Dual Checkpoint Blockade in a Neuroendocrine Carcinoma With Dual PD-L1/PD-L2 Amplification and High Tumor Mutational Burden.
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ABSTRACT:
SUBMITTER: Gong J
PROVIDER: S-EPMC7670562 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Dual Checkpoint Blockade in a Neuroendocrine Carcinoma With Dual PD-L1/PD-L2 Amplification and High Tumor Mutational Burden.
Gong Jun J Patel Sandip S Adashek Jacob J JJ Frishberg David D Guan Michelle M Placencio-Hickok Veronica R VR Gangi Alexandra A Gresham Gillian G Tuli Richard R Chae Young K YK Kurzrock Razelle R Hendifar Andrew E AE
JCO precision oncology 20200515
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Project description:BackgroundImmune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.MethodsCutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8+ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.ResultsPD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.ConclusionsIn this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.
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Project description:Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.
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Project description:IntroductionImmunotherapy, especially immune checkpoint blockade (ICB), holds promise as a therapeutic strategy in colorectal cancer (CRC) by harnessing the patient's immune system to target malignant cells. Particularly, the PD-1/PD-L1 axis is widely recognized for its critical role in tumor microenvironment immunosuppression. Antibodies targeting PD-1 or PD-L1 have shown sustained efficacy against various cancers, including CRC. Nonetheless, many CRC patients exhibit limited responses to such immunotherapy, and the resistance mechanisms remain incompletely understood.MethodsWe conducted experiments with C57BL/6 mice, and used the MC38 cell line for ICB treatment studies in syngeneic mouse models. Gene and protein analyses were performed using qPCR, Western Blot, and flow cytometry, with bioinformatics for clinical data survival analysis.ResultsIn this study, we reveal that targeting PD-L2 emerges as a complementary therapeutic strategy to PD-1/PD-L1 blockade in CRC. Although PD-L2 is also inducible by IFNγ, like PD-L1, it displays a unique spatial distribution within the tumor microenvironment, implying discrete roles in immune evasion. Additionally, we uncovered a significant correlation between PD-L1 and PD-L2 expression levels and the infiltration of various immune cells, encompassing multiple dendritic cell (DC) subtypes. This correlation implies an enhanced antigen presentation process that may be unleashed by blocking these two immune checkpoints.DiscussionOur results highlight the significance of PD-L2 as an essential immune checkpoint alongside PD-L1 and emphasize its potential as a target for bolstering antitumor immunity in colorectal cancer.
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Project description:PurposeBlocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma.MethodsPubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic.FindingsThe anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management.ImplicationsThis family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.
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Project description:Immune checkpoint inhibition represents a major recent breakthrough in the treatment of malignant diseases including breast cancer. Blocking the programmed death receptor-1 (PD-1) and its ligand, PD-L1, has shown impressive antitumor activity and may lead to durable long-term disease control, especially in the triple-negative subtypes of breast cancer (TNBC). Although immune checkpoint blockade is generally well tolerated, specific immune-related adverse events (irAEs) may occur. This review summarizes the clinical efficacy, perspectives, and future challenges of using PD-1/PD-L1-directed antibodies in the treatment of breast cancer.
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Project description:Background: Even though PD-1/PD-L1 is an identified key "don't find me" signal to active adaptive immune system for cancer treatment, the overall response rate (ORR) for all cancer patients is still limited. Other effective therapeutic modalities to bridge the innate and adaptive immunity to improve ORR are urgently needed. Recently, CD47/SIRPα interaction is confirmed as a critical "don't eat me" signal to active innate immunity. However, the red blood cell (RBC) toxicity is the big concern for the development of CD47-based anti-cancer therapeutics. Methods: Here, we report the development of a CD47/PD-L1 bispecific antibody 6MW3211 to block both PD-1/PD-L1 and CD47/SIRPα signals, and studied the effects of 6MW3211 on anti-tumor immune functions in vitro and in vivo. The pharmacokinetic and toxicity profiles of 6MW3211 were evaluated in GLP non-human primate (NHP) studies. Results: The dual immune checkpoint inhibitory signaling blocker 6MW3211 shows high binding affinity to PD-L1 and low binding affinity to CD47. This inequivalent binding affinity design makes 6MW3211 preferentially bound to PD-L1 on tumor cells followed by disrupting the interaction of CD47/SIRPα. Complex structure determination and flow cytometry assay demonstrated that 6MW3211 has no binding to either human or rhesus monkey RBCs. 6MW3211 effectively blocked both PD-1/DP-L1 and CD47/SIRPα signaling and promoted macrophage phagocytosis of tumor cells. Potent therapeutic efficacies of 6MW3211 in three different mouse models were further observed. Moreover, 6MW3211 was demonstrated to have a fairly good safety profile in a GLP NHP study. In addition, multiplex fluorescent immunohistochemistry (mIHC) staining shows that PD-L1 and CD47 co-express on several different types of human tumor tissues. Conclusions: These results support the development of 6MW3211 for the treatment of PD-L1 and CD47 double positive cancers.
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Project description:Receptor activator of NF-κB ligand (RANKL) and its receptor RANK, are members of the tumor necrosis factor and receptor superfamilies, respectively. Antibodies targeting RANKL have recently been evaluated in combination with anti-CTLA4 in case reports of human melanoma and mouse models of cancer. However, the efficacy of anti-RANKL in combination with antibodies targeting other immune checkpoint receptors such as PD1 has not been reported. In this study, we demonstrated that blockade of RANKL improves anti-metastatic activity of antibodies targeting PD1/PD-L1 and improves subcutaneous growth suppression in mouse models of melanoma, prostate and colon cancer. Suppression of experimental lung metastasis following combination anti-RANKL with anti-PD1 requires NK cells and IFN-γ, whereas subcutaneous tumor growth suppression with this combination therapy is attenuated in the absence of T cells and IFN-γ. Furthermore, addition of anti-RANKL to anti-PD1 and anti-CTLA4 resulted in superior anti-tumor responses, irrespective of the ability of anti-CTLA4 isotype to engage activating FcR, and concurrent or delayed RANKL blockade was most effective. Early-during-treatment assessment reveals this triple combination therapy compared to dual anti-PD1 and anti-CTLA4 combination therapy further increased the proportion of tumor-infiltrating CD4+ and CD8+ T cells that can produce both IFN-γ and TNF. Finally, RANKL expression appears to identify tumor-specific CD8+ T cells expressing higher levels of PD1 which can be modulated by anti-PD1. These data set the scene for clinical evaluation of denosumab use in patients receiving contemporary immune checkpoint blockade.
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Project description:BackgroundImmune checkpoint blockade (ICI) of programmed cell death protein 1 (PD-1) or PD-1 ligand (PD-L1) can induce durable responses in patients who have colorectal cancer (CRC) with a high tumor mutational burden (TMB). Two recurring clinical dilemmas show how to manage oligoprogressive disease and stable disease after ICI.MethodsA cohort study was conducted to analyze patients with metastatic CRC who underwent PD-1 or PD-L1 blockade. Tumors were mismatch repair (MMR) deficient or had more than 25 mutations per megabase. Patients were identified who had local therapy (surgery, ablation, or radiotherapy) for one to three sites of progressive disease (PD) or surgery to consolidate SD. The study evaluated clinical and biologic factors associated with patient selection, outcomes, and pathologic response rates.ResultsFrom 2014 to 2020, treatment was administered to 111 patients with ICI. Of these 111 patients, 19 (17%) survived fewer than 6 months, whereas to date, 50 have not had progression of disease. The remaining 42 patients experienced PD, and 16 (38%) were treated with local therapy for oligoprogression. Selection for local therapy was associated with response to ICI. The 2-year progression-free survival (PFS) after local therapy was 62%. Finally, 6 of the 50 patients without PD had consolidation of SD, and 5 had complete or near complete pathologic responses.ConclusionsOligoprogression, a frequent pattern of failure after ICI, can be managed effectively with local therapy. In contrast, it may not be necessary to consolidate SD for selected patients. Further research is essential to define management algorithms better and to explore heterogeneity in response patterns.
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Project description:PD-1/PD-L1 checkpoint blockades have achieved significant progress in several kinds of tumours. Pembrolizumab, which targets PD-1, has been approved as a first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with positive PD-L1 expression. However, PD-1/PD-L1 checkpoint blockades have not achieved breakthroughs in treating glioblastoma because glioblastoma has a low immunogenic response and an immunosuppressive microenvironment caused by the precise crosstalk between cytokines and immune cells. A phase III clinical trial, Checkmate 143, reported that nivolumab, which targets PD-1, did not demonstrate survival benefits compared with bavacizumab in recurrent glioblastoma patients. Thus, the combination of a PD-1/PD-L1 checkpoint blockade with RT, TMZ, antibodies targeting other inhibitory or stimulatory molecules, targeted therapy, and vaccines may be an appealing solution aimed at achieving optimal clinical benefit. There are many ongoing clinical trials exploring the efficacy of various approaches based on PD-1/PD-L1 checkpoint blockades in primary or recurrent glioblastoma patients. Many challenges need to be overcome, including the identification of discrepancies between different genomic subtypes in their response to PD-1/PD-L1 checkpoint blockades, the selection of PD-1/PD-L1 checkpoint blockades for primary versus recurrent glioblastoma, and the identification of the optimal combination and sequence of combination therapy. In this review, we describe the immunosuppressive molecular characteristics of the tumour microenvironment (TME), candidate biomarkers of PD-1/PD-L1 checkpoint blockades, ongoing clinical trials and challenges of PD-1/PD-L1 checkpoint blockades in glioblastoma.
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Project description:Background: The ability of radiotherapy (RT) to drive anti-tumor immunity is limited by adaptive resistance. While RT induces inflammation and recruits activated tumor-infiltrating lymphocytes (TILs), including cytotoxic T lymphocytes (CTLs), the resulting radiation- and IFNγ-dependent PD-L1 expression restores an immunosuppressed tumor microenvironment. Unleashing an effective anti-tumor response may require the precise sequencing of RT and checkpoint blockade immunotherapy (CBI) to block PD-L1 signaling before it can mediate its suppressive effects. Methods: Flank tumors formed in BALB/c mice with syngeneic CT26 colon or 4T1 mammary carcinoma cells were treated with otherwise ineffective doses of ionizing radiation (10 Gy) followed by CBI (0.2 mg anti-PD-L1, i.v.) after 0, 1, 3, 5, or 7 days, comparing tumor response. Anti-PD-L1 delivery was measured by fluorescence, TILs by flow cytometry and immunofluorescence, PD-L1 expression by immunohistochemistry, and tumor size by calipers. Results: In both CT26 and 4T1 tumors, 10 Gy alone resulted in a transient growth delay associated with infiltrating CTLs peaking at 3 days and PD-L1 at 5 days. CTLs returned to baseline after 7 days, consistent with adaptive resistance. Anti-PD-L1 failed to potentiate radiation except when injected 5 days after 10 Gy, which prevented CTL depletion and led to tumor elimination. Potentially contributing to compound effects, anti-PD-L1 penetrated tumors and bound PD-L1 more efficiently after irradiation. Conclusions: Optimal timing to exploit radiation-induced permeability to enhance CBI delivery and interrupt adaptive resistance by blocking PD-L1 as it peaks may offer a general strategy to enhance external beam radiotherapy by protecting activated TILs and potentiating anti-tumor immune response.
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