1st Immunotherapy of Cancer Conference (ITOC 1)

Prof Heinz Zwierina (Innsbruck Medical University, Innsbruck, Austria), chair of ITOC 2014, talks to ecancertv about the meeting's key points and future. Immunotherapy for cancer has taken huge leaps forwards in the last couple of years, and progress is only accelerating, so ITOC is set to become an important fixture.

Prof Tanja D. de Gruijl (VU University Medical Centre, Amsterdam, The Netherlands) talks to ecancertv at the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich about personalising the use of immunotherapeutic approaches by using predictive biomarkers, to avoid unnecessary treatment. Immunotherapeutic approaches such as vaccination or immune checkpoint blockade have proven to be clinically active in prostate cancer, but only in certain patients. Prof de Gruijl's team has focused on the clinical efficacy in patients with castration-resistant prostate cancer of the combination of an allogeneic cell line-based vaccine (Prostate GVAX) and an anti-CTLA4 checkpoint inhibitor (ipilimumab) in a Phase-I/II dose escalation/expansion trial. Based on their results they developed an an immune profile to predict clinical outcome. Importantly, cluster analysis revealed pre-treatment expression of CTLA-4 by circulating CD4 T cells and an immune-stimulatory myeloid profile to be dominant predictors for overall survival after Prostate GVAX/ ipilimumab therapy. These flowcytometry-based parameters may thus provide potentially useful and easy-to-use biomarkers for patient selection.

Prof Stefan Endres (Ludwig-Maximilians-Universität, Munich, Germany) talks to ecancertv at the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich about toll like receptor 7 agonists for cancer immunotherapy. Toll like receptor 7 (TLR7) is from a class of proteins that play a key role in the innate immune system. One approach is to combine TLR7 RNA with a chemical from the triphosphate group, inducing interferon and alpha helping the immune system to fight tumour cells. Dr Endres covers the different approaches for activating the patient's own immune system to fight cancer.

Dr Rajesh Chopra (Vice President of Translational and Early Drug Development, Celgene) at the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich about a newly discovered mechanism of action for immunomodulatory thalidomide analogues. These act by modulating the way certain proteins are degraded, thus preventing the growth of certain tumours such as lymphoma. This also negatively affects B-Cell development, but in turn activates T-Cells. The therapy could be combined with other antibodies and vaccines.

Prof Inge Marie Svane (Herlev Hospital, Copenhagen University, Copenhagen, Denmark) talks to ecancertv at the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich about adoptive T-cell therapy (ACT) with tumour infiltrating lymphocytes (TILs). This is a personalised treatment for cancer whereby T-cells from a patient's tumour are taken out of the body, activated, multiplied, and put back in to tackle the tumour. This treatment has achieved impressive clinical results in several single institution phase I/II clinical trials performed outside Europe, and holds the promise to enter the mainstream of standard melanoma care in the near future. However, although transient, the toxicities associated with high-dose IL-2 classically administered together with TILs are severe and recent data have questioned its use. Despite its clinical efficacy, with impressive response rates and several long surviving completely responding patients, the implementation of TIL based ACT into current practice has been severely hampered by the technical complexity of cell production, the toxicity profile demanding treatment at specialized cancer centres, and lack of investment from the pharmaceutical industry. Dr Svane suggests that the next step should be a pivotal phase III trial in melanoma; required for regulatory approval. Further improvement of the therapy could also be pursued through combination treatment.

Prof Jorge Riera-Knorrenschild (University Clinic Giessen and Marburg, Marburg, Germany) talks to ecancertv at the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich about maintenance therapy of metastatic colorectal carcinoma with the Toll-like receptor 9 (TLR-9) agonist MGN1703, including the clinical and immunological predictive pretreatment factors of activity in the IMPACT trial. MGN1703 is a synthetic DNA-based immunomodulator acting as TLR-9 agonist which has shown preclinical activity in metastatic colorectal carcinoma (mCRC) as well as a good safety profile in patients with metastatic solid tumours in a Phase 1 trial. The IMPACT trial was conducted to assess clinical efficacy, safety, and immunological effects of MGN1703 as maintenance therapy twice weekly s.c. vs. placebo. There was evidence of a superior effect of MGN1703 compared with placebo. The hazard ratio (HR) for the primary endpoint PFS on maintenance treatment group was 0.55, (p=0.040) on local assessment and 0.56 (p=0.070) by independent radiological review. Notably, at time of study closure 4 patients receiving MGN1703 were still free of progression and continued treatment in compassionate use protocols. After induction chemotherapy for mCRC, maintenance with MGN1703 is associated with improved PFS compared to placebo and low toxicity. The team found preliminary evidence that pretreatment CEA plasma levels, tumour response and activated NKT cells counts may allow identifying patients benefiting most from MGN1703 maintenance therapy. A confirmatory clinical study in patients with mCRC is planned to start in 2014.

Prof Angus Dalgleish (St George's, University of London, London, UK) talks to ecancertv at the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich about combining chemotherapy and immunotherapy. Chemotherapy and Immunotherapy were always considered incompatible in the treatment of cancer. However, analysis of sequential use has revealed that there may be significant additive - if not synergistic - potential, in enhancing the immune response to cancer. There are many reasons why chemotherapy may enhance immune therapy. These include 1) the release of tumour antigens to a primed immune response, 2) the suppression and reduction of suppressor and regulatory T cells in the tumour and stromal tissues, 3) The priming of tumour cells to make them more visible to the immune response, 4) reduction of inflammatory and growth factor drive. Enhancing the immune response prior to chemotherapy and releasing antigens as well as stimulating the immune response after chemotherapy or radiotherapy are both effective models. There is a good case to prime with non-specific vaccine activators, to then treat with chemotherapy followed by check point inhibitors and then low dose cytokines.

Dr Lorenz Jahn (Leiden Univeristy Medical Centre, Leiden, The Netherlands) talks to ecancertv at the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich about the development of a platform for the rapid identification of high affinity T cell receptors (TCRs) of therapeutic relevance targeted to self-antigens. This is done by combining gene expression data with valuable information on peptide processing from peptide elution studies and exploiting the immunogenicity of foreign human leukocyte antigen (HLA). Using this platform the team successfully isolated CD20-specific TCRs which could broaden the application of immunotherapies targeted to CD20 in cases where CD20-cell surface expression is low. Based on its general principle the developed platform could easily be adapted to target other malignancies.

Dr Kris Thielemans (Medical School of the VUB, Brussels, Belgium) talks to ecancertv the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich. Electroporation of dendritic cells (DC) with mRNA allows the loading of these cells with tumour antigens and the functional modification of a cellular vaccine. To this goal, the team provided three different molecular adjuvants to immature, monocyte derived DCs through electroporation with mRNA coding for CD40L, CD70 and caTLR4 or so-called TriMix mRNA. At Vrije Universiteit, Brussels​, clinical trials in pretreated advanced melanoma patients are being performed. These patients are treated with TriMixDC-MEL, a mixture of TriMix-DC co-electroporated with mRNA encoding a fusion of DC-LAMP and 4 different melanoma associated antigens (gp100, tyrosinase, MAGE-C2 or MAGE-A3). In a pilot clinical trial, 24x106 TriMixDC-MEL cells were administrated solely by the intradermal (ID) route. Subsequently, a phase IB was conducted to investigate the safety of administrating TriMixDC-MEL by the intravenous (IV) and ID-route. ID administration of TriMixDC-MEL was found to be feasible, safe, effectively stimulating CD8 T-cell responses, but did not result in objective tumour responses. In contrast, the combined ID/IV administration is associated with distinct but manageable side-effects and has seemingly superior clinical activity as compared to DC administered solely ID in patients with pretreated advanced melanoma. The team investigated the safety and activity of TriMixDC-MEL combined with ipilimumab. This phase II study of TriMixDC-MEL ID/IV in combination with ipilimumab demonstrates anti-melanoma activity in over 50% of the patients with therapy resistant advanced melanoma.

Dr Cristina Maccalli (Italian Network for Biotherapy of Tumours, Siena, Italy) talks to ecancertv at the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich about immuno-biological properties of human cancer stem cells. Understanding these cells could lead to understanding chemotherapy resistance, and it appears that the cells have the potential to play an immunoregulatory role in T-cell response Cells with 'stem cell properties', denominated cancer stem cells (CSCs), have been recently isolated from a variety of human solid tumours. These cells have been considered as responsible of resistance to standard therapy such as chemotherapy and radiotherapy. Immunotherapy, due to its specificity and lack of toxicity can represent a promising approach to target cancer stem cells. Thus, it is relevant to assess whether CSCs isolated from solid tumours, can be exploited as source of antigens to elicit T cell-mediated immune responses and to design novel immunotherapeutic protocols for tumours. CSCs from glioblastoma multiforme (GBM) and colorectal cancer (CRC) have been isolated from tumour biopsies and have been biologically characterized. Moreover, a detailed immunological characterization of these CSCs has been performed leading to the identification of a low immunogenic profile with negative immunoregulatory properties. Dr Maccalli's team found that both CSCs and the differentiated counterpart of tumours (FBS tumour cells) expressed immune modulatory molecules, such as CTLA-4, PD- 1, PDL-1 and B7H3, with, in some cases, higher levels in CSCS vs. FBS tumour cells. Multiple mechanisms of immunoregulation that are exploited by CSCs to escape from T cell-mediated surveillance have been identified. These results may allow designing more effective immunotherapy protocols to target CSCs from GBM and/or CRC patients.

Dr Christian Klein (Roche Pharma Research and Early Development, Roche Glycart AG, Schlieren, Switzerland) talks to ecancertv at the 1st Immunotherapy of Cancer Conference ( ITOC ) meeting in Munich. He describes a novel class of monomeric tumour-targeted immunocytokines that comprise a single IL-2 variant (IL2v) with abolished CD25 binding that is fused to the C-terminus of a tumour specific antibody with a heterodimeric Fc devoid of FcgR and C1q binding. For tumour targeting, human/humanized high affinity antibodies against CEA or FAP were selected. CEA- and FAP-IL2v activity was tested on effector cells by assessing the activation of P-STAT5, cell proliferation, sensitivity to Fas-induced apoptosis, expression of activation markers and cytokine release upon treatment. Compared to classical IL-2-based immunocytokines, CEA-IL2v and FAP-IL2v demonstrate superior safety, PK and tumour targeting due to abolished CD25 binding, monovalency and high-affinity to tumour antigens while failing to preferentially induce Tregs. CEA-IL2v and FAP-IL2v retain the capacity to activate and expand NK and CD8 effector T cells both in the periphery and tumour microenvironment supporting their further nonclinical and clinical investigation for immunotherapy of cancer.

Dr Karl-Josef Kallen (Principal Scientific Fellow, CureVac Gmbh) talks to ecancertv at the 1st Immunotherapy of Cancer Conference ( ITOC ) in Munich. CureVac have developed Messenger RNA vaccines through mouse models which are now being tested in Phase I and II trials. mRNA is known as a nucleic acid molecule that encodes proteins but it is highly unstable so difficult use, however the team have found a stable method to use it. The vaccines can enhance protein expression by around 100,000 times, increase T-Cell memory response, and are suitable for use in combination with anti-PD1 antibodies. The vaccines activate the immune system and are relatively cheap to produce. The team combined several antigens in one vaccine cocktail, a method designed to increase improved survival. A phase I trial in prostate carcinoma was carried out increasing median overall survival from 16.5 (predicted by the Halabi nomogram score) to 31 months with 44 patients, and a phase IIb trial is underway with 200 patients. Investigations are also underway in the neo-adjuvant setting and in NSCLC.