Role Of Immune Checkpoint Blockade Research Articles

Niraparib enhances antitumor immunity and contributes to the efficacy of PD-L1 blockade in cervical cancer

PurposeWith the development of immunotherapy research, the role of immune checkpoint blockade (ICB) in the treatment of cervical cancer has been emphasized, but many patients still can’t receive long-term benefits from ICB. Poly ADP ribose polymerase inhibitor (PARPi) has been proved to exert significant antitumor effects in multiple solid tumors. Whether cervical cancer patients obtain better benefits from the treatment regimen of PARPi combined with ICB remains unclear.MethodsThe alteration of PD-L1 expression induced by niraparib in cervical cancer cells and its underlying mechanism were assessed by western blot and immunofluorescence and quantitative real-time polymerase chain reaction (qRT–PCR).The regulation of PTEN by KDM5A was confirmed using Chromatin immunoprecipitation (ChIP) assay and RNA interference. Analyzing the relationship between PD-L1 and immune effector molecules through searching online databases. Therapeutic efficacy of niraparib, PD-L1 blockade or combination was assessed in syngeneic tumor model. The changes of immune cells and cytokines in vivo was detected by immunohistochemistry (IHC) and qRT–PCR.ResultsWe found that niraparib upregulated PD-L1 expression and potentiated the antitumor effects of PD-L1 blockade in a murine cervical cancer model. Niraparib inhibited the Pten expression by increasing the abundance of KDM5A, which expanded PD-L1 abundance through activating the PI3K-AKT-S6K1 pathway. PD-L1 was positively correlated with immune effector molecules including TNF-α, IFN-γ, granzyme A and granzyme B based on biological information analysis. Niraparib increased the infiltration of CD8+ T cells and the level of IFN-γ, granzyme B in vivo.ConclusionOur findings demonstrates the regulation of niraparib on local immune microenvironment of cervical cancer, and provides theoretical basis for supporting the combination of PARPi and PD-L1 blockade as a potential treatment for cervical cancer.

The role of immune checkpoint blockade in children, adolescents, and young adults: A systematic review and meta-analysis.

10057 Background: Immune checkpoint blockade (ICB) has changed the treatment landscape for many types of adult cancer. However, while certain subsets of cancer in children, adolescents, and young adults (CAYA) are ICB-responsive, ICBs are less routinely used in clinical practice, thus clinical experience lags behind that of adults. Therefore, we performed a systematic review and meta-analysis to evaluate the safety and efficacy of ICB in the CAYA population. Methods: PubMed, Cochrane and Embase libraries were systematically searched for clinical trials evaluating ICB therapies for cancer in CAYA patients. We excluded reviews, case reports, observational studies, retrospective studies, studies with overlapping populations, trials with no outcomes of interest, and studies enrolling the adult populations (>40 years). We pooled the prevalence of treatment-related adverse events (TRAE), objective response rate (ORR), stable disease (SD), and their corresponding 95% confidence intervals (95% CI). For ORR and TRAE endpoints, we performed a subgroup analysis of each drug (PD-1, PD-L1 and CTLA-4) and each tumor type. A comparative analysis of the reported median overall survival (OS) and progression-free survival (PFS) was also completed. Statistical analysis was performed using R software version 4.3.1 and heterogeneity was evaluated through I2 statistics. Results: From 3,753 initial studies, 15 clinical trials were included, comprising 797 patients with median age ranging from 6.5 to 16.0 years (1-30 years) and multiple types of hematologic and solid malignancies. An all-grade TRAE rate of 66% was found (95% CI 60-71), while the proportion of grade 3/4 TRAE was 19% (95% CI 13-27). In the tumor type subgroup analysis for all-grade TRAE and grade 3/4 TRAE, solid tumors had the highest rates; 92% (95% CI 41-99) and 50% (95% CI 14-42), respectively. Central nervous system tumors had all-grade and grade 3/4 TRAE rates of 61% (95% CI 53-68) and 21% (95% CI 12-33), respectively. Fatigue, anemia, and nausea were the most frequently reported TRAE. The ORR was 13% (95% CI 5-27) (82 of 531 patients). For drug class and tumor type subgroup analysis, PD-1 inhibitors and lymphoma presented the highest proportion of ORR, with 25% (95% CI 8-56) and 59% (95% CI 23-87), respectively. SD was noted in 21% (95% CI 14-30) of patients (97 of 467 patients). Median OS, available for 300 patients, ranged from 4.4 to 23.7 months, while median PFS, available for 299 patients, ranged from 1.2 to 6.2 months. Conclusions: This study suggests that ICB is well tolerated in CAYA patients with different cancer types. As previously reported in the literature, certain subsets of CAYA cancer are ICB-responsive. This pooled safety data supports the continued investigation of ICB in CAYA patients most likely to benefit from ICB therapy, including advancing ICB into combination strategies.

Endoscopic surgery combined chemoradiotherapy and PD-1 blockade in patients with sinonasal mucosal melanoma.

e21552 Background: Primary sinonasal mucosal melanoma (SNMM) is a rare and aggressive disease different from cutaneous melanoma. The best treatment modality including the role of immune checkpoint blockade in SNMM has not been defined. Methods: Between 2021 and 2023, patients with previously untreated sinonasal melanoma were enrolled by three single-center investigator-initiated phase II clinical trials (ChiCTR2100046498 / ChiCTR2100045797/ ChiCTR2100049031). Eligible patients in ChiCTR2100045797 trial received postoperative radical chemoradiotherapy combined with toripalimab (a PD-1 inhibitor) for a year or until the disease progressed. Eligible participants in ChiCTR2100046498 study received surgery combined with radiation without immunotherapy. And for patients in ChiCTR2100049031 study, preoperative radiation was carried out firstly. The locoregional control, distant metastasis-free survival (DMFS), and overall survival (OS) were the main efficacy goals. Results: Fifty-four patients were enrolled (mean age 62 years, 33 males [61.1%] and 21 women [38.9%]) with 2y-OS rate 62.3±7.9%, 2y-RFS rate 67.1±8.2%, and 2y-DMFS rate 63.9±8.1%. Patients with T3 (n = 23), T4a (n = 14), and T4b (n = 17) stages, including12 patients with node-positive disease, were included at baseline. During a median follow-up of 11 months, 19 patients ultimately died, 10 experienced relapses, and 17 developed metastases. Tumor T staging was demonstrated to be an independent prognostic predictor according to the Cox univariate analysis. The primary factor contributing to a poor prognosis and the primary cause of death for 73.7% of patients was distant metastases. Preoperative radiation had an improved long-term survival with 2y-OS rate of 85.7±13.2%, and it can considerably lower the risk of distant metastases (p≤0.05). The overall survival rate for patients receiving postoperative chemoradiotherapy combined with immunotherapy was higher than that for patients not receiving immunotherapy (2y-OS rate 74.1±11.4% vs. 39.3±15.8%), although the difference was not statistically significant due to a small number of patients (p = 0.16). No immune-related adverse effects grade≥3 was recorded. Conclusions: The primary cause of the poor prognostic performance of SNMM is distant metastasis. The risk of distant metastases might be considerably decreased by preoperative radiation treatment. Surgery combined with radiation and immunotherapy could bring promising survival benefit. The way forward may involve investigating the combination of immunotherapy and preoperative radiotherapy. Clinical trial information: NCT04879654 ; NCT05009446 .

Endoscopic surgery combined chemoradiotherapy and PD-1 blockade in patients with sinonasal mucosal melanoma.

e21552 Background: Primary sinonasal mucosal melanoma (SNMM) is a rare and aggressive disease different from cutaneous melanoma. The best treatment modality including the role of immune checkpoint blockade in SNMM has not been defined. Methods: Between 2021 and 2023, patients with previously untreated sinonasal melanoma were enrolled by three single-center investigator-initiated phase II clinical trials (ChiCTR2100046498 / ChiCTR2100045797/ ChiCTR2100049031). Eligible patients in ChiCTR2100045797 trial received postoperative radical chemoradiotherapy combined with toripalimab (a PD-1 inhibitor) for a year or until the disease progressed. Eligible participants in ChiCTR2100046498 study received surgery combined with radiation without immunotherapy. And for patients in ChiCTR2100049031 study, preoperative radiation was carried out firstly. The locoregional control, distant metastasis-free survival (DMFS), and overall survival (OS) were the main efficacy goals. Results: Fifty-four patients were enrolled (mean age 62 years, 33 males [61.1%] and 21 women [38.9%]) with 2y-OS rate 62.3±7.9%, 2y-RFS rate 67.1±8.2%, and 2y-DMFS rate 63.9±8.1%. Patients with T3 (n = 23), T4a (n = 14), and T4b (n = 17) stages, including12 patients with node-positive disease, were included at baseline. During a median follow-up of 11 months, 19 patients ultimately died, 10 experienced relapses, and 17 developed metastases. Tumor T staging was demonstrated to be an independent prognostic predictor according to the Cox univariate analysis. The primary factor contributing to a poor prognosis and the primary cause of death for 73.7% of patients was distant metastases. Preoperative radiation had an improved long-term survival with 2y-OS rate of 85.7±13.2%, and it can considerably lower the risk of distant metastases (p≤0.05). The overall survival rate for patients receiving postoperative chemoradiotherapy combined with immunotherapy was higher than that for patients not receiving immunotherapy (2y-OS rate 74.1±11.4% vs. 39.3±15.8%), although the difference was not statistically significant due to a small number of patients (p = 0.16). No immune-related adverse effects grade≥3 was recorded. Conclusions: The primary cause of the poor prognostic performance of SNMM is distant metastasis. The risk of distant metastases might be considerably decreased by preoperative radiation treatment. Surgery combined with radiation and immunotherapy could bring promising survival benefit. The way forward may involve investigating the combination of immunotherapy and preoperative radiotherapy. Clinical trial information: NCT04879654 ; NCT05009446 .

Phytochemicals in regulating PD-1/PD-L1 and immune checkpoint blockade therapy.

Clinical treatment and preclinical studies have highlighted the role of immune checkpoint blockade in cancer treatment. Research has been devoted to developing immune checkpoint inhibitors in combination with other drugs to achieve better efficacy or reduce adverse effects. Phytochemicals sourced from vegetables and fruits have demonstrated antiproliferative, proapoptotic, anti-migratory, and antiangiogenic effects against several cancers. Phytochemicals also modulate the tumor microenvironment such as T cells, regulatory T cells, and cytokines. Recently, several phytochemicals have been reported to modulate immune checkpoint proteins in in vivo or in vitro models. Phytochemicals decreased programmed cell death ligand-1 expression and synergized programmed cell death receptor 1 (PD-1) monoclonal antibody to suppress tumor growth. Combined administration of phytochemicals and PD-1 monoclonal antibody enhanced the tumor growth inhibition as well as CD4+ /CD8+ T-cell infiltration. In this review, we discuss immune checkpoint molecules as potential therapeutic targets of cancers. We further assess the impact of phytochemicals including carotenoids, polyphenols, saponins, and organosulfur compounds on cancer PD-1/programmed cell death ligand-1 immune checkpoint molecules and document their combination effects with immune checkpoint inhibitors on various malignancies.

Top Melanoma Articles from 2021 to Inform Your Cancer Practice.

Advances in our understanding of melanoma biology and the role of immune checkpoint blockade and targeted therapy have ushered in a new and rapidly evolving era of multidisciplinary care for patients with melanoma. Based on efficacy for patients with metastatic melanoma, these systemic treatment approaches have been introduced into the adjuvant and, more recently, the neoadjuvant landscape. This report highlights the results of key clinical studies published or initially presented in 2021 that have informed our evidence-based approach to melanoma multidisciplinary care, primarily related to adjuvant and neoadjuvant approaches for patients with resectable or resected stage III or high-risk stage II melanoma and their impact on clinical care. Knowledge concerning these areas of active clinical investigation is critical for surgical oncologists who care for melanoma patients as the treatment landscape continues to evolve.

Reverse Translation Identifies the Synergistic Role of Immune Checkpoint Blockade and IL15 to Enhance Immunotherapy of Ovarian Cancer.

Immune checkpoint blockade (ICB) has changed the standard of care for many patients with cancer, yet no ICB is approved for ovarian cancer. We hypothesized that maintenance therapy with an IL15 "superagonist" (N-803) and ICB in combination could induce potent immune activation in ovarian cancer. Using flow cytometry, cytometry by time of flight analysis, and cytotoxicity assays, we analyzed patient samples from women with advanced epithelial ovarian cancer treated with N-803 for indications of PD-1/PD-L1 upregulation with this treatment. In addition, ICB and N-803 were evaluated in preclinical studies to determine the functional impact of combination therapy on natural killer (NK) cells in vitro and in vivo. We observed that N-803 stimulated initial NK-cell expansion in patient samples; however, proliferation was not sustained beyond 2 weeks despite continued treatment. This result was reverse translated back to the laboratory to determine the functional relevance of this finding. The addition of ICB with an antibody-dependent cellular cytotoxicity IgG1 antibody against PD-L1 (avelumab) or an IgG4 antibody against PD-1 (pembrolizumab) enhanced N-803 induced NK-cell function in vitro. Using models of human ovarian cancer and NK-cell adoptive transfer in mice, we showed enhanced antitumor control with N-803 and ICB, as well as a combination effect that enhanced NK-cell persistence and expansion in vivo. This work suggests that PD-1/PD-L1 blockade combined with IL15 signaling may overcome resistance to cytokine therapy in ovarian cancer.

Visceral adipose tissue secretome from early and late-stage oesophageal cancer patients differentially affects effector and regulatory T cells

AimVisceral obesity is a key risk factor in the development of oesophagogastric junctional adenocarcinoma (OGJ), predominantly via generation of systemic low grade inflammation. Obesity-induced inflammation promotes resistance to current standards of care, enhancing tumour cell growth and survival. This study investigates the effect of the visceral adipose tissue secretome from OGJ patients with early versus advanced tumours on T-cell immunity and the role of immune checkpoint blockade in enhancing anti-tumour immunity.Methods and resultsVisceral adipose conditioned media (ACM) from both early and late-stage OGJ patients significantly altered T cell activation status, upregulating co-stimulatory marker CD27 on T cells. ACM from both early and late-stage OGJ patients significantly altered immune checkpoint expression profiles downregulating immune checkpoints (ICs) on the surface of dual Th1/17-like and Th17-like cells and upregulating ICs on the surface of Th1-like cells and Treg cells. ACM derived from early-stage OGJ patients but not late-stage OGJ patients increased IFN-γ production by T cells. The addition of immune checkpoint blockers (ICBs) did not increase IFN-γ production by T cells in the presence of late-stage ACM, collectively highlighting the dichotomous immunostimulatory effect of early-stage ACM and immune-inhibitory effect of late-stage ACM. Interestingly, ACM from early-stage OGJ patients was more pro-inflammatory than ACM from late-stage patients, reflected by decreased levels of IL-17A/F, TNF-α, IL-1RA and IL-5.ConclusionThe ACM-induced upregulation of ICs on T cells highlights a therapeutic vulnerability that could be exploited by ICBs to harness anti-cancer immunity and improve clinical outcomes for OGJ patients.Graphical Schematic workflow – (A) visceral adipose tissue was taken from OAC patients at time of surgery and cultured for 72 h in media. (B) The harvested ACM was co-cultured with healthy donor PBMCs that were concurrently activated with anti-CD3/28 for 48 h and T cell immunophenotyping was carried out by flow cytometry. Key findings – (A) Early and late stage ACM enhanced a Th1-like phenotype and upregulated CTLA-4 on Th1-like cells. A Th17-like phenotype was also enhanced in addition with a Treg-like phenotype. CTLA-4 and PD-L1 were upregulated on the surface of Treg-like cells. (B) ICB-attenuated IL-17 production by T cells. However, ACM attenuated ICB-mediated reduction in IL-10 production by T cells. Higher levels of pro-inflammatory factors were found in early stage ACM compared with late stage ACM.

Programmed death-ligand1 is a determinant of recurrence in alveolar echinococcosis

ObjectivesAlveolar echinococcosis (AE) recurrence is one of the major stakes in patients undergoing surgery, the main curative treatment. Preliminary data demonstrated an effect of programmed death-ligand1 (PD-L1) inhibitors on AE proliferation in animals. The current study aimed to analyze the prognostic value of PD-L1 expression in tissue samples of patients with AE undergoing surgery. MethodsA cross-sectional study of patients operated for AE between 2002 and 2017 was performed. Patients with recurrence were matched 1: 2 with patients without recurrence. The matching criteria were PNM staging (P = hepatic localization of the parasite, N = extra-hepatic involvement of neighboring organs, and M = absence or presence of metastasis), resection status, preoperative albendazole treatment, and lesion size. PD-L1 immunohistochemistry staining was performed in surgical liver specimens. The expression of PD-L1 was assessed in immune cells. Disease-free survival was calculated using the Kaplan-Meier method. ResultsAmong 68 consecutive patients, eight patients with recurrence were matched to 16 patients without recurrence. PD-L1 was overexpressed in patients with recurrence (recurrence: PD-L1 <1%: one, PD-L1 ≥1%: seven; no recurrence: PD-L1 <1%: nine, PD-L1 ≥1%: seven, P = 0.040). Moreover, patients with lower PD-L1 expression (<1%) showed better median disease-free survival (120 months, 95% confidence interval 104-135 vs 74, 95% confidence interval 44-104, P = 0.050). ConclusionThese findings highlight the proof of concept of PD-L1 in AE, but further data on its prognostic importance and the role of immune checkpoint blockade as a promising therapeutical strategy are needed.

The Role of Immune Checkpoint Blockade in Acute Myeloid Leukemia

Immune checkpoint inhibition (ICI) has emerged as a therapeutic option for acute myeloid leukemia (AML) for patients that suffer from relapsed or high-risk disease, or patients ineligible for standard therapy. We aimed to study ICI as monotherapy and/or combined therapy (with chemotherapy (QT), for AML patients. The PRISMA statement was used. The literature used comprised clinical trials, randomized controlled trials, and systematic reviews published within the last 7 years. The blockade of CTLA-4 presented a 42% of complete remission within AML. Nivolumab in high-risk AML showed a median recurrence-free survival (RFS) of 8.48 months. The same drug on relapsed hematologic malignancies after allogenic transplantation shows a 1-year OS of 56%. The use of prophylaxis post allogenic transplantation cyclophosphamide (PTCy), following checkpoint inhibition, demonstrated different baseline disease and transplantation characteristics when compared to no-PCTy patients, being 32% and 10%, respectively. CTLA-4 blockage was a worthy therapeutic approach in relapsed hematologic malignancies, presenting long-lasting responses. The approach to AML and myelodysplastic syndrome patients with ICI before allogenic hematopoietic stem cell transplantation and the use of a graft-versus-host disease prophylaxis have shown improvement in the transplantation outcomes, and therefore AML treatment.

Treatment of ovarian clear cell carcinoma with immune checkpoint blockade: a case series

BackgroundAlthough immune checkpoint blockade has demonstrated limited effectiveness against ovarian cancer, subset analyses from completed trials suggest possible superior efficacy in the clear cell carcinoma subtype.ObjectiveTo describe the outcomes of...

The Role of Immune Checkpoint Blockade in the Hepatocellular Carcinoma: A Review of Clinical Trials.

The prevalence of primary liver cancer is rapidly rising all around the world. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Unfortunately, the traditional treatment methods to cure HCC showed poor efficacy in patients who are not candidates for liver transplantation. Until recently, tyrosine kinase inhibitors (TKIs) were the front-line treatment for unresectable liver cancer. However, rapidly emerging new data has drastically changed the landscape of HCC treatment. The combination treatment of atezolizumab plus bevacizumab (immunotherapy plus anti-VEGF) was shown to provide superior outcomes and has become the new standard first-line treatment for unresectable or metastatic HCC. Currently, ongoing clinical trials with immune checkpoint blockade (ICB) have focused on assessing the benefit of antibodies against programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte- associated antigen 4 (CTLA-4) as monotherapies or combination therapies in patients with HCC. In this review, we briefly discuss the mechanisms underlying various novel immune checkpoint blockade therapies and combination modalities along with recent/ongoing clinical trials which may generate innovative new treatment approaches with potential new FDA approvals for HCC treatment in the near future.

Pilot Study of Pembrolizumab for Immunoprevention in Smoldering Multiple Myeloma

Background: The current management of patients with smoldering multiple myeloma (SMM) is watchful waiting. However, a fraction of these patients are at significant risk of progression to symptomatic multiple myeloma (MM). In a recent study, expression of PD-L1 on tumor cells correlated with increased risk of progression from SMM to MM (Dhodapkar et al Blood. 2015; 126(22): 2475-2478) suggesting a role for immune checkpoint blockade for immunoprevention of MM. Pembrolizumab is a humanized monoclonal antibody against programmed death receptor-1 (PD-1) and blocks the interaction between PD-1 and PD-L1. Here, we report the results of a pilot study evaluating the safety and efficacy of pembrolizumab in intermediate- and high-risk SMM patients (I-HR-SMM). Methods: Patients with I-HR-SMM by PETHEMA, Mayo or SWOG criteria were eligible. Permbrolizumab was administered at a dose of 200 mg IV every 21 days for up to 8 cycles. Patients were eligible to continue treatment for up to 24 cycles if they achieved ≥ minor response after 8 cycles. The primary objective was the overall response rate (ORR) after 8 cycles. The target ORR was 25%. The trial was conducted by the Simon's Minimax design and the ORR was estimated accordingly (Simon, 1989). Twelve patients were planned for the first stage. If at least one patient had ≥ partial response, 4 more patients could enroll for a total of 16 patients. Serial peripheral blood mononuclear cells and bone marrow samples were collected for comprehensive immunophenotyping using multiparametric flow cytometry, and molecular profiling with gene expression profiling (GEP) and exome sequencing. Results: Twelve patients with I-HR-SMM were dosed on the first stage between 08/2016 and 06/2017 (Table 1a/b). Median age was 67.5 years (range 49-74). Median number of cycles received was 8 (range 3-8) and all 12 were evaluable for safety and efficacy. Median follow up was 8.54 months (4.7 to 9.6 months). One patient achieved a stringent complete remission (sCR) (8%), ten patients had stable disease (83%), and one patient had progressive disease (8%). The patient with sCR had HR-SMM by GEP70 and FISH (deletion 17p and amplification of CKS1B) and 50% plasma cells infiltration in the bone marrow at study entry. The sCR with negative flow cytometry on bone marrow was noted in this patient after only 3 cycles of therapy and response is ongoing 8 months after the end of treatment. Five patients discontinued therapy due to related adverse events: grade 2 elevation in LFT (n=2), grade 3 myalgia (n=1), and grade 3 acute kidney injury (AKI) due to tubulo-interstitial nephritis (n=2) [all resolved with discontinuation of treatment or prednisone administration]. There were no grade 4/5 adverse events. Enrollment on second stage is ongoing. Imunophenotyping of paired baseline and end of treatment bone marrow samples showed that the patient who achieved sCR had high levels of PD-1 expression on CD4+ and CD8+ T cells at baseline and showed evidence of CD8+ T-cell activation after therapy with greater upregulation of CD69, CTLA-4, PD-1, TIM-3, 4-1BB, and ICOS relative to non-responders. In contrast, expression of other immune checkpoint molecules such as TIM-3, LAG-3, and CD244 were greater on T cells in non-responders at baseline relative to the responder suggesting greater exhaustion of T cells in non-responders. Molecular profiling including GEP, exome sequencing, and neoantigens analysis is ongoing and will be presented at the meeting. Conclusions: This pilot study of pembrolizumab monotherapy showed that it is tolerable and can induce sCR in patients with SMM. More importantly, it suggested that immunoprevention to prevent progression of SMM to MM is possible. Additional biomarker studies are needed to identify patients that are most likely to respond to this approach. Our correlative studies also provide insights into potential future combination approaches to further improve efficacy of immunoprevention strategies in SMM. [Display omitted] DisclosuresManasanch:takeda: Consultancy; celgene: Consultancy; sanofi: Research Funding; quest diagnostics: Research Funding; merck: Research Funding; adaptive biotechnologies: Consultancy. Lee:Eutropics Pharmaceuticals: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Pimera Inc: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Research Funding; Takeda: Consultancy. Patel:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Consultancy; Celgene: Consultancy. Thomas:Celgene: Research Funding; Bristol Myers Squibb: Research Funding. Neelapu:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karus: Research Funding; Cellectis Inc.: Research Funding; Poseida Therapeutics, Inc: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Orlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Synergy between hemagglutinin 2 (HA2) subunit of influenza fusogenic membrane glycoprotein and oncolytic Newcastle disease virus suppressed tumor growth and further enhanced by Immune checkpoint PD-1 blockade

BackgroundNewcastle disease virus (NDV) has shown noticeable oncolytic properties, especially against cervical cancer. However, in order to improve the spread rate and oncotoxicity of the virus, employment of other therapeutic reagents would be helpful. It has been shown that some viral fusogenic membrane glycoproteins (FMGs) could facilitate viral propagation and increase the infection rate of tumor cells by oncolytic viruses. Additionally, immune checkpoint blockade has widely been investigated for its anti-tumor effects against several types of cancers. Here, we investigated for the first time whether the incorporation of influenza hemagglutinin-2 (HA2) FMG could improve the oncolytic characteristics of NDV against cervical cancer. Next, we added anti-PD-1 mAb to our therapeutic recipe to assess the complementary role of immune checkpoint blockade in curbing tumor progression.MethodsFor this purpose, TC-1 tumor cells were injected into the mice models and treatment with NDV, iNDV, HA2, NDV-HA2, iNDV-HA2 began 10 days after tumor challenge and was repeated at day 17. In addition, PD-1 blockade was conducted by injection of anti-PD-1 mAb at days 9 and 16. Two weeks after the last treatment, sample mice were sacrificed and treatment efficacy was evaluated through immunological and immunohistochemical analysis. Moreover, tumors condition was monitored weekly for 6 weeks intervals and the tumor volume was measured and compared within different groups.ResultsThe results of co-treatment with NDV and HA2 gene revealed that these agents act synergistically to induce antitumor immune responses against HPV-associated carcinoma by enhancement of E7-specific lymphocyte proliferation, inducement of CD8+ T cell cytotoxicity responses, increase in splenic cytokines and granzyme B, decrease in immunosuppressive cytokines and E6 oncogene expression, and upregulation of apoptotic proteins expression, in comparison with control groups. Moreover, incorporation of PD-1 blockade as the third side of our suggested therapy led to noticeable regression in tumor size and augmentation of cytokine responses.ConclusionsThe invaluable results of synergy between NDV virotherapy and HA2 gene therapy suggest that tumor-selective cell killing by oncolytic NDV can be enhanced by combining with FMG gene therapy. Moreover, the adjunction of the PD-1 blockade proves that checkpoint blockade can be considered as an effective complementary therapy for the treatment of cervical cancer.

The Role of Immune Checkpoint Blockade in Uveal Melanoma.

Uveal melanoma (UM) represents the most common intraocular malignancy in adults and accounts for about 5% of all melanomas. Primary disease can be effectively controlled by several local therapy options, but UM has a high potential for metastatic spread, especially to the liver. Despite its clinical and genetic heterogeneity, therapy of metastatic UM has largely been adopted from cutaneous melanoma (CM) with discouraging results until now. The introduction of antibodies targeting CTLA-4 and PD-1 for immune checkpoint blockade (ICB) has revolutionized the field of cancer therapy and has achieved pioneering results in metastatic CM. Thus, expectations were high that patients with metastatic UM would also benefit from these new therapy options. This review provides a comprehensive and up-to-date overview on the role of ICB in UM. We give a summary of UM biology, its clinical features, and how it differs from CM. The results of several studies that have been investigating ICB in metastatic UM are presented. We discuss possible reasons for the lack of efficacy of ICB in UM compared to CM, highlight the pitfalls of ICB in this cancer entity, and explain why other immune-modulating therapies could still be an option for future UM therapies.

Role for immune checkpoint blockade in BRCA2-mutant prostate cancer.

59 Background: Except for rare cases with microsatellite instability, prostate cancer has low mutation burden and low response rate to immune checkpoint blockade (ICB). Genomic correlates of response to ICB in microsatellite stable (MSS) prostate cancer are currently unknown. Here we describe an exceptional response to ICB in BRCA2-mutant prostate cancer and explore immunologic features of BRCA-mutant tumors. Methods: A patient with BRCA2-mutant MSS prostate cancer who progressed on PARP inhibitor therapy was treated with pembrolizumab. Another 8 cases of BRCA2-mutant prostate cancer were evaluated for lymphocyte infiltration and PD-L1 expression by a pathologist. The Cancer Genome Atlas (TCGA) dataset was used to evaluate BRCA-mutant tumors from multiple histology. Presence of putative pathogenic mutations in BRCA1/2 were tested for association with mRNA levels of CD8+ T cell marker ( CD8A), immune checkpoint genes (in PD-1, CTLA-4 pathways), and expression of endogenous retroviruses (ERV). Markers of homologous recombination (HR) defects, namely number of Signature 3 mutations and large ( &gt; 3bp) indels, were also analyzed. Results: Initial patient with BRCA2-mutant MSS prostate cancer had a rapid and ongoing response to pembrolizumab. Analysis of local cohort will be presented. In the TCGA prostate cancer dataset, BRCA2-mutant tumors showed significant overexpression of CD8A, PD-1 and CTLA-4 pathway genes, and ERV3-2. Similar results were observed in BRCA1-mutant (but not BRCA2-mutant) ER+ HER2− breast cancer, but not in BRCA-mutant triple-negative breast and ovarian cancer. Analyses of HR defect markers corroborated these observations. Conclusions: BRCA-mutation accompanied by ERV3-2 overexpression, observed in BRCA2-mutant prostate and BRCA1-mutant ER+ HER2− breast cancer, is associated with CD8+ T cell infiltration and checkpoint pathway upregulation. The effect of BRCA1/2 mutation on immunogenicity may be very tissue and/or cell-of-origin specific, with different cancer types having different levels of immune activation. The association between ERV expression and BRCA2-mutation in prostate cancer requires further investigation. BRCA2-mutant prostate cancers are a class of MSS tumors that may be sensitive to ICB.

Microsatellite Instability in Prostate Cancer and the Role of Immune Checkpoint Blockade

Although immune checkpoint blockade has evolved to play a significant role in the therapeutic approach to many solid and liquid neoplasms, its role in

Emerging Role of Immune Checkpoint Blockade in Pancreatic Cancer.

Immune checkpoint blockade (ICB) with programmed cell death protein-1(PD-1)/programmed death ligand -1(PD-L1) antibodies has revolutionized the management of several cancers, especially non-small cell lung cancer, melanoma, urothelial, and renal cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers associated with high morbidity and mortality. Based on available data, it’s obvious that ICB has limited success in PDACs, which can be explained by the low immunogenicity and immunosuppressive tumor microenvironment of these tumors. In this review article, we focus on PD-L1 expression and microsatellite instability (MSI) in PDAC, and their roles as prognostic and predictive markers. We also discuss data supporting combination therapies to augment cancer immunity cycle. Combining anti-PD-1/PD-L1 agents with other modalities such as vaccines, chemotherapy, and radiation could potentially overcome resistance patterns and increase immune responsiveness in PDAC.

Unmasking of intracranial metastatic melanoma during ipilimumab/nivolumab therapy: case report and literature review

BackgroundWhile data from several studies over the last decade has demonstrated that introduction of immunologic checkpoint blockage therapy with anti-CTLA-4/PD-1 drugs leads to improved survival in metastatic melanoma patients, relatively little is known about brain-specific therapeutic response and adverse events in the context of immunotherapeutic treatment of intracranial disease. Here we report two independent cases of new intracranial metastases presenting after initiation of combined checkpoint blockade Ipilimumab and Nivolumab for recurrent metastatic melanoma in the context of positive systemic disease response.Case presentationCase #1: A 43-year-old Caucasian male with Stage III melanoma of the left knee had subsequent nodal, hepatic and osseous metastases and was started on ipilimumab/nivolumab. He developed an intractable headache one week later. MRI revealed new enhancing and hemorrhagic brain metastases. After 6 weeks of immunotherapy, there was interval hemorrhage of a dominant intracranial lesion but substantial improvement in systemic metastatic disease. Durable, near complete intracranial and systemic response was achieved after completion of both induction and maintenance immunotherapy.Case #2: A 58-year old Caucasian woman with stage II melanoma of the right index finger developed cutaneous, pulmonary and hepatic metastases within 4 months of adjuvant radiation. Although combined checkpoint blockade resulted in improvement in both cutaneous and systemic disease, brain MR performed for eye discomfort demonstrated new enhancing and hemorrhagic brain metastases. Serial MR imaging five months later revealed only a solitary focus of brain enhancement with continued improved systemic disease.ConclusionsThese cases raise the question of whether the initial immune activation and modulation of the blood brain barrier by Ipilimumab/Nivolumab somehow “unmasks” previously clinically silent metastatic disease, rather than representing new or progressive metastatic disease. An overview of currently available literature discussing the role of immune checkpoint blockade in the treatment of intracranial metastatic melanoma will be provided, as well as discussion highlighting the need for future work elucidating the response of brain metastases to anti-CTLA/PD-1 drugs and documentation of brain-specific adverse events.

The role of immune checkpoint blockade for treatment of thymic epithelial tumors—a delicate balance between efficacy and side effects

Therapeutic options for patients with unresectable or metastatic thymic epithelial tumors (TETs) are limited. There is no approved treatment for patients with advanced TETs whose disease has progressed after first-line platinum-based chemotherapy. Immune checkpoint inhibitors (ICIs) that target the programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) pathway have been shown to be effective in a number of tumor types and have gained approval for multiple indications. Emerging evidence from clinical trials suggests that immune checkpoint blockade may be a viable therapeutic option for patients with TETs. Anti-PD-1/PD-L1 antibodies are active in a fraction of patients with advanced TETs with objective response rates (ORRs) ranging between 20–25%. As observed in other tumor types, responses to anti-PD-1/PD-L1 therapy tend to be durable in TETs. The incidence of serious immune-related adverse events (irAEs) however is higher in TETs than in other tumor types, necessitating vigilant monitoring of adverse events (AEs). Future studies of ICIs in patients with TETs should focus on developing more effective immunotherapy strategies, defining subsets of patients who are likely to benefit from immune checkpoint therapy, and potentially identifying patients at higher risk of autoimmune toxicity.