8.4months, HR 0.82, p = 0.0331) and OS (not reached vs 26months, p < 0.0001). Responses were greater in patients with positive programmed death receptor ligand-1 (PD-L1) tumor staining, and pending regulatory approval may become standard of care in untreated patients with intermediate to poor risk disease with positive PD-L1 status. This likely represents the beginning of additional novel immunotherapy combinations for the first-line treatment of mccRCC.

Enhancing CAR T Cell Anti-Tumor Efficacy through Secreted Single Chain Variable Fragment (scFv) Immune Checkpoint Blockade

T cell therapies have had valuable clinical responses in patients with cancer. Chimeric antigen receptor (CAR) T cells can be genetically engineered to recognize tumor cells and CAR T cell therapy has shown impressive results in the setting of B cell acute lymphoblastic leukemia but has been less effective in treating other types of hematologic and solid tumors. The inhibitory tumor microenvironment (TME), including expression of ligands that bind inhibitory receptors on T cells, e.g. programmed death receptor 1 (PD-1), can dampen CAR T cell responses. Separately, immune checkpoint blockade therapy involving the disruption of PD-1 and programmed death receptor ligand1 (PD-L1) interaction allows for re-activation of tumor-infiltrating lymphocytes (TIL) to have anti-tumor function. This approach has shown clinical responses in a range of malignancies, but has been less efficacious in poorly immunogenic tumors.To prevent PD-1-mediated dampening of CAR T cell function, we have co-modified CAR T cells to secrete PD-1 blocking single chain variable fragments (scFv). We first designed mouse constructs with which we could investigate the scFv-secreting CAR T cells in the context of a syngeneic immune-competent intact TME. CAR constructs were engineered directed against either human CD19 or MUC-16 (ecto) with mouse signaling domains and a anti-mouse PD-1 scFv. Mouse T cells transduced with these constructs expressed the CAR on the surface and secreted detectable amounts of scFv that bound to mouse PD-1. The scFv-secreting CAR T cells were cytotoxic and produced IFN-g when co-cultured with PD-L1 expressing tumors in vitro . We utilized a syngeneic mouse model to study scFv secreting CAR T cells in a model with an intact TME. In tumor-bearing mice treated with CAR T cells, scFv-secreting CAR T cells enhanced survival as compared to second generation CAR T cells. The survival benefit achieved with scFv-secreting CAR T cells was comparable to that achieved with systemic infusion of PD-1 blocking antibody, but with localized delivery of PD-1 blockade. Mice treated with scFv-secreting CAR T cells had detectable scFv in vivo in the TME. Lastly, long term surviving mice had detectable CAR T cells in the bone marrow by PCR, demonstrating persistence and suggesting an immunological memory.We next aimed to translate PD-1 blocking scFv CAR T cells to a clinically relevant human model utilizing a novel anti-human PD-1 blocking scFv. CAR constructs were engineered with recognition domains directed against human CD19 or MUC-16 (ecto) and human signaling domains. Human T cells modified with the CAR constructs express the CAR on the surface and secrete detectable amounts of PD-1 blocking scFv. The scFv binds to human PD-1 and scFv-secreting CAR T cells are cytotoxic to PD-L1 expressing tumors. Expression of PD-1-blocking scFv enhances CAR T cell function against PD-L1 expressing tumors in xenograft models of hematological and solid tumors by enhancing survival in tumor-bearing mice as compared to second generation CAR T cells. Furthermore, scFv-secreting CAR T cells exhibit in vivo bystander T cell enhancement of function, suggesting scFv-secreting CAR T cells can reactivate endogenous TILs in the TME.These data support the novel concept that localized delivery of scFv by CAR T cells can successfully block PD-1 binding to PD-L1 and work in an autocrine manner to prevent dampening of CAR T cell responses as well as a paracrine manner to activate endogenous tumor infiltrating lymphocytes to enhance the overall anti-tumor efficacy of CAR T cell therapy. DisclosuresCurran:Juno Therapeutics: Research Funding; Novartis: Consultancy. Yan:Eureka Therapeutics Inc: Employment. Wang:Eureka Therapeutics Inc.: Employment, Equity Ownership. Xiang:Eureka Therapeutics Inc.: Employment. Liu:Eureka Therpeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Brentjens:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Cure in Advanced Renal Cell Cancer: Is It an Achievable Goal?

Immunotherapy has historically been of interest in the management of metastatic renal cell cancer (mRCC) because of its relative chemoresistance and the reproducible but low incidence of spontaneous remission in metastatic disease. Recently, targeted immunotherapies in the form of checkpoint inhibitors have shown durable responses in approximately 20%-30% of patients with solid tumors, with a much more acceptable side-effect profile. Anti-programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 antibodies rely on the presence of host T cells in the tumor microenvironment to be stimulated in order to activate an antitumor response. The presence of tumor antigens augments this stimulation. This has led to further research into combination therapy with anti-PD-1 inhibitors and radiotherapy, chemotherapy, or targeted therapy with the aim of increasing the response rate to these agents. We describe three cases of patients with mRCC treated with anti-PD-1 antibody therapy in combination with targeted therapy (bevacizumab), anti-cytotoxic T lymphocyte antigen 4 therapy (ipilimumab), or radiotherapy. We perform a comprehensive literature review on combination immunotherapy and the scope for the future. Two patients had a complete clinical response within 3 months of commencing treatment. The third patient had a further significant response to radiotherapy outside the field of treatment after initial response to anti-PD-1 therapy, which lasted for over 12 months. We are now in the era of immunotherapy with promising results in select patients. However, the number of complete remissions with single agents are low. This report demonstrates the potential for combination therapy in mRCC to produce complete responses and improved survival rates. Whether these results equate to cure in a subset of patients requires longer follow-up. Further evaluation of dosing regimens, sequencing methods, and biomarkers to select patient population is required to advance this treatment strategy. Multiple phase I-III studies exploring the benefit of combination immunotherapy are currently under way. Further research into predictive biomarkers to identify the cohort of patients who gain this benefit is pertinent. This case series demonstrates that the combination of immunotherapy with other treatments can lead to complete responses, even in patients with initially bulky disease. Combination therapy with immunotherapy seems to cause more durable responses in patients with metastatic renal cell cancer compared with monotherapy. Significantly longer follow-up is necessary to determine whether durable complete response confers a cure in a select group of patients.

PD-1 Blockade Prevents the Development and Progression of Carcinogen-Induced Oral Premalignant Lesions.

Oral squamous cell carcinoma (OSCC) is preceded by progressive oral premalignant lesions (OPL). Therefore, therapeutic strategies that prevent malignant progression of OPLs are expected to reduce the incidence of OSCC development. Immune checkpoint inhibitors that target the interaction of programmed death receptor 1 (PD-1) on T cells with the PD-1 ligand PD-L1 on cancer cells have been shown to extend the survival of patients with advanced OSCC. Here, we used the 4-nitroquinoline-1-oxide (4-NQO) mouse model of oral carcinogenesis to test the hypothesis that PD-1 blockade may control the progression of OPLs. Mice were exposed to 4-NQO in their drinking water and then randomly assigned to two treatment groups that received either a blocking antibody for PD-1 or a control IgG. We found that anti-PD-1 treatment significantly reduced the number of oral lesions that developed in these mice and prevented malignant progression. Low-grade dysplastic lesions responded to PD-1 blockade with a significant increase in the recruitment of CD8+ and CD4+ T cells and the accumulation of CTLA-4+ T cells in their microenvironment. Notably, PD-1 inhibition was accompanied by induction of IFNγ, STAT1 activation and the production of the T-cell effector granzyme B in infiltrating cells, and by the induction of apoptosis in the epithelial cells of the oral lesions, suggesting that T-cell activation mediates the immunopreventive effects of anti-PD-1. These results support the potential clinical benefit of PD-1 immune checkpoint blockade to prevent OSCC development and progression and suggest that CTLA-4 inhibitors may enhance the preventive effects of anti-PD-1. Cancer Prev Res; 10(12); 684-93. ©2017 AACRSee related editorial by Gutkind et al., p. 681.

PL 03.04 Current Status and Future of Immunotherapy in Lung Cancer

The therapeutic approach to overcome Tumor-induced suppression of specific T-cell activation by using specific antibodies, which are interacting with regulating pathways, the immune check-points has substantially changed treatment of patients with advanced NSCLC. In particular the development of antibodies inhibiting cytotoxic T-lymphocyte-associated antigen 4 (anti CTL4), programmed death receptor 1 (anti PD-1) or programmed death receptor ligand 1 (anti PDL-1) have shown efficacy in NSCLC. In five randomized trials anti PD-1/anti PD-L1 antibodies have shown significant improvement in overall survival (OS) compared to chemotherapy and an improved safety profile. Efficacy was correlated to PD-L1 expression on tumor cells. However confirmed activity has also been documented in patients with PD-L1 negative tumors. Besides harmonization of different existing tests for assessment of PD-L1 expression identification of novel markers like tumor mutational burden (TMB) might help to identify best benefitting patients. In selected patients with high PD-L1 expression on tumor cells (TPS =/> 50%) monotherapy with the anti PD1 antibody pembrolizumab has demonstrated superiority in response, progression free survival and OS compared to platinum based chemotherapy in first-line treatment. Current randomized trials evaluate the activity of combinations of chemotherapy with checkpoint inhibitors or of immunotherapy combinations compared to chemotherapy and will provide important information about the next steps in the development of immunotherapy in lung cancer. For the future the development of novel immunotherapeutic agents either as monotherapy or in combination with checkpoint inhibitors as well as the understanding of resistance mechanisms and strategies to overcome resistance will be of paramount importance.

Abstract 5654: Lymphodepletion induces T cell homeostatic proliferation and augments antitumor effects of PD-1/PD-L1 blockade therapy

Abstract Programmed death receptor-1 (PD-1)/programmed death receptor ligand-1 (PD-L1) blockade therapy has demonstrated to enhance antitumor immunity. Recent evidence has shown that anti-PD-1/PD-L1 therapy restores the function of exhausted effector T cells and augments antitumor immune responses. The expression of PD-L1 has been best studied as a biomarker for the anti-PD-1/PD-L1 therapy. Because PD-L1 expression on tumor cells is induced by IFN-γ which is mainly produced by effector T cells, induction of antitumor effector T cells in cancer patients could be an important for the anti-PD-1/PD-L1 therapy. Indeed, previous studies have suggested that the increase of tumor-infiltrating lymphocytes is the predictive biomarker for PD-1/PD-L1 blockade therapy. We and others have demonstrated that lymphodepletive therapies, such as chemotherapy and radiotherapy, induce tumor-specific effector T cells from naïve T cells. Naïve T cells rapidly proliferate and elicit memory-like functions after lymphodepletion (homeostatic proliferation). These findings indicate that lymphodepletive regimens could augment the antitumor efficacies of the anti-PD-1/PD-L1 therapy. In the current study, we transferred naïve T cells into mice after whole-body irradiation or chemotherapy. These mice were inoculated s.c. with PD-L1+ B16F10 melanoma cells or PD-L1- MCA205 fibrosarcoma and then were treated with anti-PD-1 mAbs. Lymphodepletion by whole body irradiation, but not cytotoxic agents following the transfer of naïve T cells significantly enhanced antitumor immunity of anti-PD-1 mAbs. This augmentation required both of CD4+ and CD8+ T cells, but not NK cells. Further experiments revealed that immune cells infiltrating MCA205 expressed PD-L1. Transfer of naïve T cells from IFN-γ knockout mice abrogated the enhancement of antitumor effects of anti-PD-1 mAb therapy by lymphodepletion. These results suggest that lymphodepletion induces homeostatic proliferation of T cells and augments antitumor effects of PD-1/PD-L1 blockade therapy. Citation Format: Masashi Arita, Satoshi Watanabe, Takahashi Miho, Miyuki Sato, Aya Ohtsubo, Kosuke Ichikawa, Rie Kondo, Tetsuya Abe, Junta Tanaka, Toshiyuki Koya, Toshiaki Kikuchi. Lymphodepletion induces T cell homeostatic proliferation and augments antitumor effects of PD-1/PD-L1 blockade therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5654. doi:10.1158/1538-7445.AM2017-5654

Abstract NG02: Lymphatic vessels: Balancing immune priming and immune evasion in melanoma

Abstract NG02: Lymphatic vessels: Balancing immune priming and immune evasion in melanoma

Abstract 2667: In vitro properties and pre-clinical activity of PF-06801591, a high-affinity engineered anti-human PD-1

Abstract Monoclonal-antibody-based therapies targeting the immune checkpoint receptors have become the new standard of care in many cancers. Antibodies that specifically target programmed death receptor-1 (PD-1) or its cognate ligand, programmed death receptor ligand-1 (PD-L1), alone or in combination, have yielded clinical benefits and durable responses in patient subsets with various cancers (including metastatic melanoma, NSCLC, RCC, urothelial cancer, cHL and others). Here we report on the biophysical characteristics and non-clinical antagonistic activities of PF-06801591. PF-06801591 is a humanized anti-PD-1 antibody of human IgG4 isotype, that binds selectively and with similar potency to human and cynomolgus monkey PD-1 receptor (EC50 ~50 pM) and blocks its interaction with its cognate ligands PD-L1 and PD-L2 (IC50 &amp;lt; 1 nM) with no detectable Fc effector function. The interaction of PF-06801591 to PD-1 rescues T cell suppression and exhaustion that translates into NFAT activation, IL-2 and IFN-gamma secretion and T cell proliferation both in vitro cultures and in vivo using an acute xeno GvHD model with human PBMC transfer. Binding of PF-068001591 to human and cynomolgus PD-1 is characterized by the formation of a very stable complex (T1/2 = 2 h) as measured by SPR at 37 C, resulting in high affinity (KD ~20 pM) as measured in solution by KinExA at 23 C. In addition, we explored therapeutic potential of anti-PD-1 in combination with other immunotherapy agents using surrogate antibodies in non-clinical tumor models. The data presented here support future development of PF-06801591 as a single agent or in combination with other immunotherapies. Citation Format: Sawsan Youssef, Yasmina Abdiche, HoangKim Nguyen, Joyce Chou, Sherman Michael Chin, Cris Kamperschroer, Patricia A. Schneider, Eugenia Kraynov, Heike I. Krupka, Arvind Rajpal, John Lin. In vitro properties and pre-clinical activity of PF-06801591, a high-affinity engineered anti-human PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2667. doi:10.1158/1538-7445.AM2017-2667

Promoter hypomethylation of NY-ESO-1, association with clinicopathological features and PD-L1 expression in non-small cell lung cancer.

Cancer-Testis antigens (CTA) are immunogenic molecules with normal tissue expression restricted to testes but with aberrant expression in up to 30% of non-small cell lung cancers (NSCLCs). Regulation of CTA expression is mediated in part through promoter DNA methylation. Recently, immunotherapy has altered treatment paradigms in NSCLC. Given its immunogenicity and ability to be re-expressed through demethylation, NY-ESO-1 promoter methylation, protein expression and its association with programmed death receptor ligand-1 (PD-L1) expression and clinicopathological features were investigated. Lung cancer cell line demethylation resulting from 5-Aza-2′-deoxycytidine treatment was associated with both NY-ESO-1 and PD-L1 re-expression in vitro but not increased chemosensitivity. NY-ESO-1 hypomethylation was observed in 15/94 (16%) of patient samples and associated with positive protein expression (P < 0.0001). In contrast, PD-L1 expression was observed in 50/91 (55%) but strong expression in only 12/91 (13%) cases. There was no association between NY-ESO-1 and PD-L1 expression, despite resultant re-expression of both by 5-Aza-2′-deoxycytidine. Importantly, NY-ESO-1 hypomethylation was found to be an independent marker of poor prognosis in patients not treated with chemotherapy (HR 3.59, P = 0.003) in multivariate analysis. In patients treated with chemotherapy there were no differences in survival associated with NY-ESO-1 hypomethylation. Collectively, these results provided supporting evidence for the potential use of NY-ESO-1 hypomethylation as a prognostic biomarker in stage 3 NSCLCs. In addition, these data highlight the potential to incorporate demethylating agents to enhance immune activation, in tumours currently devoid of immune infiltrates and expression of immune checkpoint genes.

CARSKIN: Pembrolizumab as first line therapy in patients with unresectable cutaneous squamous cell carcinoma (cSCC).

TPS9596 Background: Treatment options are limited for patients (pts) with locally advanced or metastatic cSCCs. Cisplatin-based combinations have some efficacy but their toxicity often prohibits their use, particularly for the elderly. New therapeutic options are needed. Tumors divert the programmed death receptor 1 (PD-1) pathway suppressing immune control. Pembrolizumab (MK-3475) is a high-affinity humanized monoclonal anti-PD-1 antibody. It leads to dual PD-1 ligand (PD-L1 and PD-L2) blockade that may reactivate the immune surveillance and elicit anti-tumor response. It has antitumor activity in several tumors including head and neck SCCs. Moreover, an efficacy of pembrolizumab in cSCCs has been reported recently in a series of 6 cases. Methods: CARSKIN (ClinicalTrials.gov, NCT02883556) is a French multicenter, open-label, nonrandomized phase 2 trial, designed to evaluate the efficacy and safety of pembrolizumab in 39 pts with unresectable and/or metastatic cSCCs, naive of chemotherapy and of EGFR inhibitors. Pembrolizumab is administered (200 mg IV Q3W) for up to 24 months or until disease progression or unacceptable toxicity. Eligible pts must undergo a baseline biopsy of the tumor prior to treatment for PD-L1 evaluation. Response is to be assessed at baseline, wk 9, 15 and 24, and thereafter Q12W by central radiology review per RECIST 1.1 and per modified RECIST v1.1. The primary objective is response rate (RR) at wk 15 per RECIST 1.1. Secondary efficacy objectives are to assess whether patients with PD-L1+ tumors have a better RR than the whole sample at wk 15 and to assess in the whole sample and in PD-L1+ pts, disease control rate (DCR) at wk15, RR at wk 24, best RR, overall survival (OS), progression free survival (PFS), duration of response / control and time to disease progression. A Simon optimal two-stage design will be used. Four responders among 19 pts will be needed in the 1st step to continue the trial. Overall 9 responses will be needed to conclude the effectiveness. Kaplan-Meier statistics will assess PFS and OS. Adverse events (AEs) will be assessed throughout the study and for 30 d thereafter (6 m for serious AEs) and graded per NCI CTCAE v4.0. Clinical trial information: NCT02883556.

MP80-06 EVALUATION OF ‘PROGRAMMED DEATH-1’ / ‘PROGRAMMED DEATH LIGAND 1 AND 2’ PATHWAY IN TUMOR SAMPLES OF SEMINOMA AND NON-SEMINOMA, AND ITS PROGNOSTIC ROLE IN TESTICULAR CANCERS

You have accessJournal of UrologySexual Function/Dysfunction: Penis/Testis/Urethra: Benign Disease & Malignant Disease III1 Apr 2017MP80-06 EVALUATION OF ‘PROGRAMMED DEATH-1’ / ‘PROGRAMMED DEATH LIGAND 1 AND 2’ PATHWAY IN TUMOR SAMPLES OF SEMINOMA AND NON-SEMINOMA, AND ITS PROGNOSTIC ROLE IN TESTICULAR CANCERS Asgar Garayev, Emine Bozkurtlar, Deniz Filinte, Haydar Kamil Cam, Ferruh Simsek, and Ilker Tinay Asgar GarayevAsgar Garayev More articles by this author , Emine BozkurtlarEmine Bozkurtlar More articles by this author , Deniz FilinteDeniz Filinte More articles by this author , Haydar Kamil CamHaydar Kamil Cam More articles by this author , Ferruh SimsekFerruh Simsek More articles by this author , and Ilker TinayIlker Tinay More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2511AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Inhibition of the Programmed Death Receptor 1 (PD-1) and Programmed Death Receptor Ligand 1 (PD-L1) pathway is a promising treatment alterative and improves survival in a number of different cancers, including melanoma and kidney cancer. Recent data showed that evaluation of PD-1 and PD-L1 expression in various tumors could be used for the prognostic value of anti-PD-1 or anti-PD-L1 treatments. We aimed to analyze the expressions of PD-1, PD-L1 and PD-L2 in the testicular germ cell tumors (TGCTs) and evaluate their potential as immunotherapeutic target. METHODS Formalin-fixed paraffin-embedded tumor specimens of 60 patients diagnosed with TGCTs were evaluated, where there are 24 pure seminomas and 36 mixed germ cell tumors. Immunohistochemistry was performed to evaluate expression of PD-1 (EH33 antibody), PD-L1 (E1L3N antibody), PD-L2 (D7U8C antibody), CD8 (4B11 antibody) and CD4 (368) using monoclonal antibodies mentioned in the brackets. RESULTS None of seminoma specimens exhibited PD-L1 expression, where PD-L1 expression was found in 19.4% of mixed germ cell tumors. None of seminomas and nonseminomas expressed PD-L2. In mixed germ cell tumors PD-1 negativity or poor expression of PD-1 in both stromal and intra-tumoral lymphocytes was associated with statistically lower overall survival (figure) and high progression and mortality rates. CONCLUSIONS The PD-1 expression profiles in mixed germ cell tumors could help to identify patients with poor prognosis potential and those patients could benefit from early therapeutic interventions and immunotherapeutic strategies using anti-PD1 and anti-PDL1 antibodies. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1082-e1083 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Asgar Garayev More articles by this author Emine Bozkurtlar More articles by this author Deniz Filinte More articles by this author Haydar Kamil Cam More articles by this author Ferruh Simsek More articles by this author Ilker Tinay More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...