The Heat Shock Protein Gp96 - The Immune System's Swiss Army Knife

Das Hitzeschockprotein Glycoprotein-96 (Gp96, Grp94) und andere Hitzeschockproteine (HSP) sind als wirkungsvolle Tumor-Vakzine im Tiermodell beschrieben worden und werden zur Zeit in klinischen Studien untersucht. Der durch HSP vermittelten Immunantwort liegen Peptide zugrunde, die von den HSP intrazellulär während des Prozesses der Antigenprozessierung gebunden werden. In dieser Dissertation werden mehrere neue Eigenschaften von Gp96 beschrieben, die die eindrucksvolle Fähigkeit dieses Moleküls aufzeigen, angeborene und adaptive Immunantworten zusammenzuführen. Erstens wird gezeigt, daß Gp96 an Rezeptoren der Zelloberfläche von antigenpräsentierenden Zellen (APC) bindet. Rezeptorvermittelte Endocytose führt zur Kreuzpräsentation (cross-presentation) von Gp96-gebundenen Peptiden auf Major Histocompatibility Complex (MHC) Klasse-I Moleküle für die Aktivierung von cytotoxischen T-Lymphocyten. Zweitens wird gezeigt, daß Gp96 dendritische Zellen (DC), die nach gängiger Auffassung wichtigsten APC, aktivieren kann, was zu einer Steigerung der immunstimulatorischen Fähigkeiten der DCs führt. An dieser Aktivierung sind die Toll-like Rezeptoren 2 und 4 beteiligt, die zuvor ausschließlich als Rezeptoren zur Verteidigung gegen Mikroorganismen bekannt waren. Basierend auf diesen Beobachtungen schlagen die Autoren dieser Arbeit folgendes Modell vor: Gp96 wird von nekrotischen (z.B. virusinfizierten) Zellen freigesetzt und von umgebenden APC durch rezeptor-vermittelte Endocytose effektiv aufgenommen und kreuzpräsentiert. Gleichzeitig werden die APC über Toll-like Rezeptoren aktiviert. Beides zusammen führt zu einer effizienten Aktivierung von naiven T-Zellen und zum Auslösen einer effektiven Immunantwort.The heat shock protein Glycoprotein-96 (also known as Gp96, Grp94) and other heat shock proteins (HSPs) have been described as potent tumor vaccines in animal models and are currently studied in clinical trials. The underlying immune response relies on immunogenic peptides that the HSPs have acquired intracellularly by interfering with the classical antigen processing pathways. In this dissertation several novel functions of Gp96 are described revealing the powerful nature of Gp96 to bring together innate and adaptive immune responses. First, Gp96 binds to cell surface receptors on antigen-presenting cells (APCs). Receptor-mediated endocytosis leads to the cross-presentation of Gp96-bound peptides on Major Histocompatiblitiy Complex (MHC) class I molecules for activation of cytotoxic T cells. Second, Gp96 can activate dendritic cells (DCs), considered as most potent APCs, to enhance their immunstimulatory capacities. This activation of APCs by Gp96 is facilitated via Toll-like receptors 2 and 4, so far known for their role in defense against microorganisms. Based on these observations the authors of this work propose that HSPs may act as ideal antigen carriers: Gp96 is released from necrotic cells (e.g. that have been infected by virus) leading to cross-priming of the Gp96-attached peptides by neighbouring APCs. Simultaneously, these APCs are activated by Gp96 via Toll-like receptors. Both, cross-presentation and activation of APCs leads to efficient priming of naïve T cells and initiates an effective immune response

Targeted therapy in renal cell carcinoma: moving from molecular agents to specific immunotherapy

Non-specific immunotherapy has been for a long time a standard treatment option for patients with metastatic renal cell carcinoma but was redeemed by specific targeted molecular therapies, namely the VEGF and mTOR inhibitors. After moving treatment for mRCC to specific molecular agents with a well-defined mode of action, immunotherapy still needs this further development to increase its accuracy. Nowadays, an evolution from a rather non-specific cytokine treatment to sophisticated targeted approaches in specific immunotherapy led to a re-launch of immunotherapy in clinical studies. Recent steps in the development of immunotherapy strategies are discussed in this review with a special focus on peptide vaccination which aims at a tumor targeting by specific T lymphocytes. In addition, different combinatory strategies with immunomodulating agents like cyclophosphamide or sunitinib are outlined, and the effects of immune checkpoint modulators as anti-CTLA-4 or PD-1 antibodies are discussed

Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy

Peptides presented at the cell surface reflect the protein content of the cell; those on HLA class I molecules comprise the critical peptidome elements interacting with CD8 T lymphocytes. We hypothesize that peptidomes from ex vivo tumour samples encompass immunogenic tumour antigens. Here, we uncover >6000 HLA-bound peptides from HLA-A*02+ glioblastoma, of which over 3000 were restricted by HLA-A*02. We prioritized in-depth investigation of 10 glioblastoma-associated antigens based on high expression in tumours, very low or absent expression in healthy tissues, implication in gliomagenesis and immunogenicity. Patients with glioblastoma showed no T cell tolerance to these peptides. Moreover, we demonstrated specific lysis of tumour cells by patients' CD8+ T cells in vitro. In vivo, glioblastoma-specific CD8+ T cells were present at the tumour site. Overall, our data show the physiological relevance of the peptidome approach and provide a critical advance for designing a rational glioblastoma immunotherapy. The peptides identified in our study are currently being tested as a multipeptide vaccine (IMA950) in patients with glioblastom

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer