Programmed Death-1 Blockade Therapy Research Articles

Cytokine release syndrome triggered by programmed death 1 blockade (sintilimab) therapy in a psoriasis patient: A case report

BACKGROUND In recent years, immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy across diverse malignancies. Notably, in patients with advanced gastric cancer, the use of programmed death 1 (PD-1) blockade has significantly prolonged overall survival, marking a pivotal advancement comparable to the impact of Herceptin over the past two decades. While the therapeutic benefits of ICIs are evident, the increasing use of immunotherapy has led to an increase in immune-related adverse events. CASE SUMMARY This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis. Following sintilimab therapy, the patient developed severe rashes accompanied by cytokine release syndrome (CRS). Fortunately, effective management was achieved through the administration of glucocorticoid, tocilizumab, and acitretin, which resulted in favorable outcomes. CONCLUSION Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.

Prognostic model for unresectable hepatocellular carcinoma treated with dual PD-1 and angiogenesis blockade therapy

Background and aimsDual programmed death 1 (PD-1) and angiogenesis blockade therapy is a frontline treatment for hepatocellular carcinoma (HCC). An accepted model for survival prediction and risk stratification in individual...

PD-1 blockade and lenalidomide combination therapy for chronic active Epstein-Barr virus infection

ObjectivesChronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T-or NK-cell lymphoproliferative diseases. It is a disease with poor outcome. Almost all current therapies are ineffective except of allogeneic hematopoietic stem cell transplantation. MethodsWe investigated the efficacy and safety of programmed death 1 (PD-1) blockade (Sintilimab), combined with lenalidomide, which is an immunomodulatory drug, in an open-label, single-center, prospective study involving CAEBV patients. PD1 blockade 2mg/kg was given every two weeks by intravenous infusion on day 1, and lenalidomide 5mg (age<18 years)/10mg (age ≥ 18 years) was given orally once a day on day 1-14. ResultsAs of Nov 15, 2020, 34 patients were enrolled. As of the Feb 1, 2021 analysis cut-off date, 24 cases completed at least 3 courses and were assessed for efficacy. The overall response rate is 54.2% (13/24, 45.8% complete response; 8.3% partial response). EBV-DNA copies in PBMC decreased significantly (p = 0.002). The proportion of CD8+T cells in lymphocytes increased (p = 0.007). The comparative analysis between response group and non-response group showed the proportion of Effector Memory CD8+ T cells and cytokines of CTLs activation (IFN-γ, CD27, CD30, MIG, IP-10) increased significantly in Response-group after treatment. Whole-exome sequencing generated from peripheral blood and saliva samples reveal that Non-Response group had a higher somatic mutational load of copy number variation in background. With a median follow-up time of 17.8 months, 22 of 24 patients were alive with an estimated survival probability of 91.3% at 1 year. All 34 patients were assessed for safety evaluation. The possible drug-related adverse events were reported in 17 (50%) patients. ConclusionsPD-1 blockade combined with lenalidomide was an effective and safe therapy for CAEBV patients. The significant therapeutic effect and the different characteristics between response and non-response group, provides a possible predictive value for CAEBV treatment option.

OX40 enhances T cell immune response to PD-1 blockade therapy in non-small cell lung cancer

Immune-checkpoint blockade is widely studied for cancer therapy. Although the co-inhibitory receptor Programmed death-1(PD-1) blockade benefits some non-small cell lung cancer (NSCLC) patients, a large portion of NSCLC patients still fail to respond to this immunotherapy, and the underlying mechanism is unclear. Thus, a synergistic therapy to enhance the effect of PD-1 is urgently needed to improve the poor outcome of NSCLC patients. Here, we demonstrated that effector memory T cells were increased and T cell response became stronger in PD-1 immunotherapy responders (n = 20) but not in non-responders (n = 10). The expression of co-stimulatory receptor OX40 was upregulated on T cells following PD-1 immunotherapy and was positively associated with the percentage of PD-1+T cells and the responsiveness of T cells. Combination treatment of antagonistic anti-PD-1 and agonistic anti-OX40 antibodies (Abs) promoted the proliferation and cytokines production of T cells from PBMCs of non-responders ex vivo. Consistently, anti-PD-1 and anti-OX40 therapy synergistically augmented T cell response in an in vivo mouse lung cancer model. Our study confirmed the antitumor effects of anti-PD-1/OX40 combination in lung cancer patients as well as in the murine lung cancer model, and the results provide a rationale for clinical trials evaluating the therapeutic effect of this combination of antibodies for NSCLC immunotherapy.

Lactic acid promotes PD-1 expression in regulatory Tcells in highly glycolytic tumor microenvironments.

The balance of programmed death-1 (PD-1)-expressing CD8+ Tcells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector Tcells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector Tcells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.

Severe gastritis in a patient treated with immunotherapy: immune-mediated or reactivation of cytomegalovirus?

Cancer patients receiving programmed death 1 (PD-1) immune checkpoint blockade therapy are susceptible, due to immunosuppression, to a variety of infections including cytomegalovirus infection. We report an unusual case of histologically confirmed gastritis due to cytomegalovirus infection in a patient who had metastatic melanoma and received PD-1 blockade therapy with pembrolizumab. Pembrolizumab was discontinued and treatment with intravenous ganciclovir and oral vangaciclovir was initiated; the patient's symptoms improved significantly.

Effect of Systemic or Intraperitoneal Administration of Anti-PD-1 Antibody for Peritoneal Metastases from Gastric Cancer.

Programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) blockade therapy is widely used for the treatment of patients with metastatic gastric cancer (GC). However, it is unclear how PD-1 antibodies affect the local immunity related to the growth of peritoneal metastases (PM). The clinical efficacy of PD-1/PD-L1 inhibitors against PM from GC has not been clearly determined. We established a highly metastatic subclone of murine GC cells to the peritoneum, YTN16P, by in vivo selection and evaluated the effects of intravenous (IV) or intraperitoneal (IP) administration of anti-PD-1 antibody on PM in immunocompetent mice model. Phenotypes of immune cells in the spleen and peritoneal metastatic lesions were determined with flow cytometry and immunohistochemistry. IP inoculation of YTN16P (1×106) resulted in multiple mesenteric metastases after 3 weeks. IV and IP administration of anti-PD-1mAb reduced the number of metastases to the mesentery by 30~40% compared with isotype controls. However, no differences were observed depending on the route of administration. Although splenocyte phenotypes were not altered, the densities of CD8(+) T cells in peritoneal tumors were significantly increased, whereas those of Gr-1(+) myeloid derived suppressor cells (MDSC) were significantly reduced in mice treated with anti-PD-1 mAb. PD-1 blockade therapy remodels the cellular immune composition of peritoneal tumors, which can partially suppress the PM from GC regardless of the route of administration. Adding anti-PD-1 antibody to chemotherapeutic regimens may enhance their anti-tumor effects against PM, which can lead to the prolongation of survival of patients with GC with peritoneal involvement.

Impact of PD-1 Blockade on Severity of COVID-19 in Patients with Lung Cancers.

The coronavirus disease 2019 (COVID-19) pandemic has led to dramatic changes in oncology practice. It is currently unknown whether programmed death 1 (PD-1) blockade therapy affects severity of illness from COVID-19 in patients with cancer. To address this uncertainty, we examined consecutive patients with lung cancers who were diagnosed with COVID-19 and examined severity on the basis of no or prior receipt of PD-1 blockade. Overall, the severity of COVID-19 in patients with lung cancer was high, including need for hospitalization in more than half of patients and death in nearly a quarter. Prior PD-1 blockade was, as expected, associated with smoking status. After adjustment for smoking status, PD-1 blockade exposure was not associated with increased risk of severity of COVID-19. PD-1 blockade does not appear to affect the severity of COVID-19 in patients with lung cancers. SIGNIFICANCE: A key question in oncology practice amidst the COVID-19 pandemic is whether PD-1 blockade therapy affects COVID-19 severity. Our analysis of patients with lung cancers supports the safety of PD-1 blockade treatment to achieve optimal cancer outcomes.This article is highlighted in the In This Issue feature, p. 1079.

Overall survival and biomarker analysis of a phase Ib combination study of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) with axitinib in patients with metastatic mucosal melanoma.

10007 Background: Metastatic mucosal melanoma responds poorly to PD-1 blockade therapy in comparison with cutaneous melanoma. Vascular endothelial growth factor (VEGF) is indicated to play an important immunosuppressive role in mucosal melanoma. Combination of VEGF inhibition with PD-1 blockade might provide therapeutic opportunities. Toripalimab was approved as a second-line treatment for metastasis melanoma in Dec 2018. This study is to evaluate the safety and clinical efficacy of toripalimab combined with axitinib for the treatment of metastatic mucosal melanoma. (Clinical trial ID: NCT03086174). Methods: Patients with metastatic melanoma receive 1 or 3 mg/kg toripalimab Q2W in combination with 5 mg axitinib BID until disease progression, unacceptable toxicity, or voluntary withdrawal. Clinical response is assessed every 8 weeks according to RECISTv1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and gene expression profile (GEP) will be evaluated for correlation with clinical response. Results: From April 2017 to April 2018, 33 patients were enrolled in the study. No DLT or treatment related death was observed. 97% patients experienced treatment related AE (TRAE) and 39.4% patients experienced Grade 3-4 TRAEs. Most common TRAEs include diarrhea, proteinuria, hand and foot syndrome and hypothyroidism. Only one patient discontinued treatment due to TRAE. Among 29 treatment naïve mucosal melanoma patients, 14 PR and 11 SD were observed for an ORR of 48.3% and a DCR of 86.2%. The median DOR was 13.7 months. The median PFS was 7.5 months and the median OS was 20.7 months. PD-L1 expression or TMB had no significant differences in responders versus non-responders. In contrast, GEP scores of eight selected immune-related and four angiogenesis-related genes showed strong correlation with clinical response, whereas previous published immune related signature or angiogenesis signature alone had no correlation. Conclusions: Toripalimab combined with axitinib is a promising treatment option for metastatic mucosal melanoma. GEP scores of selected immune-related and angiogenesis-related genes might predict the response to the combination. A randomized 3-arm Phase 2 trial has been initiated to compare toripalimab plus axitinib with toripalimab or axitinib alone. Clinical trial information: NCT03086174.

Interferon gamma inhibits CXCL8–CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer

BackgroundPancreatic cancer (PC) is a common malignancy of the digestive system and is characterized by poor prognosis and early metastasis. Tumor immune escape plays an important role in PC progression....

Cytokines as potential combination agents with PD-1/PD-L1 blockade for cancer treatment.

Immunotherapy has caused a paradigm shift in the treatment of several malignancies, particularly the blockade of programmed death-1 (PD-1) and its specific receptor/ligand PD-L1 that have revolutionized the treatment of a variety of malignancies, but significant durable responses only occur in a small percentage of patients, and other patients failed to respond to the treatment. Even those who initially respond can ultimately relapse despite maintenance treatment, there is considerable potential for synergistic combinations of immunotherapy and chemotherapy agents with immune checkpoint inhibitors into conventional cancer treatments. The clinical experience in the use of cytokines in the clinical setting indicated the efficiency of cytokine therapy in cancer immunotherapy. Combinational approaches to enhancing PD-L1/PD-1 pathways blockade efficacy with several cytokines such as interleukin (IL)-2, IL-15, IL-21, IL-12, IL-10, and interferon-α (IFN-α) may result in additional benefits. In this review, the current state of knowledge about PD-1/PD-L1 inhibitors, the date in the literature to ascertain the combination of anti-PD-1/PD-L1 antibodies with cytokines is discussed. Finally, it is noteworthy that novel therapeutic approaches based on the efficient combination of recombinant cytokines with the PD-L1/PD-1 blockade therapy can enhance antitumor immune responses against various malignancies.

PGC-1α activator-induced fatty acid oxidation in tumor-infiltrating CTLs enhances effects of PD-1 blockade therapy in lung cancer.

The present study aims to investigate the efficacy and mechanisms of peroxisome proliferator-activated receptor γ coactivator 1-α agonist, as adjuvant to programmed death-1 (PD-1) blockade in hyporesponsive lung cancer cells-derived in vivo tumor model, using bezafibrate. Mouse Lewis lung carcinoma (LLC) xenograft models were established and treated with programmed death-ligand 1 (PD-L1) monoclonal antibodies with or without bezafibrate. Tumors or peripheral blood of mice were harvested to investigate the quality, quantity, and function as well as energetic metabolism of cytotoxic T lymphocytes (CTLs) by flow cytometry or quantitative real-time polymerase chain reaction. The combination of bezafibrate plus anti-PD-L1 reached synergistic tumoricidal effect in LLC xenograft mouse models, even though bezafibrate alone had no effect on tumor growth. Bezafibrate significantly facilitated CD8+ T cells infiltrating into tumor tissues by enhancing the expression of CXCL9 and CXCL10 within tumors as well as the receptor CXCR3 in infiltrating CTLs. Activated CTLs within tumors were also significantly upregulated by bezafibrate. Further data demonstrated that bezafibrate treatment could maintain the survival and functional capacity of tumor-infiltrating CTLs. Moreover, cellular reactive oxygen species in infiltrating CTLs and fatty acid oxidation (FAO)-related genes (PGC-1α, Cpt1a, and LCAD) expression within tumors were significantly increased after treatment with bezafibrate. Bezafibrate synergized the tumoricidal effect of PD-1 blockade in hyporesponsive lung cancer by expansion of effector CTLs within tumor microenvironment. The potential mechanism may relate to the capacity of bezafibrate in regulating FAO of tumor-infiltrating CTLs.

PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell–inflamed phenotype

AbstractProgrammed death-ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism across a variety of human cancers. A unique genetic mechanism underlying PD-L1 upregulation has been uncovered in classical Hodgkin lymphoma (cHL), in which copy gains of the chromosomal region (9p24.1) containing the programmed death-1 (PD-1) ligands PD-L1 and PD-L2 are recurrently observed. While chromosome 9p24.1 copy-number alterations are ubiquitous in cHL, they also occur in diffuse large B-cell lymphoma (DLBCL), albeit with a lower incidence. Here, fluorescence in situ hybridization was used to identify DLBCLs harboring PD-L1 gene alterations, thereby enabling a characterization of the immunogenomic landscape of these lymphomas. Among 105 DLBCL cases analyzed, PD-L1 alterations were identified in 27%. PD-L1 alterations were highly enriched among non–germinal center DLBCLs and exhibited robust PD-L1 protein expression. These lymphomas were heavily infiltrated by clonally restricted T cells and frequently downregulated human leukocyte antigen expression. RNA sequencing of PD-L1–altered DLBCLs revealed upregulation of genes involved in negative T-cell regulation and NF-κB pathway activation, while whole-exome sequencing identified frequent mutations in genes involved in antigen presentation and T-cell costimulation. Many of these findings were validated in a large external data set. Interestingly, DLBCL patients with PD-L1 alterations had inferior progression-free survival following front-line chemoimmunotherapy; however, in the relapsed/refractory setting, PD-L1 alterations were associated with response to anti-PD-1 therapy. Collectively, our results indicate that PD-L1 alterations identify a unique biological subset of DLBCL in which an endogenous antilymphoma immune response has been activated, and that is associated with responsiveness to PD-1 blockade therapy.

Italian expert panel consensus statement on the optimal use of PD-1 blockade therapy in classical Hodgkin lymphoma

Programmed death 1 (PD-1) blocking antibodies now represent a major advance in the treatment of patients with classical Hodgkin lymphoma (cHL) who relapse after autologous stem cell transplantation (ASCT) and pre- and/or post-ASCT brentuximab vedotin or after at least three lines of therapy. However, uncertainties still remain on the optimal use of these agents in refractory Hodgkin disease. A panel of experts was convened to produce a consensus document aimed at providing practice recommendations for the optimal use of PD-1 blocking antibodies in cHL, especially on pretreatment selection and evaluation of cHL patients’ response and treatment length, management of PD-1 blockade therapy–treated patients, evaluation and management of toxicity. Our hope is that these recommendations might help hematologists to improve optimal management of patients with pretreated cHL.

Modulation of Gut Microbiota: A Novel Paradigm of Enhancing the Efficacy of Programmed Death-1 and Programmed Death Ligand-1 Blockade Therapy.

Blockade of programmed death 1 (PD-1) protein and its ligand programmed death ligand 1 (PD-L1) has been used as cancer immunotherapy in recent years, with the blockade of PD-1 being more widely used than blockade of PD-L1. PD-1 and PD-L1 blockade therapy showed benefits in patients with various types of cancer; however, such beneficial effects were seen only in a subgroup of patients. Improving the efficacy of PD-1 and PD-L1 blockade therapy is clearly needed. In this review, we summarize the recent studies on the effects of gut microbiota on PD-1 and PD-L1 blockade and discuss the new perspectives on improving efficacy of PD-1 and PD-L1 blockade therapy in cancer treatment through modulating gut microbiota. We also discuss the possibility that chronic infections or inflammation may impact on PD-1 and PD-L1 blockade therapy.

Management of gastrointestinal adverse events induced by immune-checkpoint inhibitors

Immune-checkpoint inhibitors (ICIs) have been proven promising for advanced cancers, and they are characterized by a unique treatment-related adverse event (AE) spectrum. Toxicity of the gastrointestinal (GI) tract is one of the most common AEs and often results in discontinuation of ICIs. Since most of the current studies have focused on the incidence, characteristics, and management of colitis, very little is known about other types of GI AEs. Herein, we review the available relevant literature on upper and lower GI toxicities, and present an algorithm for GI AE management based on the existing evidence and our clinical experience. Nausea and decreased appetite are the most common upper GI AEs, and gastric bleeding has been observed. Glucocorticoids are not recommended for upper GI bleeding and should be carefully used for cases without bleeding. Diarrhea and colitis are the most common lower GI AEs characterized by inflammation of the mucosa, and high-dose glucocorticoids with other immunomodulators are recommended as salvage treatments. Constipation and paralytic bowel obstruction caused by dysfunction of the GI tract are less frequent and respond well to medications promoting bowel movements. Severe GI AEs should be managed by a multidisciplinary team based on a comprehensive assessment of disease severity. Further clinical trials are warranted to investigate the optimal management of GI AEs.

Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy.

Programmed death 1 (PD-1) is an immune checkpoint molecule that negatively regulates T-cell immune function through the interaction with its ligand PD-L1. Blockage of this interaction unleashes the immune system to fight cancer. Immunotherapy using PD-1 blockade has led to a paradigm shift in the field of cancer drug discovery, owing to its durable effect against a wide variety of cancers with limited adverse effects. A brief history and development of PD-1 blockade, from the initial discovery of PD-1 to the recent clinical output of this therapy, have been summarized here. Despite its tremendous clinical success rate over other cancer treatments, PD-1 blockade has its own pitfall; a significant fraction of patients remains unresponsive to this therapy. The key to improve the PD-1 blockade therapy is the development of combination therapies. As this approach has garnered worldwide interest, here, we have summarized the recent trends in the development of PD-1 blockade-based combination therapies and the ongoing clinical trials. These include combinations with checkpoint inhibitors, radiation therapy, chemotherapy and several other existing cancer treatments. Importantly, FDA has approved PD-1 blockade agent to be used in combination with either CTLA-4 blockade or chemotherapy. Responsiveness to the PD-1 blockade therapy is affected by tumour and immune system-related factors. The role of the immune system, especially T cells, in determining the responsiveness has been poorly studied compared with those factors related to the tumour side. Energy metabolism has emerged as one of the important regulatory mechanisms for the function and differentiation of T cells. We have documented here the recent results regarding the augmentation of PD-1 blockade efficacy by augmenting mitochondrial energy metabolism of T cell.

PD-1 Blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Preliminary Results from a Phase 1b Study (KEYNOTE-013)

The programmed death-1 (PD-1) pathway serves as an immune checkpoint to temporarily dampen immune responses upon chronic antigen stimulation. Normal antigen presenting cells and certain tumor cells express the PD-1 ligands, PD-L1 and PD-L2, which engage PD-1 receptors on activated T cells and induce T-cell exhaustion. PD-1 signaling is a potent mechanism of tumor immune escape and a compelling target for therapy. Antibody-mediated PD-1 blockade has already been successfully exploited as a therapeutic strategy in solid tumors and is currently being evaluated in hematologic malignancies. Classical Hodgkin lymphoma (cHL) may represent a uniquely vulnerable target for PD-1 blockade therapy. This disease is characterized by an extensive inflammatory immune cell infiltrate and a dominant genetic alteration in chromosome 9p24.1 that leads to PDL1 and PDL2 copy gain and associated overexpression of these PD-1 ligands. In cHL, Epstein-Barr virus infection represents an additional mechanism of upregulating PD-1 ligand expression. For these reasons, cHL was included as a cohort of the ongoing, multicenter, open-label, phase 1b clinical trial of the monoclonal antibody pembrolizumab (MK-3475; Merck, Whitehouse Station, NJ) in hematologic malignancies (KEYNOTE-013; ClinicalTrials.gov identifier, NCT01953692).Eligibility criteria for the cHL arm of KEYNOTE-013 include relapsed or refractory cHL, relapse from or failure to respond to brentuximab vedotin treatment, and adequate performance status and organ function. Patients with autoimmune disease or interstitial lung disease are excluded. Treatment consists of single-agent pembrolizumab 10 mg/kg administered intravenously every 2 weeks until confirmed tumor progression, excessive toxicity, or completion of 2 years of therapy. The main end points of this study are safety, tolerability, and complete remission (CR) rate. The first time point for radiologic restaging is at week 12 (ie, after 6 cycles of treatment).Herein, we report preliminary results from the 15 patients with cHL who were evaluable for response to pembrolizumab at the 12-week time point. The median patient age was 28 years (range, 21-67), and the median number of prior therapies was 4. By design, all patients previously failed brentuximab vedotin; 67% also failed prior autologous stem cell transplantation. Pembrolizumab was well tolerated. There were no serious adverse events (AEs), and only 1 patient experienced grade 3-5 AEs (grade 3 pain and grade 3 joint swelling, both considered to be unrelated to study drug). Overall, 10 patients experienced ≥1 AE. The most common drug-related AEs were grade 1-2 respiratory events (20%) and thyroid disorders (20%). One patient discontinued study treatment because of an AE (grade 2 pneumonitis), and 3 patients ended therapy after progressive disease (PD). Based on investigator assessment using the Cheson 2007 International Harmonization Project response criteria, 3 patients (20%) had a CR at 12 weeks. Five additional patients (33%) had partial remission as best overall response, for an overall response rate of 53%. Four patients (27%) experienced PD, although all 4 experienced a decrease in their overall tumor burden (Figure 1). In conclusion, pembrolizumab therapy appears to be safe, tolerable, and associated with clinical benefit in patients with heavily pretreated cHL.Figure 1: Best percentage change from baseline in tumor size for all patients. [Display omitted] DisclosuresMoskowitz:Merck: Research Funding. Off Label Use: Pembrolizumab is a humanized, monoclonal IgG4-kappa isotype antibody against PD-1 that is currently in clinical development for multiple advanced solid tumors and hematologic malignancies.. Ribrag:Servier: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Epizyme: Research Funding; Pharmamar: Consultancy; Celgene: Consultancy. Martinelli:Novartis: Speakers Bureau; Ariad: Consultancy; Pfizer: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Giallella:Merck: Employment. Weimer Anderson:Merck: Employment. Derosier:Merck: Employment. Wang:Accenture: Employment. Yang:Merck: Employment. Rubin:Merck: Employment. Rose:Merck: Employment. Shipp:Merck: Membership on an entity’s Board of Directors or advisory committees; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bayer: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R&D: Membership on an entity’s Board of Directors or advisory committees. Armand:Merck: Consultancy.

B7-H1/PD-1 blockade therapy in non-small cell lung cancer: current status and future direction.

Over the past few years, there has been a mounting enthusiasm around the potential of immunotherapy in the treatment of non-small cell lung cancer (NSCLC). This interest was catalyzed in 2012 by initial reports of responses to programmed death 1 (PD-1) pathway inhibition in patients with heavily pretreated advanced NSCLC. Since then, a number of antibodies targeting either PD-1 or the primary ligand of PD-1, programmed death ligand 1 (PD-L1), have shown durable responses in phase I studies with large NSCLC expansion cohorts. Therapies have been well tolerated, with rare severe autoimmune toxicity. Two phase III trials have completed accrual in pretreated NSCLC patients, with a phase III trial underway in chemotherapy-naive patients with advanced NSCLC. Efforts are now focusing on identifying predictive biomarkers such as tumor PD-L1 expression and combinations of PD-1/PD-L1 inhibitors with either standard therapies for advanced NSCLC or other immunotherapies. This review summarizes clinical trial results to date and discusses challenges with ongoing and future clinical trials evaluating this new class of drugs.

A novel method to identify and monitor endogenous tumor-reactive T cells by high expression of CD11a (LFA-1) and PD-1 (CD279) as immunologic readout for evaluating the efficacy of PD-1 blockade.

3037 Background: Tumor immunotherapies directed towards enhancing natural or endogenous anti-tumor T-cell immunity in patients with advanced malignancies are currently being implemented in clinic with promising results. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, a reliable T-cell marker is needed. Methods: We utilized CD11a (LFA-1, lymphocyte functional-associated antigen 1), an integrin up-regulated on effector and memory CD8 T-cells, and PD-1 (programmed death-1), an immunoregulatory receptor expressed by activated T cells, as biomarkers to identify, quantitate and monitor endogenous tumor-reactive cytotoxic lymphocytes (CTLs) in two mouse tumor models and the peripheral blood (PB) of 12 patients with stage IV melanoma. Results: High expression of CD11a and PD-1 was identified among CD8 T-cells residing within primary and metastatic murine tumor sites, as well as in spontaneous murine breast cancer tissues. In the PB of melanoma patients, tumor antigen-specific CD8 T cells were associated with a population of CD11a high CD8 T-cells which co-expressed high levels of PD-1, as opposed to eleven healthy donors who had a much lower frequency of PD-1+ CD11a high CD8 T-cells (p &lt;0.0001). Phenotypic analysis showed that CD11a high CD8 T-cells are proliferating (Ki67 positive) activated (CD62L low, CD69 high) T-cells. Increased CD11a high CD8 T-cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector function of CD8 T cells is compromised by co-expression of elevated levels of PD-1. Conclusions: CD11a high CD8 T-cell population expresses high levels of PD-1 and is likely the cellular target of PD-1 blockade therapy. High expression of CD11a (LFA-1) and PD-1 (CD279) by CD8 T-cells may represent a novel biomarker to identify and monitor endogenous tumor-reactive CTLs. This may not only provide an immunological readout for evaluating the efficacy of therapy, but also contribute to the selection of patients with solid malignancies likely to benefit from anti-PD-1 therapy.