Differentiated activity profile for the PD-1 inhibitor balstilimab.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5529-5529
Author(s):  
Cailin Joyce ◽  
Dhan Chand ◽  
Benjamin Duckless ◽  
Manuel Hidalgo ◽  
Joseph Elan Grossman ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Culture System ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Activity Profile ◽  
Double Positive ◽  
Programmed Death

5529 Background: The development and clinical application of immune checkpoint inhibitors has transformed the therapeutic landscape for cancer treatment in recent years. Balstilimab (AGEN2034) is a fully human, monoclonal IgG4 antibody that binds with high affinity to programmed death 1 (PD-1), thus preventing the interaction between this receptor and its ligands programmed death ligand 1 and 2 (PD-L1, PD-L2). Emerging evidence suggests that balstilimab exhibits a differentiated activity profile compared to currently approved anti-PD-1 agents, including pembrolizumab and nivolumab. Methods: Balstilimab as monotherapy was evaluated in a large phase 2 study in patients (pts) with recurrent/metastatic cervical cancer who had relapsed after a platinum-based treatment regimen for advanced disease. Pts were dosed at 3 mg/kg once every 2 weeks for up to 24 months and antitumor activity was assessed using RECIST v1.1. The tumor cell killing activity of balstilimab was evaluated preclinically in a human co-culture system of (1) primary T cells engineered to recognize NY-ESO-1 and (2) NY-ESO-1+ cancer cell lines, including PD-L1 and/or PD-L2-deficient engineered lines. The co-culture system was maintained for ̃ two weeks to drive partial T cell exhaustion; a state where cytotoxicity is compromised but recoverable with PD-1 blockade. Cytotoxicity of these partially exhausted T cells was quantified against PD-L1/L2 double positive, single positive, or double negative cancer cells in the presence or absence of PD-(L)1 antibodies. Results: In the second-line treatment setting for pts with advanced cervical cancer, balstilimab showed a numerically higher objective response rate (ORR) in subjects with PD-L1+, squamous cell carcinoma (SCC) tumors (21%, 95% CI, 12.7-32.6%) than those reported for pembrolizumab. Unlike pembrolizumab, balstilimab showed activity in PD-L1(-) pts, and irrespective of tumor histology (ORR 7.9%, 95% CI, 2.7-20.8%). Despite lower overall PD-L1 positivity compared to SCC (41.7 v 72.9%), an ORR of 12.5% (95% CI, 5.9-24.7%) was observed in the subset of pts with a poorer prognosis, those with cervical adenocarcinoma. Concordant with clinical observations, balstilimab demonstrated superior rescue of antigen-specific T cell cytotoxicity in vitro relative to pembrolizumab, nivolumab, or atezolizumab. Balstilimab also induced cytotoxicity against PD-L1 and/or PD-L2 deficient target cancer cells. Conclusions: Taken together, these data suggest functional differentiation of balstilimab from other PD-1 inhibitors with potentially important implications for extending the therapeutic reach of anti-PD-1 therapy. Investigation of the underlying mechanistic basis for these findings is ongoing. Clinical trial information: NCT03104699.

scholarly journals Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 738 ◽  
Author(s):  
Raju K. Vaddepally ◽  
Prakash Kharel ◽  
Ramesh Pandey ◽  
Rohan Garje ◽  
Abhinav B. Chandra
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Hematopoietic Cells ◽  
Fda Approval ◽  
Programmed Death ◽  
Cancerous Cells

Cancer is associated with higher morbidity and mortality and is the second leading cause of death in the US. Further, in some nations, cancer has overtaken heart disease as the leading cause of mortality. Identification of molecular mechanisms by which cancerous cells evade T cell-mediated cytotoxic damage has led to the modern era of immunotherapy in cancer treatment. Agents that release these immune brakes have shown activity to recover dysfunctional T cells and regress various cancer. Both cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Death-1 (PD-1) play their role as physiologic brakes on unrestrained cytotoxic T effector function. CTLA-4 (CD 152) is a B7/CD28 family; it mediates immunosuppression by indirectly diminishing signaling through the co-stimulatory receptor CD28. Ipilimumab is the first and only FDA-approved CTLA-4 inhibitor; PD-1 is an inhibitory transmembrane protein expressed on T cells, B cells, Natural Killer cells (NKs), and Myeloid-Derived Suppressor Cells (MDSCs). Programmed Death-Ligand 1 (PD-L1) is expressed on the surface of multiple tissue types, including many tumor cells and hematopoietic cells. PD-L2 is more restricted to hematopoietic cells. Blockade of the PD-1 /PDL-1 pathway can enhance anti-tumor T cell reactivity and promotes immune control over the cancerous cells. Since the FDA approval of ipilimumab (human IgG1 k anti-CTLA-4 monoclonal antibody) in 2011, six more immune checkpoint inhibitors (ICIs) have been approved for cancer therapy. PD-1 inhibitors nivolumab, pembrolizumab, cemiplimab and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab are in the current list of the approved agents in addition to ipilimumab. In this review paper, we discuss the role of each immune checkpoint inhibitor (ICI), the landmark trials which led to their FDA approval, and the strength of the evidence per National Comprehensive Cancer Network (NCCN), which is broadly utilized by medical oncologists and hematologists in their daily practice.

scholarly journals Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e000967 ◽  
Author(s):  
Christopher A Chuckran ◽  
Chang Liu ◽  
Tullia C Bruno ◽  
Creg J Workman ◽  
Dario AA Vignali
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Modulation ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Standard Of Care ◽  
Peripheral Tolerance ◽  
Neuropilin 1

Checkpoint blockade immunotherapy established a new paradigm in cancer treatment: for certain patients curative treatment requires immune reinvigoration. Despite this monumental advance, only 20%–30% of patients achieve an objective response to standard of care immunotherapy, necessitating the consideration of alternative targets. Optimal strategies will not only stimulate CD8+ T cells, but concomitantly modulate immunosuppressive cells in the tumor microenvironment (TME), most notably regulatory T cells (Treg cells). In this context, the immunoregulatory receptor Neuropilin-1 (NRP1) is garnering renewed attention as it reinforces intratumoral Treg cell function amidst inflammation in the TME. Loss of NRP1 on Treg cells in mouse models restores antitumor immunity without sacrificing peripheral tolerance. Enrichment of NRP1+ Treg cells is observed in patients across multiple malignancies with cancer, both intratumorally and in peripheral sites. Thus, targeting NRP1 may safely undermine intratumoral Treg cell fitness, permitting enhanced inflammatory responses with existing immunotherapies. Furthermore, NRP1 has been recently found to modulate tumor-specific CD8+ T cell responses. Emerging data suggest that NRP1 restricts CD8+ T cell reinvigoration in response to checkpoint inhibitors, and more importantly, acts as a barrier to the long-term durability of CD8+ T cell-mediated tumor immunosurveillance. These novel and distinct regulatory mechanisms present an exciting therapeutic opportunity. This review will discuss the growing literature on NRP1-mediated immune modulation which provides a strong rationale for categorizing NRP1 as both a key checkpoint in the TME as well as an immunotherapeutic target with promise either alone or in combination with current standard of care therapeutic regimens.

scholarly journals Pancreatic cancer cells assemble a CXCL12-keratin 19 coating to resist immunotherapy

2019 ◽  
Author(s):  
Zhikai Wang ◽  
Ran Yan ◽  
Jiayun Li ◽  
Ya Gao ◽  
Philip Moresco ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Checkpoint Inhibitors ◽  
Transglutaminase 2 ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblast ◽  
Pancreatic Cancer Cells ◽  
Keratin 19

AbstractHow pancreatic ductal adenocarcinoma (PDA) cells stimulate CXCR4 to exclude T cells and resist T cell checkpoint inhibitors is not known. Here, we find that CXCL12, the ligand for CXCR4 that is produced by the cancer-associated fibroblast, “coats” human PDA and colorectal cancer cells as covalent heterodimers with keratin 19 (KRT19). Modeling the formation of the heterodimer with three proteins shows that KRT19 binds CXCL12 and transglutaminase-2 (TGM2), and that TGM2 converts the reversible KRT19-CXCL12 complex into a covalent heterodimer. We validate this model by showing that cancer cells in mouse PDA tumors must express KRT19 and TGM2 to become coated with CXCL12, exclude T cells, and resist immunotherapy with anti-PD-1 antibody. Thus, PDA cells have a cell-autonomous means by which they capture CXCL12 to mediate immune suppression, which is potentially amenable to therapy.One Sentence SummaryCancer cells in pancreatic ductal adenocarcinoma use transglutaminase-2 to assemble a coating comprised of covalent CXCL12-keratin 19 heterodimers that excludes T cells and mediates resistance to inhibition of the PD-1 T cell checkpoint.

scholarly journals Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study

2021 ◽  
Author(s):  
David M. O'Malley ◽  
Maryna Neffa ◽  
Bradley J. Monk ◽  
Tamar Melkadze ◽  
Marilyn Huang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Phase Ii ◽  
T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Cervical Cancer ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Duration Of Response

PURPOSE Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte–associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882 ) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy. PATIENTS AND METHODS Patients were intravenously dosed with balstilimab 3 mg/kg once every 2 weeks and zalifrelimab 1 mg/kg once every 6 weeks, for up to 24 months. The primary end point was objective response rate (ORR, RECIST version 1.1, assessed by independent central review). Secondary end points included duration of response, safety and tolerability, and survival. RESULTS In total, 155 women (median age, 50 years [range 24-76 years]) were enrolled and treated with balstilimab plus zalifrelimab; 125 patients had measurable disease at baseline and one prior line of platinum-based therapy in the advanced setting, and these patients constituted the efficacy-evaluable population. The median follow-up was 21 months. The confirmed ORR was 25.6% (95% CI, 18.8 to 33.9), including 10 complete responders and 22 partial responders, with median duration of response not reached (86.5%, 75.5%, and 64.2% at 6, 9, and 12 months, respectively). The ORRs were 32.8% and 9.1% in patients with programmed death ligand-1–positive and programmed death ligand-1–negative tumors, respectively. For patients with squamous cell carcinoma, the ORR was 32.6%. The overall disease control rate was 52% (95% CI, 43.3 to 60.6). Hypothyroidism (14.2%) and hyperthyroidism (7.1%) were the most common immune-mediated adverse events. CONCLUSION Promising and durable clinical activity, with favorable tolerability, was seen in this largest trial to date evaluating dual programmed death-1/cytotoxic T-lymphocyte–associated antigen-4 blockade in patients with recurrent and/or metastatic cervical cancer. Further investigation of the balstilimab and zalifrelimab combination in this setting is continuing.

scholarly journals Breast Cancer Cells and PD-1/PD-L1 Blockade Upregulate the Expression of PD-1, CTLA-4, TIM-3 and LAG-3 Immune Checkpoints in CD4+ T Cells

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 149 ◽  
Author(s):  
Saleh ◽  
Toor ◽  
Khalaf ◽  
Elkord
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Checkpoint Inhibitors ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Immune Checkpoints ◽  
Tnbc Cell

: Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and it exhibits resistance to common breast cancer therapies. Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and its ligand, PD-L1, have been approved to treat various cancers. However, the therapeutic efficacy of targeting PD-1/PD-L1 axis in breast cancer is under clinical investigation. In addition, the mechanisms of action of drugs targeting PD-1 and PD-L1 have not been fully elucidated. In this study, we investigated the effect of human TNBC cell lines, MDA-MB-231 and MDA-MB-468, and the non-TNBC cell line, MCF-7, on the expression of immune checkpoints (ICs) on CD4+ T cell subsets, including regulatory T cells (Tregs), using a co-culture system. We also examined the effect of blocking PD-1 or PD-L1 separately and in combination on IC expression by CD4+ T cell subsets. We found that breast cancer cells upregulate the expression of ICs including PD-1, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte activation gene-3 (LAG-3) in CD4+ T cell subsets. We also found that the co-blockade of PD-1 and PD-L1 further upregulates the co-expression of TIM-3 and LAG-3 on CD4+CD25+ T cells and CD4+CD25+FoxP3+Helios+ Tregs in the presence of TNBC cells, but not in non-TNBC cells. Our results indicate the emergence of compensatory inhibitory mechanisms, most likely mediated by Tregs and activated non-Tregs, which could lead to the development of TNBC resistance against PD-1/PD-L1 blockade.

Margetuximab (M) combined with anti-PD-1 (retifanlimab) or anti-PD-1/LAG-3 (tebotelimab) +/- chemotherapy (CTX) in first-line therapy of advanced/metastatic HER2+ gastroesophageal junction (GEJ) or gastric cancer (GC).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS264-TPS264
Author(s):  
Daniel V.T. Catenacci ◽  
Minori Koshiji Rosales ◽  
Hyun Cheol Chung ◽  
Harry H. Yoon ◽  
Lin Shen ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Checkpoint Inhibitors ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Open Label ◽  
Double Positive ◽  
Line Therapy

TPS264 Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care 1st-line therapy for advanced HER2+ GEJ/GC patients. M, an investigational Fc-engineered anti-HER2 mAb, targets the same HER2 epitope but with higher affinity for both 158V (high binding) and 158F (low binding) alleles of activating Fc receptor CD16A. Data suggest margetuximab coordinately enhances both innate and adaptive immunity, including antigen-specific T-cell responses to HER2. PD-1 and LAG-3 are T-cell checkpoint molecules that suppress T-cell function. Retifanlimab (also known as MGA012 or INCMGA00012) is a humanized, hinge-stabilized, IgG4 Κ anti-PD-1 mAb blocking binding of PD-L1 or PD-L2 to PD-1. Tebotelimab (also known as MGD013) is a humanized Fc-bearing bispecific tetravalent DART® protein that binds to both PD-1 and LAG-3, inhibiting their respective ligand binding. We previously reported that a CTX-free regimen of M+PD-1 blockade was well tolerated in GEJ/GC patients, and induced a 44% objective response rate (ORR) in a double-positive biomarker population. This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition ± CTX in metastatic/locally advanced, treatment-naïve, HER2+ GEJ/GC patients. Methods: This is a 2-cohort, adaptive open-label phase 2/3 study (NCT04082364). The first single arm, CTX-free cohort A, evaluates M+retifanlimab in HER2+ (immunohistochemistry [IHC] 3+) and PD-L1+ (excluding microsatellite instability high) patients. After 40 patients are evaluated for response/safety, additional patients will be enrolled if the threshold for continuation is met. In randomized cohort B, HER2+ (IHC 3+ or 2+/fluorescent in situ hybridization+) patients are enrolled irrespective of PD-L1 status. Part 1 of cohort B randomizes patients to 1 of 4 arms (50 patients each): control arm (T+CTX) or 1 of 3 experimental arms (M+CTX; M+CTX+retifanlimab; M+CTX+tebotelimab). CTX is investigator’s choice XELOX or mFOLFOX-6. Part 2 of cohort B consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either retifanlimab or tebotelimab, depending on results from part 1; with 250 patients each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival. Clinical trial information: NCT04082364.

scholarly journals Talimogene laherparepvec upregulates immune-cell populations in non-injected lesions: findings from a phase II, multicenter, open-label study in patients with stage IIIB–IVM1c melanoma

2021 ◽  
Vol 9 (3) ◽  
pp. e001621
Author(s):  
Josep Malvehy ◽  
Igor Samoylenko ◽  
Dirk Schadendorf ◽  
Ralf Gutzmer ◽  
Jean-Jacques Grob ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Density ◽  
Phase Ii ◽  
Response Rate ◽  
Objective Response ◽  
Stage Iiib ◽  
Talimogene Laherparepvec ◽  
Durable Response ◽  
Programmed Death

BackgroundTalimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response.MethodsIn this phase II study in patients with unresectable stage IIIB–IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8+ T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response.ResultsOf 112 enrolled patients, 111 received ≥1 dose of T-VEC. After a median follow-up of 108.0 weeks, objective/complete response rates were 28%/14% in the overall population and 32%/18% in patients with stage IIIB–IVM1a disease. No unexpected toxicity occurred. Baseline and week 6 change from baseline CD8+ T-cell density results were available for 91 and 65 patients, respectively. Neither baseline nor change in CD8+ T-cell density correlated with objective response rate, changes in tumor burden, duration of response or durable response rate. However, a 2.4-fold median increase in CD8+ T-cell density in non-injected lesions from baseline to week 6 was observed. In exploratory analyses, multiparameter immunofluorescence showed that after treatment there was an increase in the proportion of infiltrating CD8+ T-cells expressing granzyme B and checkpoint markers (programmed death-1, programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4) in non-injected lesions, together with an increase in helper T-cells. Consistent with T-cell infiltrate, we observed an increase in the adaptive resistance marker PD-L1 in non-injected lesions.ConclusionsThis study indicates that T-VEC induces systemic immune activity and alters the tumor microenvironment in a way that will likely enhance the effects of other immunotherapy agents in combination therapy.Trial registration numberNCT02366195.

scholarly journals Current Clinical Applications and Future Perspectives of Immune Checkpoint Inhibitors in Non-Hodgkin Lymphoma

2020 ◽  
Vol 2020 ◽  
pp. 1-18
Author(s):  
John Apostolidis ◽  
Ayman Sayyed ◽  
Mohammed Darweesh ◽  
Panayotis Kaloyannidis ◽  
Hani Al Hashmi
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
B Cell ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

Cancer cells escape immune recognition by exploiting the programmed cell-death protein 1 (PD-1)/programmed cell-death 1 ligand 1 (PD-L1) immune checkpoint axis. Immune checkpoint inhibitors that target PD-1/PD-L1 unleash the properties of effector T cells that are licensed to kill cancer cells. Immune checkpoint blockade has dramatically changed the treatment landscape of many cancers. Following the cancer paradigm, preliminary results of clinical trials in lymphoma have demonstrated that immune checkpoint inhibitors induce remarkable responses in specific subtypes, most notably classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, while in other subtypes, the results vary considerably, from promising to disappointing. Lymphomas that respond to immune checkpoint inhibitors tend to exhibit tumor cells that reside in a T-cell-rich immune microenvironment and display constitutive transcriptional upregulation of genes that facilitate innate immune resistance, such as structural variations of the PD-L1 locus, collectively referred to as T-cell-inflamed lymphomas, while those lacking such characteristics are referred to as noninflamed lymphomas. This distinction is not necessarily a sine qua non of response to immune checkpoint inhibitors, but rather a framework to move the field forward with a more rational approach. In this article, we provide insights on our current understanding of the biological mechanisms of immune checkpoint evasion in specific subtypes of B-cell and T-cell non-Hodgkin lymphomas and summarize the clinical experience of using inhibitors that target immune checkpoints in these subtypes. We also discuss the phenomenon of hyperprogression in T-cell lymphomas, related to the use of such inhibitors when T cells themselves are the target cells, and consider future approaches to refine clinical trials with immune checkpoint inhibitors in non-Hodgkin lymphomas.

Phase 1b study of AMG 757, a half-life extended bispecific T-cell engager (HLE BiTEimmune-oncology therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5100-TPS5100
Author(s):  
Rahul Raj Aggarwal ◽  
Ana Aparicio ◽  
Axel Heidenreich ◽  
Shahneen Kaur Sandhu ◽  
Yiran Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Tumor Cells ◽  
De Novo ◽  
Objective Response ◽  
Human Study ◽  
Histological Transformation ◽  
Phase 1B

TPS5100 Background: NEPC is an aggressive cancer with poor prognosis. No standard treatment approach for NEPC exists and it remains an unmet need. NEPC is usually treatment-emergent, characterized by histological transformation from adenocarcinoma to a high-grade neuroendocrine tumor (NET), and may develop in 15%–20% of patients (pts) treated with standard prostate adenocarcinoma therapies, including novel hormonal therapies. The inhibitory Notch ligand, Delta-like ligand 3 (DLL3), is highly expressed on the surface of cancer cells, including NEPC cells, making it an attractive and a promising therapeutic target. AMG 757 is an HLE BiTE immuno-oncology therapy designed to redirect cytotoxic T cells to tumor cells by binding DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. AMG 757 showed in vitro activity in DLL3-expressing NETs, including NEPC. Preliminary results of an on-going first-in-human study suggest AMG 757 is safe and effective in pts with small cell lung cancer (NCT03319940), which prompted its study in NEPC. Methods: NCT04702737 is an open-label, phase 1b study evaluating AMG 757 infusion in pts with metastatic de novo or treatment-emergent NEPC, consisting of dose exploration and then dose expansion. Key eligibility criteria include adults (≥18 y) with NEPC whose disease progressed/recurred after ≥1 treatment course including a platinum-based regimen for de novo NEPC or an androgen signaling inhibitor, measurable disease per modified RECIST 1.1 per Prostate Cancer Working Group 3 modifications, ECOG performance status ≤2, life expectancy > 3 mo, adequate organ function, and no untreated/symptomatic brain metastases. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757. Secondary objectives are to evaluate antitumor activity (ie, objective response, duration of response, progression-free survival, overall response) and characterize pharmacokinetics. The starting dose for dose exploration will be based on the dose deemed safe and tolerable in the ongoing trial of AMG 757 in SCLC. The study is open to enrollment. Clinical trial information: NCT04702737.

scholarly journals A review on immune checkpoint blockage therapy

2020 ◽  
Vol 2 (1) ◽  
pp. 12-17
Author(s):  
Thamrook s Shajahan ◽  
Shaiju S Dharan ◽  
Merlin Nj
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cancer Cells ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
The Body

Activating the immune system to eliminate cancer cells and produce clinically relevant response has been a long standing goal of cancer research. Most promising therapeutic approaches of activating antitumor immunity include immune checkpoint inhibitors. Our immune system protect us from disease, killing bacteria and virus. One main type of immune cell called T-cells. T-cells have protein that turn it off. These are called checkpoint. Immune checkpoint are accessory molecules that either promote or inhibit T-cell activation. Checkpoint inhibitor are a type of immunotherapy. They block protein that stops the immune system from attacking the cancer cells. Checkpoint inhibitor are a type of monoclonal antibody or targeted treatment. Immune system cells, such as T-cells and Antigen presenting cells (APCs), defend and protect the body. Immune system play an important role in controlling and eradicating cancer. Cytotoxic T lymphocytes associated protein 4(CTLA-4) and Programmed cell dealth protein (PD-1) are checkpoint protein which is the negative regulation of T-cell immune function. Inhibition of the target, results in increased activation of immune system.

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