Overcoming immune checkpoint blockade resistance in solid tumors with intermittent ITK inhibition.

Cytotoxic CD8 + T cell (CTL) exhaustion is driven by chronic antigen stimulation. Reversing CTL exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. We, therefore, investigated whether modulating chronic antigen stimulation and T-cell receptor (TCR) signaling with an IL2-inducible T-cell kinase (ITK) inhibitor, could confer ICB responsiveness to ICB resistant solid tumors.

PD-L1 checkpoint blockade promotes regulatory T cell activity that underlies therapy resistance.

Despite the clinical success of immune checkpoint blockade (ICB), in certain cancer types, most patients with cancer do not respond well. Furthermore, in patients for whom ICB is initially successful, this is often short-lived because of the development of resistance to ICB. The mechanisms underlying primary or secondary ICB resistance are incompletely understood.

Combination of PD-1/PD-L1 checkpoint inhibition and dendritic cell therapy in mice models and in patients with mesothelioma.

Immunotherapy with anti-PD1/PD-L1 is effective in only a subgroup of patients with malignant pleural mesothelioma (MPM). We investigated the efficacy of a combination of anti-PD1/PD-L1 and dendritic cell (DC) therapy to optimally induce effective anti-tumor immunity in MPM in both humans and mice. Data of nine MPM patients treated with DC therapy and sequential anti-PD1 treatment were collected and analyzed for progression-free survival (PFS) and overall survival (OS).

Low-Dose JAK3 Inhibition Improves Antitumor T-Cell Immunity and Immunotherapy Efficacy.

Terminal T-cell exhaustion poses a significant barrier to effective anticancer immunotherapy efficacy, with current drugs aimed at reversing exhaustion being limited. Recent investigations into the molecular drivers of T-cell exhaustion have led to the identification of chronic IL2 receptor (IL2R)-STAT5 pathway signaling in mediating T-cell exhaustion. We targeted the key downstream IL2R-intermediate JAK 3 using a clinically relevant highly specific JAK3-inhibitor (JAK3i; PF-06651600) that potently inhibited STAT5-phosphorylation in vitro.

Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response.

Background: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown.

Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19): an investigator-initiated, randomised, open-label, phase 2 trial.

Background: Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy.

The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes.

PD-1/PD-L1-checkpoint blockade therapy is generally thought to relieve tumor cell-mediated suppression in the tumor microenvironment but PD-L1 is also expressed on non-tumor macrophages and conventional dendritic cells (cDCs). Here we show in mouse tumor models that tumor-draining lymph nodes (TDLNs) are enriched for tumor-specific PD-1 T cells which closely associate with PD-L1 cDCs. TDLN-targeted PD-L1-blockade induces enhanced anti-tumor T cell immunity by seeding the tumor site with progenitor-exhausted T cells, resulting in improved tumor control.

Dendritic cell vaccination and CD40-agonist combination therapy licenses T cell-dependent antitumor immunity in a pancreatic carcinoma murine model.

Background: Pancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to treatment including checkpoint-blockade immunotherapy. We hypothesized that a bimodal treatment approach consisting of dendritic cell (DC) vaccination to prime tumor-specific T cells, and a strategy to reprogram the desmoplastic tumor microenvironment (TME) would be needed to break tolerance to these pancreatic cancers. As a proof-of-concept, we investigated the efficacy of combined DC vaccination with CD40-agonistic antibodies in a poorly immunogenic murine model of PDAC.

Correction to: Role of Bruton's tyrosine kinase in B cells and malignancies.

Following publication of the original article [1], the authors reported an error in Table 1.

Combination Strategies to Optimize Efficacy of Dendritic Cell-Based Immunotherapy.

Dendritic cells (DCs) are antigen-presenting cells (APCs) that are essential for the activation of immune responses. In various malignancies, these immunostimulatory properties are exploited by DC-therapy, aiming at the induction of effective anti-tumor immunity by vaccination with antigen-loaded DCs. Depending on the type of DC-therapy used, long-term clinical efficacy upon DC-therapy remains restricted to a proportion of patients, likely due to lack of immunogenicity of tumor cells, presence of a stromal compartment, and the suppressive tumor microenvironment (TME), thereby leading to the development of resistance.

Current State of Dendritic Cell-Based Immunotherapy: Opportunities for Antigen Loading of Different DC Subsets?

Dendritic cell (DC) based cancer immunotherapy aims at the activation of the immune system, and in particular tumor-specific cytotoxic T lymphocytes (CTLs) to eradicate the tumor. DCs represent a heterogeneous cell population, including conventional DCs (cDCs), consisting of cDC1s, cDC2s, plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs). These DC subsets differ both in ontogeny and functional properties, such as the capacity to induce CD4 and CD8 T-cell activation.

Role of Bruton's tyrosine kinase in B cells and malignancies.

Bruton's tyrosine kinase (BTK) is a non-receptor kinase that plays a crucial role in oncogenic signaling that is critical for proliferation and survival of leukemic cells in many B cell malignancies. BTK was initially shown to be defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) and is essential both for B cell development and function of mature B cells. Shortly after its discovery, BTK was placed in the signal transduction pathway downstream of the B cell antigen receptor (BCR).

Rationally combining immunotherapies to improve efficacy of immune checkpoint blockade in solid tumors.

With the widespread application of immune checkpoint blocking antibodies (ICBs) for the treatment of advanced cancer, immunotherapy has proven to be capable of yielding unparalleled clinical results. However, despite the initial success of ICB-treatment, still a minority of patients experience durable responses to ICB therapy. A plethora of mechanisms underlie ICB resistance ranging from low immunogenicity, inadequate generation or recruitment of tumor-specific T cells or local suppression by stromal cells to acquired genetic alterations leading to immune escape.

Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy.

New immunotherapeutic strategies are needed to induce effective antitumor immunity in all cancer patients. Malignant mesothelioma is characterized by a poor prognosis and resistance to conventional therapies. Infiltration of tumor-associated macrophages (TAM) is prominent in mesothelioma and is linked to immune suppression, angiogenesis, and tumor aggressiveness.

Immunotherapeutic strategies in non-small-cell lung cancer: the present and the future.

Non-small cell lung cancer (NSCLC) is still the leading cause of cancer death worldwide, with a poor prognosis. In the era of immunotherapies, the field is rapidly changing, and the clinician needs to be aware of the current state and future perspectives of immunotherapeutic strategies. In this review, we discuss the current status of immune checkpoint inhibitors, cancer vaccines and cellular therapies specifically in NSCLC.

Efficacy of Tumor Vaccines and Cellular Immunotherapies in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Purpose: Programmed cell death protein-1- checkpoint blockers have recently been approved as second-line treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, only a subgroup of patients responds and shows long-term survival to these therapies. Tumor vaccines and cellular immunotherapies could synergize with checkpoint blockade, but which of these treatments is most efficacious is unknown.