Abstract 1633: ABL501, PD-L1 x LAG-3, a bispecific antibody promotes enhanced human T cell activation through targeting simultaneously two immune checkpoint inhibitors, LAG-3 and PD-L1

e21025 Background: Irradiation (IR) combined with chemotherapy is the post-surgical standard of care treatment for melanoma, but metastasis still results in high mortality rates. Immune checkpoint inhibitors such as cytotoxic T-lymphocyte antigen-4 (CTLA4) have proven effective for immunotherapy of melanoma. CTLA-4 is up-regulated post-T cell activation and blockade enhances tumor responses in immunocompetent rodents and humans. Trials suggest that combinations of immune checkpoint inhibitors are more efficacious than single agents, but tumors remain resistant. We are investigating CD47 blockade for the treatment of cancer. CD47 is frequently elevated in cancers and serves as an inhibitory receptor for thrombospondin-1 on immune cells in the tumor stroma. CD47 blockade on CD8 T or tumor cells significantly enhances immune-targeted tumor cell killing post-IR compared to IR alone. Here we explore the potential for antisense CD47 and anti-CTLA4 therapy alone or in combination with IR using a syngeneic mouse melanoma model. Methods: C57BL/6 mice were inoculated with 1x106B16F10 melanoma cells in the hind limb and treated with 10 Gy IR combined with CTLA4 blocking antibody, CD47 translational blocking morpholino, or the combination of CTLA4/CD47 therapies. Granzyme B along with CD4/CD8 T cell infiltration were examined in tumors. Histology was evaluated for CD3 and necrosis. Results: The combination of CD47/CTLA4 with IR significantly increased survival by 25% compared to IR/CTLA4 alone at 50 days. Granzyme B expression was significantly increased in IR mice with CTLA4/CD47 combination, which correlated with infiltration of CD8+ T cells and a concomitant decrease in Gr1+CD11b suppressor cells compared to controls. In non-IR tumors, histology revealed minimal necrosis, while all IR groups showed increased necrosis. Tumor IR in combination with CTLA4 or CD47 increased immune cell infiltration. However, the combination of IR with CTLA4/CD47 showed widespread necrosis. All groups treated with the CD47 exhibited focal hemorrhage, which was more extensive when combined with CTLA4. Conclusions: Results herein suggest IR combined CTLA4/CD47 checkpoint blockade provides a survival benefit by activating a beneficial adaptive immune response.

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Exclusive Cutaneous and Subcutaneous Sarcoidal Granulomatous Inflammation due to Immune Checkpoint Inhibitors: Report of Two Cases with Unusual Manifestations and Review of the Literature

Case Reports in Dermatological Medicine ◽

10.1155/2019/6702870 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Narciss Mobini ◽

Rummit Dhillon ◽

Jason Dickey ◽

Jordan Spoon ◽

Kaviyon Sadrolashrafi

Keyword(s):

T Cell ◽

T Cell Activation ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Granulomatous Inflammation ◽

Number Of Patients ◽

Recent Emergence

Recent emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of cancers and produced prolonged response by boosting the immune system against tumor cells. The primary target antigens are cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), a downregulator of T-cell activation, and programmed cell death-1 receptor (PD-1), a regulator of T-cell proliferation. This enhanced immune response can induce autoimmune adverse effects in many organs. Although skin toxicities are the most common, sarcoidal inflammation with exclusive cutaneous involvement is a rare occurrence with only 6 cases reported to date. We report 2 cases with unusual features. One patient is a female who was treated for metastatic renal cell carcinoma with combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). She developed deep nodules showing sarcoidal dermatitis and panniculitis on histopathologic exam. The second patient is a male with melanoma of eyelid conjunctiva who was treated prophylactically with ipilimumab. He presented with papules/plaques confined to black tattoos, where the biopsy revealed sarcoidal dermatitis. By a comprehensive literature review, we intend to raise awareness about this potential skin side effect in the growing number of patients receiving targeted immunotherapies. It is crucial to have a high index of suspicion and perform timely biopsies to implement appropriate management strategies.

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The Tumor Microenvironment Factors That Promote Resistance to Immune Checkpoint Blockade Therapy

Frontiers in Oncology ◽

10.3389/fonc.2021.641428 ◽

2021 ◽

Vol 11 ◽

Author(s):

Bonnie L. Russell ◽

Selisha A. Sooklal ◽

Sibusiso T. Malindisa ◽

Lembelani Jonathan Daka ◽

Monde Ntwasa

Keyword(s):

Immune System ◽

T Cell ◽

T Cell Activation ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cell Activation ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Immune Checkpoints ◽

Therapy Strategy

Through genetic and epigenetic alterations, cancer cells present the immune system with a diversity of antigens or neoantigens, which the organism must distinguish from self. The immune system responds to neoantigens by activating naïve T cells, which mount an anticancer cytotoxic response. T cell activation begins when the T cell receptor (TCR) interacts with the antigen, which is displayed by the major histocompatibility complex (MHC) on antigen-presenting cells (APCs). Subsequently, accessory stimulatory or inhibitory molecules transduce a secondary signal in concert with the TCR/antigen mediated stimulus. These molecules serve to modulate the activation signal’s strength at the immune synapse. Therefore, the activation signal’s optimum amplitude is maintained by a balance between the costimulatory and inhibitory signals. This system comprises the so-called immune checkpoints such as the programmed cell death (PD-1) and Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and is crucial for the maintenance of self-tolerance. Cancers often evade the intrinsic anti-tumor activity present in normal physiology primarily by the downregulation of T cell activation. The blockade of the immune checkpoint inhibitors using specific monoclonal antibodies has emerged as a potentially powerful anticancer therapy strategy. Several drugs have been approved mainly for solid tumors. However, it has emerged that there are innate and acquired mechanisms by which resistance is developed against these therapies. Some of these are tumor-intrinsic mechanisms, while others are tumor-extrinsic whereby the microenvironment may have innate or acquired resistance to checkpoint inhibitors. This review article will examine mechanisms by which resistance is mounted against immune checkpoint inhibitors focussing on anti-CTL4-A and anti-PD-1/PD-Ll since drugs targeting these checkpoints are the most developed.

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Severe Gastritis after Administration of Nivolumab and Ipilimumab

Case Reports in Oncology ◽

10.1159/000491862 ◽

2018 ◽

Vol 11 (2) ◽

pp. 549-556 ◽

Cited By ~ 10

Author(s):

Yoshito Nishimura ◽

Miho Yasuda ◽

Kazuki Ocho ◽

Masaya Iwamuro ◽

Osamu Yamasaki ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Immune Checkpoint ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Metastatic Malignant Melanoma ◽

Japanese Woman ◽

H Pylori ◽

Inhibitor Treatment

Immune checkpoint inhibitors such as ipilimumab, a cytotoxic T-lymphocyte-associated antigen-4 inhibitor, have been widely used for advanced malignancies. As these inhibitors improve antitumor immunity via T-cell modulation, immune-mediated adverse events associated with T-cell activation, such as colitis, might occur. Herein, we describe a 75-year-old Japanese woman with metastatic malignant melanoma who developed hemorrhagic gastritis after ipilimumab treatment. There was no macroscopic or clinical improvement of gastritis after proton pump inhibitor treatment. However, her condition improved after approximately 3 weeks of corticosteroid therapy and Helicobacter pylori eradication. This case suggests a potential association between severe gastritis and immune checkpoint inhibitor treatment. Although several reports have mentioned ipilimumab-associated colitis, gastritis is considered to be rare. In the present case, H. pylori-associated gastritis might have been exacerbated by the T-cell modulation effect of ipilimumab. To date, no report has clarified the mechanism by which ipilimumab modifies H. pylori infection. The present treatment course provides a helpful perspective for similar cases.

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Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4

Molecular Cancer ◽

10.1186/s12943-019-1091-2 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 67

Author(s):

Shuang Qin ◽

Linping Xu ◽

Ming Yi ◽

Shengnan Yu ◽

Kongming Wu ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

T Cell Activation ◽

Immune Checkpoint ◽

Cell Activation ◽

De Novo ◽

Checkpoint Inhibitors ◽

Immune Checkpoints ◽

Immune Checkpoint Molecules

Abstract The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.

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Immune checkpoint inhibitors in the treatment of cancer

Current Clinical Pharmacology ◽

10.2174/1574884716666210325095022 ◽

2021 ◽

Vol 16 ◽

Author(s):

Wissam Zam ◽

Lina Ali

Keyword(s):

T Cell Activation ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Small Cell Lung Carcinoma ◽

Research Field ◽

Cell Lung Carcinoma ◽

Checkpoint Proteins

Background: Immunotherapy drugs, known as immune checkpoint inhibitors (ICIs), work by blocking checkpoint proteins from binding with their partner proteins. The two main pathways that are specifically targeted in clinical practice are cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) that showed potent immune-modulatory effects through their function as negative regulators of T cell activation. Methods: In view of the rapid and extensive development of this research field, we conducted a comprehensive review of the literature and update on the use of CTLA-4, PD-1 and PD-L1 targeted therapy in the treatment of several types of cancer including melanoma, non-small-cell lung carcinoma, breast cancer, hepatocellular carcinoma, hodgkin lymphoma, cervical cancer, head and neck squamous cell carcinoma. Results: Based on the last updated list released on March 2019, seven ICIs are approved by the FDA including ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, and cemiplimab. Conclusion: This review also highlighted the most common adverse effects caused by ICIs and which affect people in different ways.

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268 KVA 12.1 a novel fully human anti-VISTA antibody: clinical trial design in monotherapy and in combination with an anti-PD1 antibody

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.268 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A291-A291

Author(s):

Thierry Guillaudeux ◽

Shawn Iadonato ◽

Eric Tarcha ◽

Craig Philips

Keyword(s):

T Cell ◽

T Cell Activation ◽

Immune Checkpoint ◽

Cell Activation ◽

Checkpoint Inhibitors ◽

Clinical Chemistry ◽

T Cell Response ◽

Fixed Dose ◽

List Type ◽

Cytokine Levels

BackgroundV-domain Ig Suppressor of T cell Activation (VISTA) is an immune-suppressive checkpoint inhibitor of T cell response. VISTA is expressed in the immuno-suppressive tumor microenvironment, mostly by cells of the myeloid lineage, and its blockade can restore an efficient antitumor immune response especially in hard-to-treat tumors.1 In addition, an increase in VISTA expression has been described after treatment by the current immune checkpoint inhibitors, anti-CTLA-4 or anti-PD1-(L),1 especially in patients refractory to these treatments.2 3 Therefore, VISTA may be involved in a compensatory resistance mechanism to checkpoint inhibitors.MethodsKineta has selected a lead candidate anti-VISTA monoclonal antibody, KVA12.1, after a deep screen of 107 fully human and highly diverse antibodies directed against the extracellular domain of VISTA.ResultsKVA12.1 exhibits high potency and binds to a unique epitope. It restores T cell activation and induces a pro-inflammatory response in in vitro assays. In vivo, in human VISTA knock-in mice, KVA12.1 treatment mediates strong single-agent antitumor activity in multiple syngeneic tumor models and shows enhanced efficacy in combination with either anti-PD-(L)1 or anti-CTLA-4 treatment. Finally, our anti-VISTA antibody was well-tolerated in exploratory toxicology studies in cynomolgus monkey, where hematology and clinical chemistry evaluations as well as clinical observations including monitoring of body weight revealed no indicators of toxicity. Safety endpoints, including the monitoring of cytokine levels related to cytokine release syndrome (CRS), clinical pathology and immunogenicity were evaluated. Cytokine levels associated with CRS (e.g., TNF-alpha, IL-6, IL-1β) were assessed, and none were elevated to levels associated with CRS. These studies provided drug exposures (AUC) well over the expected exposures required for clinical efficacy, and KVA12.1 exhibits a good half-life consistent with other monoclonal check-point inhibitors. We are currently engaged in pre-IND studies and manufacturing of KVA12.1.ConclusionsHere we are presenting the design of a phase 1/2 multicenter, open label, dose escalation and dose expansion study of intravenous infusion of KVA12.1 as a monotherapy and in combination with a fixed dose of an anti-PD1 antibody in patients with advanced refractory or metastatic solid tumors.ReferencesElTanbouly MA, Schaafsma E, Noelle RJ, Lines JL. VISTA: Coming of age as a multi-lineage immune checkpoint. Clin Exp Immunol 2020;200(2):120–130.Kuklinski LF, Yan S, Li Z, Fisher JL, Cheng C, Noelle RJ, Angeles CV, Turk MJ, Ernstoff MS. VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. Cancer Immunol Immunother 2018 July;67(7):1113–1121.Kakavand H, Jackett LA, Menzies AM, Gide TN, Carlino MS, Saw RPM, Thompson JF, Wilmott JS, Long GV, Scolyer RA. Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod Pathol 2017 December;30(12):1666–1676.

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Altered interactions between circulating and tissue-resident CD8 T cells with the colonic mucosa define colitis associated with immune checkpoint inhibitors

10.1101/2021.09.17.460868 ◽

2021 ◽

Author(s):

Molly Thomas ◽

Kamil Slowikowski ◽

Kasidet Manakongtreecheep ◽

Pritha Sen ◽

Jessica Tantivit ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Intestinal Barrier Function ◽

Cell Populations ◽

Communication Analysis

Therapeutic blockade of co-inhibitory immune receptors PD-1 and CTLA-4 has revolutionized oncology, but treatments are limited by immune-related adverse events (IRAEs). IRAE Colitis (irColitis) is the most common, severe IRAE affecting up to 25% of patients on dual PD-1 and CTLA-4 inhibition. Here, we present a systems biology approach to define the cell populations and transcriptional programs driving irColitis. We collected paired colon mucosal biopsy and blood specimens from 13 patients with irColitis, 8 healthy individuals, and 8 controls on immune checkpoint inhibitors (ICIs), and analyzed them with single-cell/nuclei RNA sequencing with paired TCR and BCR sequencing, multispectral fluorescence microscopy, and secreted factor analysis (Luminex). We profiled 299,407 cells from tissue and blood and identified 105 cell subsets that revealed significant tissue remodeling in active disease. Colon mucosal immune populations were dominated by tissue-resident memory (Trm) ITGAE-expressing CD8 T cells representing a phenotypic spectrum defined by gene programs associated with T cell activation, cytotoxicity, cycling, and exhaustion. CD8 Trm and effector CD4 T cells upregulated type 17 immune programs (IL17A, IL26) and Tfh-like programs (CXCL13, PDCD1). We also identified for the first time an increased abundance of two KLRG1 and ITGB2-expressing CD8 T cell populations with circulatory cell markers, including a GZMK Trm-like population and a CX3CR1 population that is predicted to be intravascular. These two populations were more abundant in irColitis patients treated with dual PD-1/CTLA-4 inhibition than those receiving anti-PD-1 monotherapy. They also had significant TCR sharing with PBMCs, suggesting a circulatory origin. In irColitis we observed significant epithelial turnover marked by fewer LGR5-expressing stem cells, more transit amplifying cells, and upregulation of apoptotic and DNA-sensing programs such as the cGAS-STING pathway. Mature epithelial cells with top crypt genes upregulated interferon-stimulated pathways, CD274 (PD-L1), anti-microbial genes, and MHC-class II genes, and downregulated aquaporin and solute-carrier gene families, likely contributing to epithelial cell damage and absorptive dysfunction. Mesenchymal remodeling was defined by increased endothelial cells, both in irColitis patients and specifically in patients on dual PD-1/CTLA-4 blockade. Cell-cell communication analysis identified putative receptor-ligand pairs that recruit CD8 T cells from blood to inflamed endothelium and positive feedback loops such as the CXCR3 chemokine system that retain cells in tissue. This study highlights the cellular and molecular drivers underlying irColitis and provides new insights into the role of CTLA-4 and PD-1 signaling in maintaining CD8 Trm homeostasis, regulating CD8 T recruitment from blood, and promoting epithelial-immune crosstalk critical to gastrointestinal immune tolerance and intestinal barrier function.

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Immune checkpoint inhibitors increase T cell immunity during SARS-CoV-2 infection

Science Advances ◽

10.1126/sciadv.abg4081 ◽

2021 ◽

Vol 7 (34) ◽

pp. eabg4081

Author(s):

Nader Yatim ◽

Jeremy Boussier ◽

Pauline Tetu ◽

Nikaïa Smith ◽

Timothée Bruel ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

T Cell Immunity ◽

Immune Checkpoints ◽

Effector Memory ◽

Type I ◽

Cell Immunity

The COVID-19 pandemic has spread worldwide, yet the role of antiviral T cell immunity during infection and the contribution of immune checkpoints remain unclear. By prospectively following a cohort of 292 patients with melanoma, half of which treated with immune checkpoint inhibitors (ICIs), we identified 15 patients with acute or convalescent COVID-19 and investigated their transcriptomic, proteomic, and cellular profiles. We found that ICI treatment was not associated with severe COVID-19 and did not alter the induction of inflammatory and type I interferon responses. In-depth phenotyping demonstrated expansion of CD8 effector memory T cells, enhanced T cell activation, and impaired plasmablast induction in ICI-treated COVID-19 patients. The evaluation of specific adaptive immunity in convalescent patients showed higher spike (S), nucleoprotein (N), and membrane (M) antigen-specific T cell responses and similar induction of spike-specific antibody responses. Our findings provide evidence that ICI during COVID-19 enhanced T cell immunity without exacerbating inflammation.

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