Melanoma Clonal Heterogeneity Leads to Secondary Resistance after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes.

Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) is effective in patients with melanoma, although long-term responses seem restricted in patients who have complete remissions. Many patients develop secondary resistance to TIL-ACT but the involved mechanisms are unclear. In this study, we describe a case of secondary resistance to TIL-ACT possibly due to intratumoral heterogeneity and selection of a resistant tumor cell clone by the transferred T cells.

A multicenter phase II trial of anti-EGFR-immunoliposomes loaded with doxorubicin in patients with advanced triple negative breast cancer.

Advanced triple negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience progression 12 months after the initiation of conventional first-line chemotherapy. Approximately two thirds of TNBC express epidermal growth factor receptor 1 (EGFR).

Plinabulin, a Distinct Microtubule-Targeting Chemotherapy, Promotes M1-Like Macrophage Polarization and Anti-tumor Immunity.

Reprogramming tumor infiltrating myeloid cells to elicit pro-inflammatory responses is an exciting therapeutic maneouver to improve anti-tumor responses. We recently demonstrated that a distinct microtubule-targeting drug, plinabulin-a clinical-stage novel agent-modulates dendritic cell maturation and enhances anti-tumor immunity. Here, we investigated the effects of plinabulin on macrophage polarization and .

PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy.

Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the and activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models. This study included preclinical activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on models and primary cells, proteomics and gene-expression profiling, and comparison with other signaling inhibitors.

mTORC1/autophagy-regulated MerTK in mutant BRAFV600 melanoma with acquired resistance to BRAF inhibition.

BRAF inhibitors (BRAFi) and the combination therapy of BRAF and MEK inhibitors (MEKi) were recently approved for therapy of metastatic melanomas harbouring the oncogenic BRAFV600 mutation. Although these therapies have shown pronounced therapeutic efficacy, the limited durability of the response indicates an acquired drug resistance that still remains mechanistically poorly understood at the molecular level. We conducted transcriptome gene profiling in BRAFi-treated melanoma cells and identified that Mer tyrosine kinase (MerTK) is specifically upregulated.

Simultaneous targeting of VEGF-receptors 2 and 3 with immunoliposomes enhances therapeutic efficacy.

Background: Tumor progression depends on angiogenesis. Vascular endothelial growth factor (VEGF) receptors (VEGFRs) are the main signal transducers that stimulate endothelial cell migration and vessel sprouting. At present, only VEGFR2 is targeted in the clinical practice.

Large-scale manufacturing of GMP-compliant anti-EGFR targeted nanocarriers: production of doxorubicin-loaded anti-EGFR-immunoliposomes for a first-in-man clinical trial.

We describe the large-scale, GMP-compliant production process of doxorubicin-loaded and anti-EGFR-coated immunoliposomes (anti-EGFR-ILs-dox) used in a first-in-man, dose escalation clinical trial. 10 batches of this nanoparticle have been produced in clean room facilities. Stability data from the pre-GMP and the GMP batch indicate that the anti-EGFR-ILs-dox nanoparticle was stable for at least 18 months after release.

Tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded anti-EGFR immunoliposomes in advanced solid tumours: a phase 1 dose-escalation study.

Background: Results of preclinical studies have shown that EGFR immunoliposomes have substantial antitumour effects. We aimed to assess the tolerability, safety, pharmokinetics, and efficacy of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in patients with solid tumours.

Methods: In this first-in-man, open-label, phase 1 clinical study, we enrolled patients at University Hospital of Basel, Switzerland, who had EGFR-overexpressing advanced solid tumours no longer amenable to standard treatment.

Immunoliposomal delivery of doxorubicin can overcome multidrug resistance mechanisms in EGFR-overexpressing tumor cells.

Immunoliposomes (ILs) can be constructed to target the epidermal growth factor receptor (EGFR) to provide efficient intracellular drug delivery in tumor cells. We hypothesized that this approach might be able to overcome drug resistance mechanisms, which remain an important obstacle to better outcomes in cancer therapy. ILs were evaluated in vitro and in vivo against EGFR-overexpressing pairs of human cancer cells (HT-29 and MDA-MB-231) that either lack or feature the multidrug resistance (mdr) phenotype.

Targeting tumor-associated endothelial cells: anti-VEGFR2 immunoliposomes mediate tumor vessel disruption and inhibit tumor growth.

Purpose: Angiogenesis is a key process in tumor progression. By binding VEGF, VEGF receptor-2 (VEGFR2) is a main signaling transducer in tumor-associated angiogenesis. Accordingly, therapeutic approaches against the VEGF/VEGFR2 signaling axis have been designed.

EGFR-targeted immunoliposomes derived from the monoclonal antibody EMD72000 mediate specific and efficient drug delivery to a variety of colorectal cancer cells.

We hypothesized that immunoliposomes (ILs) constructed using Fab' from the humanized anti-EGFR monoclonal antibody, EMD72000, can provide efficient intracellular drug delivery in EGFR-overexpressing colorectal tumor cells.ILs were constructed modularly with various MAb fragments, including Fab' from EMD72000 (matuzumab) or C225 (cetuximab, Erbitux) covalently linked to stabilized liposomes containing chemotherapeutic drugs or probes. Immunoliposome preparation was optimized, including Fab' reduction and linkage, and evaluated for specific binding and cytotoxicity in epidermal growth factor receptor (EGFR)--overexpressing colorectal cancer cell lines in vitro.