Association of PD-1, LAG-3 and TIM-3 expression on intratumoral CD8 T-cells with response to atezolizumab in a Real-World-Evidence biomarker study for advanced urothelial carcinoma patients.

Blockade of the PD-1/PD-L1 pathway is part of the standard treatment for advanced urothelial cancer, but reliable predictive biomarkers have not been identified. Here, we analyze with Multiplexed Quantitative Immunofluorescence the pretreatment tumor microenvironment (TME) of urothelial cancer samples from patients treated with atezolizumab to identify correlations with treatment efficacy in a Real-World-Evidence (RWE) study. We assessed with Multiplexed Quantitative Immunofluorescence the expression of CD8, PD-1, TIM-3 and LAG-3 on T-cells in the different compartments of the TME (tumor, stroma and whole tissue) in pre-treatment tissue microarrays.

Dasatinib Remodels the Tumor Microenvironment and Sensitizes Small Cell Lung Cancer to Immunotherapy.

Effective strategies to reinvigorate the immune system are needed to improve outcomes in small cell lung cancer (SCLC). Targeting Src family kinases with dasatinib (Dasa) can elicit immunomodulatory effects in some cancer types. Here, we explored the potential of combining Dasa with immune checkpoint blockade in SCLC.

Phase I Dose-Escalation Results for the Delta-Like Ligand 3/CD3 IgG-Like T-Cell Engager Obrixtamig (BI 764532) in Patients With Delta-Like Ligand 3+ Small Cell Lung Cancer or Neuroendocrine Carcinomas.

Purpose: We report phase I results for obrixtamig (BI 764532), a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager, in patients with previously treated DLL3-positive small cell lung cancer (SCLC), extrapulmonary neuroendocrine carcinomas (epNECs), or large cell neuroendocrine carcinoma of the lung (LCNEC-L).

Methods: Patients received escalating intravenous obrixtamig doses using four regimens: a fixed dose once every 3 weeks (A); a fixed dose once weekly (B1); a step-up dose once weekly for two weeks and target dose once weekly (B2); and a step-up dose once weekly for 3 weeks, target dose once weekly for 3 weeks, and once every 3 weeks thereafter (B3). The primary objective was maximum tolerated dose (MTD).

BO-112 Plus Pembrolizumab for Patients With Anti-PD-1-Resistant Advanced Melanoma: Phase II Clinical Trial SPOTLIGHT-203.

Purpose: Patients with anti-PD-1-resistant melanoma (MEL) have no well-defined standard of care. BO-112 is a synthetic, double-stranded RNA (poly I:C) nanoplexed with polyethylenimine that when administered intratumorally has showed in patients with solid tumors potential to revert this resistance. We report efficacy and safety of the phase II clinical trial of intratumoral BO-112 plus intravenous pembrolizumab for patients with anti-PD-1-resistant MEL (ClinicalTrials.

Co-targeting of epigenetic regulators and BCL-XL improves efficacy of immune checkpoint blockade therapy in multiple solid tumors.

Epigenetic modulators in combination with proapoptotic drugs have become the standard of care treatment in hematological malignancies. Conversely, these combinations have failed to demonstrate clinical efficacy in solid tumors. To address this discrepancy, we conducted a comprehensive analysis of the anti-tumor activity of epigenetic inhibitors in combination with BH3 mimetics that block anti-apoptotic proteins BCL-XL, BCL2 or MCL1 in a large set of solid tumor cell lines derived from patients and mouse models.

A Phase I, First-in-Human, Dose-Escalation, Expansion Trial of Cytokine-Encoding Synthetic mRNA Mixture Alone or with Cemiplimab in Advanced Solid Tumors.

Purpose: We investigated SAR441000 (mixture of four mRNAs encoding IL-12, single-chain IFN-α-2b, GM-CSF, and IL-15 sushi domain) alone or in combination with cemiplimab in patients with advanced solid tumors.

Patients And Methods: SAR441000 was intratumorally administered weekly in a 4-week cycle in monotherapy and in a 3-week cycle at a predefined dose level with 350 mg cemiplimab (intravenously) every 3 weeks in combination therapy. The primary objective was to determine MTD or maximum administered dose, overall safety, tolerability, and objective response rate of SAR441000.

Safety and Antitumor Activity of a Novel aCD25 Treg Depleter RG6292 as a Single Agent and in Combination with Atezolizumab in Patients with Solid Tumors.

Purpose: Therapeutic depletion of immunosuppressive regulatory T cells (Treg) may overcome resistance to cancer immunotherapies. RG6292 is an anti-CD25 antibody that preferentially depletes Tregs while preserving effector T-cell functions in preclinical models. The safety, pharmacokinetics, pharmacodynamics, and antitumor efficacy of selective Treg depletion by RG6292 administered as monotherapy or in combination with atezolizumab were evaluated in two phase I studies.

Phase Ib Study of Immunocytokine Simlukafusp Alfa (FAP-IL2v) Combined with Pembrolizumab for Treatment of Advanced and/or Metastatic Melanoma.

Purpose: This study explored the combination of fibroblast activation protein (FAP) IL2 variant (FAP-IL2v), a novel immune-cytokine, with pembrolizumab in patients with advanced and/or metastatic melanoma.

Patients And Methods: This open-label, multicenter, phase Ib clinical study (NCT03875079) evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of FAP-IL2v (simlukafusp alfa, RO6874281) in combination with pembrolizumab. Patients with advanced and/or metastatic melanoma were either checkpoint inhibitor (CPI)-naïve or CPI-experienced.

Biological and clinical significance of tumour-infiltrating lymphocytes in the era of immunotherapy: a multidimensional approach.

Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes across several solid tumour types. Prominent efforts have focused on understanding the anticancer mechanisms of these agents, identifying biomarkers of response and uncovering resistance mechanisms to develop new immunotherapeutic approaches. This research has underscored the crucial roles of the tumour microenvironment and, particularly, tumour-infiltrating lymphocytes (TILs) in immune-mediated tumour elimination.

Targeting T-Cell Costimulation to the Surface of Tumor Cells.

Bispecific agents targeting tumor-cell surface antigens and activating receptors on T lymphocytes are being developed for solid tumors. Effective and safe strategies depend on target specificity and at least relative tumor-tissue confinement of T-cell activation. Novel evidence suggests that constructs targeting HER2 on tumor cells with the aim of providing costimulation (signal 2) to T lymphocytes via cluster of differentiation 137 (4-1BB) are safe and can meaningfully invigorate antitumor responses in a proportion of patients.

Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma.

Background: The impact of the order of treatment with checkpoint inhibitors or BRAF/MEK inhibitors on the development of brain metastases in patients with metastatic unresectable V600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients.

Methods: In this three-arm trial, we reviewed patients without brain metastases who received the BRAF/MEK inhibitors encorafenib and binimetinib until they had progressive disease followed by the immune checkpoint inhibitors ipilimumab and nivolumab (arm A); or treatment with ipilimumab and nivolumab until they had progressive disease followed by encorafenib and binimetinib (arm B); or treatment with encorafenib and binimetinib for 8 weeks followed by ipilimumab and nivolumab until they had progressive disease followed by retreatment with encorafenib arm binimetinib (arm C).

MHC class I and II-deficient humanized mice are suitable tools to test the long-term antitumor efficacy of immune checkpoint inhibitors and T-cell engagers.

Background: Immunodeficient mice engrafted with peripheral blood mononuclear cells (PBMCs) are models to study new cancer immunotherapy agents. However, this approach is associated with xenograft-versus-host disease (xGVHD), which starts early after PBMC transfer and limits the duration and interpretation of experiments. Here, we explore different approaches to overcome xGVHD and better support the development of cancer immunotherapies.

Protein Biomarkers in Lung Cancer Screening: Technical Considerations and Feasibility Assessment.

Lung cancer remains the leading cause of cancer-related deaths worldwide, mainly due to late diagnosis and the presence of metastases. Several countries around the world have adopted nation-wide LDCT-based lung cancer screening that will benefit patients, shifting the stage at diagnosis to earlier stages with more therapeutic options. Biomarkers can help to optimize the screening process, as well as refine the TNM stratification of lung cancer patients, providing information regarding prognostics and recommending management strategies.

Thyroid dysfunction caused by immune checkpoint inhibitors improves cancer outcomes.

A common immune-related adverse event (irAE) with immune checkpoint inhibitors (ICIs) is thyroid dysfunction (TD-irAEs). The clinical presentation can be varied, and its association with prognosis remains unclear. We investigated the characteristics of TD-irAEs and their association with clinical outcomes among cancer patients treated with ICIs in a real-life setting.

Short-term cultured tumor fragments to study immunotherapy combinations based on CD137 (4-1BB) agonism.

Biomarkers for cancer immunotherapy are an unmet medical need. The group of Daniela Thommen at the NKI recently reported on novel methodologies based on short-term cultures of patient-derived tumor fragments whose cytokine concentrations in the supernatants and activation markers on infiltrating T cells were associated with clinical response to PD-1 blockade. We set up a similar culture technology with tumor-derived fragments using mouse tumors transplanted into syngeneic immunocompetent mice to test an agonist anti-CD137 mAb and its combinations with anti-PD-1 and/or anti-TGF-β.

Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity.

T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell-recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues.

Phase 1, first-in-human study of TYRP1-TCB (RO7293583), a novel TYRP1-targeting CD3 T-cell engager, in metastatic melanoma: active drug monitoring to assess the impact of immune response on drug exposure.

Introduction: Although checkpoint inhibitors (CPIs) have improved outcomes for patients with metastatic melanoma, those progressing on CPIs have limited therapeutic options. To address this unmet need and overcome CPI resistance mechanisms, novel immunotherapies, such as T-cell engaging agents, are being developed. The use of these agents has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs), which is challenging to predict preclinically and can lead to neutralization of the drug and loss of efficacy.

A first-in-human study of the fibroblast activation protein-targeted, 4-1BB agonist RO7122290 in patients with advanced solid tumors.

This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent ( = 65) or in combination with a 1200-milligram fixed dose of the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab given every 3 weeks ( = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis).