Cancer immunotherapy:From the lab to clinical applications - Potential impact on cancer centres' organisation

This report covers the Immunotherapy sessions of the 2016 Organisation of European Cancer Institutes (OECI) Oncology Days meeting, which was held on 15th–17th June 2016 in Brussels, Belgium. Immunotherapy is a potential cancer treatment that uses an individual’s immune system to fight the tumour. In recent years significant advances have been made in this field in the treatment of several advanced cancers. Cancer immunotherapies include monoclonal antibodies that are designed to attack a very specific part of the cancer cell and immune checkpoint inhibitors which are molecules that stimulate or block the inhibition of the immune system. Other cancer immunotherapies include vaccines and T cell infusions. This report will summarise some of the research that is going on in this field and will give us an update on where we are at present

Standardization and clinical implementation of liquid biopsy assays - IMI's CANCER-ID

The innovative medicine initiative (IMI) project CANCER-ID (www.cancer-id.eu) is a 5 year (2014-2019) international public-private partnership of currently 40 partners from 14 countries, with the aim to evaluate technologies for Circulating Tumor Cell (CTC), circulating free tumor DNA (ctDNA), microRNA (miRNA) and exosome enrichment, isolation and analysis. At the core of CANCER-ID's activities are establishment of harmonized best practice protocols from patient sample collection, pre-analytical sample handling, sample and bioinformatics analyses down to the actionable information guiding patient selection and personalized treatment. CANCER-ID is furthermore testign and supporting development of standards for liquid biopsy as well as clinical implementation of liquid biopsy based protocols in the clinical setting. This included interaction with regulatory bodies in Europe (EMA InnovationTask Force) and the US (FDA Public-Private Partnership liaison) to support future approval of liquid biopsies in multi-centered worldwide clinical studies. During the clincial validation phase of the project, clinical-ready liquid biopsies protocols have been implemented in an observational study on the potential predictive value of monitoring treatment response to Immune Checkpoint Inhibition (ICI) in 180 NSCLC patients in the UMC Groningen, The Netherlands, as well as in two ICI-chemotherapy combination studies in triple-Negative BReast Cancer and Luminal B-type breast cancer, respectively, run by the University of Oslo, Norway (Alice NCT03164993 and ICON NCT03409198). Within both studies, blood has been collected at baseline and at follow-up visits for ctDNA and CTC analysis, including technical evaluation of CTC PD-L1 protein expression. The aim is to assess whether the allelic frequency of mutations identified by plasma NGS as a potential measure for Tumor Mutational Burden or the number of PD-L1 positive/overall CTC at different time points is indicative of treatment success. The studies aim at providing data to assess whehter clinical predictive information could be inferred from baseline number of detected mutations and PD-L1 expressing CTCs. Preliminary data of these analyses will be presented. As a follow-up activity of the IMI CANCER-ID program, the European Liquid Biopsy society (ELBS) is currently being established by Prof. Pantel at UKE Hamburg, Germany. The ELBS will be open to all interested liquid biopsy stakeholders worldwide as a platform for scientific exchange, further efforts to standardize technologies and protocols in the field as well as for the initiation of the new basic and clinical research projects with the aim to make liquid biopsies and integral part of clinical studies and patient care. This work is supported by IMI JU & EFPIA (grant no. 115749, CANCER-ID). Samples from patients and healthy volunteers, respectively, were collected under signed informed consent

Strategies for Improving the Efficacy of CAR T Cells in Solid Cancers

Therapy with T cells equipped with chimeric antigen receptors (CARs) shows strong efficacy against leukaemia and lymphoma, but not yet against solid cancers. This has been attributed to insufficient T cell persistence, tumour heterogeneity and an immunosuppressive tumour microenvironment. The present article provides an overview of key strategies that are currently investigated to overcome these hurdles. Basic aspects of CAR design are revisited, relevant for tuning the stimulatory signal to the requirements of solid tumours. Novel approaches for enhancing T cell persistence are highlighted, based on epigenetic or post-translational modifications. Further, the article describes CAR T strategies that are being developed for overcoming tumour heterogeneity and the escape of cancer stem cells, as well as for countering prevalent mechanisms of immune suppression in solid cancers. In general, personalised medicine is faced with a lack of drugs matching the patient’s profile. The advances and flexibility of modern gene engineering may allow for the filling of some of these gaps with tailored CAR T approaches addressing mechanisms identified as important in the individual patient. At this point, however, CAR T cell therapy remains unproved in solid cancers. The further progress of the field will depend on bringing novel strategies into clinical evaluation, while maintaining safety

How I treat endocrine-dependent metastatic breast cancer

Estrogen receptor-positive (ER+)/HER2-negative (HER2−), the so-called luminal-type breast cancer, is the most frequent subset, accounting for around 70% of all breast cancer cases. Endocrine therapy (ET) combined with cyclin-dependent kinases (CDK) 4/6 inhibitors is the standard first option in the management of advanced luminal breast cancer independently of disease extension. Classically, patients undergo multiple lines of ET ± targeted treatments until endocrine resistance occurs and palliative chemotherapy is proposed. Understanding endocrine resistance mechanisms and development of novel ET options is one of the main challenges in current clinical research. Another area of utmost interest is the improvement of post-endocrine therapeutic approaches. Among others, the development of antibody–drug conjugates (ADCs) is very promising, and some of these drugs will probably soon become a part of the therapeutic arsenal against this incurable disease. This review paper provides an overview of currently available treatment options in ER+/HER2− metastatic breast cancer and extensively discusses new approaches in late clinical development.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Development of a TGFβ—IL-2/15 Switch Receptor for Use in Adoptive Cell Therapy

Therapy employing T cells modified with chimeric antigen receptors (CARs) is effective in hematological malignancies but not yet in solid cancers. CAR T cell activity in solid tumors is limited by immunosuppressive factors, including transforming growth factor β (TGFβ). Here, we describe the development of a switch receptor (SwR), in which the extracellular domains of the TGFβ receptor are fused to the intracellular domains from the IL-2/15 receptor. We evaluated the SwR in tandem with two variants of a CAR that we have developed against STEAP1, a protein highly expressed in prostate cancer. The SwR-CAR T cell activity was assessed against a panel of STEAP1+/− prostate cancer cell lines with or without over-expression of TGFβ, or with added TGFβ, by use of flow cytometry cytokine and killing assays, Luminex cytokine profiling, cell counts, and flow cytometry phenotyping. The results showed that the SwR-CAR constructs improved the functionality of CAR T cells in TGFβ-rich environments, as measured by T cell proliferation and survival, cytokine response, and cytotoxicity. In assays with four repeated target-cell stimulations, the SwR-CAR T cells developed an activated effector memory phenotype with retained STEAP1-specific activity. In conclusion, the SwR confers CAR T cells with potent and durable in vitro functionality in TGFβ-rich environments. The SwR may be used as an add-on construct for CAR T cells or other forms of adoptive cell therapy

Development of a TGFβ—IL-2/15 Switch Receptor for Use in Adoptive Cell Therapy

Therapy employing T cells modified with chimeric antigen receptors (CARs) is effective in hematological malignancies but not yet in solid cancers. CAR T cell activity in solid tumors is limited by immunosuppressive factors, including transforming growth factor β (TGFβ). Here, we describe the development of a switch receptor (SwR), in which the extracellular domains of the TGFβ receptor are fused to the intracellular domains from the IL-2/15 receptor. We evaluated the SwR in tandem with two variants of a CAR that we have developed against STEAP1, a protein highly expressed in prostate cancer. The SwR-CAR T cell activity was assessed against a panel of STEAP1+/− prostate cancer cell lines with or without over-expression of TGFβ, or with added TGFβ, by use of flow cytometry cytokine and killing assays, Luminex cytokine profiling, cell counts, and flow cytometry phenotyping. The results showed that the SwR-CAR constructs improved the functionality of CAR T cells in TGFβ-rich environments, as measured by T cell proliferation and survival, cytokine response, and cytotoxicity. In assays with four repeated target-cell stimulations, the SwR-CAR T cells developed an activated effector memory phenotype with retained STEAP1-specific activity. In conclusion, the SwR confers CAR T cells with potent and durable in vitro functionality in TGFβ-rich environments. The SwR may be used as an add-on construct for CAR T cells or other forms of adoptive cell therapy