Recent updates in cancer immunotherapy: a comprehensive review and perspective of the 2018 China Cancer Immunotherapy Workshop in Beijing

The immune system is the hard-wired host defense mechanism against pathogens as well as cancer. Five years ago, we pondered the question if the era of cancer immunotherapy was upon us (Li et al., Exp Hem Oncol 2013). Exciting progresses have been made at all fronts since then, including (1) sweeping approval of six agents by the US Food and Drug Administration (FDA) to block the PD-1/PD-L1 pathway for treatment of 13 cancer types; (2) a paradigm shifting indication of PD-1 and CTLA4 blockers for the management of a broad class of cancers with DNA mismatch repair defect, the first-ever tissue agnostic approval of cancer drugs; (3) real world practice of adoptive T cell therapy with two CD19-directed chimeric antigen receptor T cell products (CAR-T) for relapsed and/or refractory B cell malignancies including acute lymphoid leukemia and diffuse large B cell lymphoma, signaling the birth of a field now known as synthetic immunology; (4) the award of 2018 Nobel Prize in Physiology and Medicine from the Nobel Committee to Tasuku Honjo and James Allison “for their discovery of cancer medicine by inhibition of negative immune regulation” (www.nobelprize.org/prizes/medicine/2018); and (5) the emerging new concept of normalizing rather than amplifying anti-tumor immunity for guiding the next wave of revolution in the field of immuno-oncology (IO) (Sanmamed and Chen, Cell 2018).This article will highlight the significant developments of immune-oncology as of October 2018. The US FDA approved indications of all seven immune checkpoint blockers, and two CD19-directed CAR-T products are tabulated for easy references. We organized our discussion into the following sections: introduction, cell therapy, emerging immunotherapeutic strategies, expediting oncology drug development in an era of breakthrough therapies, new concepts in cancer immunology and immunotherapy, and concluding remarks. Many of these topics were covered by the 2018 China Cancer Immunotherapy Workshop in Beijing, the fourth annual conference co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), China FDA (CFDA; now known as China National Medical Product Administration (NMPA)), and the Tsinghua University. We significantly expanded our discussion of important IO developments beyond what were covered in the conference, and proposed a new Three Rs conceptual framework for cancer immunotherapy, which is to reverse tolerance, rejuvenate the immune system, and restore immune homeostasis. We conclude that the future of immuno-oncology as a distinct discipline of cancer medicine has arrived.     

The Italian Network for the allergenic pollen monitoring

Summary The organization of the Italian Network for the Allergenic Pollen Monitoring is introduced. This Network is made up of 83 survey stations, 70 of which have operated regularly during 1988. They all carry out their activities utilizing the same methods, which are standardized by the Associazione Italiana di Aerobiologia (AIA). The spreading of the sampling and analysis methods worked out by AIA has been supported by preparatory and specialization courses held all over Italy and having as their goal the technical training of all station operators. The data transfer is primarily based on the utilization of Personal Computers with the aim of speeding up the building of the National Data Bank. Some specific stations, which better represent the Italian situation have been selected to join the European Aeroallergen Network.     

Innovative Therapy,Monoclonal Antibodies and Beyond

The seventh Edition of “Innovative Therapy, Monoclonal Antibodies and Beyond” Meeting took place in Milan, Italy, on January 27, 2017. The two sessions of the meeting were focused on: 1) Preclinical assays and novel biotargets; and 2) monoclonal antibodies, cell therapies and targeted molecules. Between these two sessions, a lecture entitled “HLA-antigens modulation and response to immune checkpoint inhibitor immunotherapy” was also presented. Despite the impressive successes in cancer immunotherapy in recent years, the response to immune based interventions occurs only in a minority of patients (∼20%). Several basic and translational mechanisms of resistance to immune checkpoint blockers (ICBs) were discussed during the meeting: 1. the impact of tumor microenvironment on the activity of immune system; 2. strategies to inhibit the cross-talk between extracellular matrix and myeloid-derived suppressor cells (MDSC) in the preclinical setting; 3. microRNA expression as a biomarker and as a target of therapy in non-small cell lung cancer (NSCLC); 4. the significance of complement activation pathways in response to immune checkpoint inhibitors; 5. the immunosuppressive activity of the microbiota by inducing IL-17 producing cells; and 6. modulation of HLA antigens as possible markers of response to ICB therapy. In order to overcome the deficiency in active anti-tumor T cells, several clinically applicable combination strategies were also discussed: 1. strategies to enhance the anticancer effects of immunogenic cell death inducing-chemotherapy; 2. the use of CAR T-cells in solid tumors; 3. the use of combination strategies involving oncolytic viruses and ICBs; 4. combinations of new ICBs with anti-PD-1/CTLA-4 therapy; and 4. combinations of targeted therapies and ICBs in melanoma. Overall, this conference emphasized the many novel strategies that are being investigated to improve the overall patient response to cancer immunotherapy. Optimization of biomarkers to accurately select patients who will respond to immunotherapy, coupled with combination strategies to improve long term patient survival remain critical challenges in the immuno-oncology field.     

Towards a more precise therapy in cancer: Exploring epigenetic complexity

A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. Nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. In this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. Specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. By exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours.     

TRAIN: Training through Research Application Italian iNitiative

Training through Research Application Italian iNitiative (TRAIN) is a mobility program financed under the EU action called "Cofinancing of regional, national and international programs" (COFUND) of the European Commission Seventh Framework Program (FP7) - People, and has been designed to encourage the promotion and development of international programs of research through mobility at various stages of research careers. The aim of TRAIN is to improve translational skills in the field of cancer by promoting a three-year international mobility program assigning a total of 51 fellowships subdivided into incoming, outgoing and reintegration fellowships.?The TRAIN proposal has been submitted in February 2009 to the European Commission in reply to the 2008 FP7-PEOPLE-COFUND call and has been successfully evaluated. TRAIN is addressed to postdoctoral scientists or scientists who have at least four years' full-time equivalent research experience and who wish to improve their careers spending one year abroad. The mobility program is open also to non-Italian experienced scientists wishing to spend one year in an Italian research center or private company. Part of the scheme is targeted to experienced Italian scientists who have completed at least three years of research in a foreign country and are interested in returning to Italy.?TRAIN is part of an overall Italian strategy outlined by the International Program of the Italian Cancer Network "Alleanza Contro il Cancro" to promote Italian participation in the building of the European Area for translational cancer research and to enhance the interaction between academy and industry.     

Quality control for biomarker determination in oncology: the experience of the Italian Network for Quality Assessment of Tumor Biomarkers (INQAT)

Biomarker analysis and evaluation in oncology is the product of a number of processes (including managerial, technical and interpretation steps) which need to be monitored and controlled to prevent and correct errors and guarantee a satisfactory level of quality. Several biomarkers have recently moved to clinical validation studies and successively to clinical practice without any definition of standard procedures and/or quality control (QC) schemes necessary to guarantee the reproducibility of the laboratory information. In Italy several national scientific societies and single researchers have activated -- often on a pilot level -- specific external quality assessment protocols, thereby potentially jeopardizing the clinical reality even further. In view of the seriousness of the problem, in 1998 the Italian Ministry of Health sponsored a National Survey Project to coordinate and standardize the procedures and to develop QC programs for the analysis of cancer biomarkers of potential clinical relevance. Twelve QC programs focused on biomarkers and concerning morphological, immunohistochemical, biochemical, molecular, and immunoenzymatic assays were coordinated and implemented. Specifically, external QC programs for the analytical phase of immunohistochemical p53, Bcl-2, c-erb-2/neu/HER2, and microvessel density determination, of morphological evaluation of tumor differentiation grade, and of molecular p53 analysis were activated for the first time within the project. Several hundreds of Italian laboratories took part in these QC programs, the results of which are available on the web site of the Network (www.cqlaboncologico.it). Financial support from the Italian Government and the National Research Council (CNR) will guarantee the pursuit of activities that will be extended to new biomarkers, to preanalytical phases of the assays, and to revision of the criteria of clinical usefulness for evaluating the cost/benefit ratio.     

The Achilles’ heel of cancer: targeting tumors via lysosome-induced immunogenic cell death

Interest in the lysosome’s potential role in anticancer therapies has recently been appreciated in the field of immuno-oncology. Targeting lysosomes triggers apoptotic pathways, inhibits cytoprotective autophagy, and activates a unique form of apoptosis known as immunogenic cell death (ICD). This mechanism stimulates a local and systemic immune response against dead-cell antigens. Stressors that can lead to ICD include an abundance of ROS which induce lysosome membrane permeability (LMP). Dying cells express markers that activate immune cells. Dendritic cells engulf the dying cell and then present the cell’s neoantigens to T cells. The discovery of ICD-inducing agents is important due to their potential to trigger autoimmunity. In this review, we discuss the various mechanisms of activating lysosome-induced cell death in cancer cells specifically and the strategies that current laboratories are using to selectively promote LMP in tumors.Subject terms: Cancer immunotherapy, Immunotherapy, Tumour immunology, Apoptosis, Adaptive immunity     

肿瘤免疫治疗新药研发及生物标记物研究

由于免疫学和肿瘤学发展的不断深入以及交叉渗透,肿瘤免疫学渐渐成为肿瘤治疗的新热点,为肿瘤治疗带来了新的希望。肿瘤免疫疗法主要是通过激活或正常化机体免疫系统,例如T细胞,NK细胞等,对肿瘤细胞进行杀伤,以期达到缓解或治愈的目的。随着肿瘤免疫研究的不断深入,多种肿瘤免疫新药已成功获批,并展现出了前所未有的多癌种普适性,但提高患者响应率仍是肿瘤免疫治疗领域之重要议题。从肿瘤免疫新靶点的研究,联合治疗的探索及生物标记物的应用三个方面浅析肿瘤免疫发展过程中的机遇与挑战。     

The empowerment of translational research: lessons from laminopathies

The need for a collaborative approach to complex inherited diseases collectively referred to as laminopathies, encouraged Italian researchers, geneticists, physicians and patients to join in the Italian Network for Laminopathies, in 2009. Here, we highlight the advantages and added value of such a multidisciplinary effort to understand pathogenesis, clinical aspects and try to find a cure for Emery-Dreifuss muscular dystrophy, Mandibuloacral dysplasia, Hutchinson-Gilford Progeria and forms of lamin-linked cardiomyopathy, neuropathy and lipodystrophy.     

Folic acid and primary prevention of birth defects

Birth defects (BDs) are an important public health problem, due to their overall incidence, occurring in 2-3% of live births in European Union. Neural tube defects (NTDs) are among major NTDs, due to their severity and relatively high incidence; in the meanwhile NTDs are also the most effectively preventable BDs to date. In particular, an adequate folic acid (FA) intake reduces both the occurrence and the recurrence of NTDs; FA is the synthetic form of folates, naturally occurring vitamins in a number of foods, especially vegetables. The daily intake of 0.4 mg of FA should be recommended to all women of childbearing age who plan to become pregnant. The Italian Network for Primary Prevention of BDs through FA Promotion has achieved a significant improvement in FA awareness and use in the periconceptional period. Nevertheless, primary prevention of BDs needs to make further progress; the Italian National Centre for Rare Diseases participates in european sureveillance of congenital anomalies (EUROCAT) Joint Action as coordinator of activities on the effectiveness of BDs prevention. Mandatory food fortification with FA has not been introduced in any European country. The health benefits of FA in reducing the risk of NTDs are undisputed; however mechanistic and animal studies suggest a relationship between high FA intakes and increased cancer promotion, while human studies are still inconsistent and inconclusive. A Working Group organized by the European Food Safety Authority pointed out significant uncertainties about fortification safety and the need for more studies; currently, FA intake from fortified foods and supplements should not exceed 1 mg/day in adults. In conclusion, based on up-to-date scientific evidence, the Italian Network strategy pivots on periconceptional supplementation integrated with promotion of healthy eating habits, support to health education, enhancing the role of women in managing life choices about their health and pregnancy and increasing the scientific knowledge about BDs primary prevention.     

Cervical cancer screening: are the 1989 recommendations still valid? National Workshop on Screening for Cancer of the Cervix.

Although screening for cervical cancer has been shown to be effective in reducing the morbidity and mortality associated with this disease, and despite many attempts to encourage the development of provincial programs, as of 1995 no province had a comprehensive screening program for cervical cancer. Participants at the Interchange ''95 workshop, held in Ottawa in November 1995, reviewed the recommendations of the 1989 National Workshop on Screening for Cancer of the Cervix and identified factors that have impeded their implementation. Participants discussed the need for comprehensive information systems, quality control and strategies to increase recruitment of unscreened and underscreened women. They concluded that the formation of a Cervical Cancer Prevention Network involving key stakeholders will facilitate the development and implementation of provincial programs to ensure optimal screening. They agreed that, in the interim, recommendations for practising physicians should remain as they were following the 1989 workshop.     

Quantitative Imaging Network: Data Sharing and Competitive AlgorithmValidation Leveraging The Cancer Imaging Archive

The Quantitative Imaging Network (QIN), supported by the National Cancer Institute, is designed to promote research and development of quantitative imaging methods and candidate biomarkers for the measurement of tumor response in clinical trial settings. An integral aspect of the QIN mission is to facilitate collaborative activities that seek to develop best practices for the analysis of cancer imaging data. The QIN working groups and teams are developing new algorithms for image analysis and novel biomarkers for the assessment of response to therapy. To validate these algorithms and biomarkers and translate theminto clinical practice, algorithms need to be compared and evaluated on large and diverse data sets. Analysis competitions, or “challenges,” are being conducted within the QIN as a means to accomplish this goal. The QIN has demonstrated, through its leveraging of The Cancer Imaging Archive (TCIA), that data sharing of clinical images across multiple sites is feasible and that it can enable and support these challenges. In addition to Digital Imaging and Communications in Medicine (DICOM) imaging data, many TCIA collections provide linked clinical, pathology, and “ground truth” data generated by readers that could be used for further challenges. The TCIA-QIN partnership is a successful model that provides resources for multisite sharing of clinical imaging data and the implementation of challenges to support algorithm and biomarker validation.     

Old and new targets for innovative antimalarial compounds: the different strategies of the Italian Malaria Network

Clinical treatment-failures to affordable drugs encouraged new investigation for discovery and development of new prophylactic and therapeutic interventions against malaria. The Drug Discovery Cluster (DDcl) of the Italian Malaria Network gathers several highly integrated and complementary laboratories from different Italian Institutions to identify, synthesise, screen in vitro and in vivo new antimalarial molecules directed against the intraerythrocytic stage of P. falciparum parasites and/or with transmission blocking activity to select lead compounds for further development. Complementary research activities, both in vitro and in the clinics, aim at investigating the pathogenetic mechanisms of severe malaria anaemia and the different manifestations of the disease in malaria-HIV co-infected patients to identify new therapies and improve survival.     

Prevention of Falls Network Europe: a thematic network aimed at introducing good practice in effective falls prevention across Europe. Four years on

ProFaNE, Prevention of Falls Network Europe, is a four-year thematic network co-ordinated by the University of Manchester, UK, with 25 partners across Europe and funded by the European Community Framework 5. There are also Network Associates from a number of EU and non-EU countries who give their advice and experience at steering meetings, seminars and conferences. There are four main themes (taxonomy and co-ordination of trials; clinical assessment and management of falls; assessment of balance function; psychological aspects of falling). The work of ProFaNE is practical, in terms of developing the evidence base for implementation of effective interventions, standardising the health processes for people with a history of falls and encouraging best practice across Europe. Over the four years of the Network many key publications by the members have been regularly cited, the web membership has increased to over 2,000 members from 30 countries, there is an active discussion board and there are nearly 1,000 resources available to download. The success of the networking and relationship building in these four years has meant that many countries have adopted new national strategies to prevent falls and injuries.     

A strategy for young members within national radiation oncology societies: the Italian experience (AIRO Giovani group)

AimTo briefly review history, structure, past events and future projects of AIRO (Associazione Italiana Radioterapia Oncologica) young group (AIRO Giovani), focusing on its specific commitment to multidisciplnary networking among junior clinical oncologists at a national and international level.BackgroundAIRO Giovani is a part of AIRO composed by members under 40 years old. Its main activities are scientific and educational meetings dedicated to young Italian radiation oncologists and collaborative research projects.Materials and MethodsAIRO Giovani structure, events organized and supported by AIRO giovani as well as scientific activities are here reported from its creation in 2007 up to current days.ResultsAIRO Giovani group was able to create a consolidated network between Italian junior radiation oncologists, while opening the possibility to collaborate with junior groups of other national scientific societies in the field of oncology and with ESTRO young members. Scientific projects carried out by the group have been successful and will be further implemented in next years.ConclusionsAIRO Giovani is still in its infancy, but its early positive experience supports the creation and development of young groups within national radiation oncology societies.     

Bayesian hierarchical quantile regression with application to characterizing the immune architecture of lung cancer

The successful development and implementation of precision immuno-oncology therapies requires a deeper understanding of the immune architecture at a patient level. T-cell receptor (TCR) repertoire sequencing is a relatively new technology that enables monitoring of T-cells, a subset of immune cells that play a central role in modulating immune response. These immunologic relationships are complex and are governed by various distributional aspects of an individual patient's tumor profile. We propose Bayesian QUANTIle regression for hierarchical COvariates (QUANTICO) that allows simultaneous modeling of hierarchical relationships between multilevel covariates, conducts explicit variable selection, estimates quantile and patient-specific coefficient effects, to induce individualized inference. We show QUANTICO outperforms existing approaches in multiple simulation scenarios. We demonstrate the utility of QUANTICO to investigate the effect of TCR variables on immune response in a cohort of lung cancer patients. At population level, our analyses reveal the mechanistic role of T-cell proportion on the immune cell abundance, with tumor mutation burden as an important factor modulating this relationship. At a patient level, we find several outlier patients based on their quantile-specific coefficient functions, who have higher mutational rates and different smoking history.     

Small molecule immuno-oncology therapeutic agents

Treatment of cancer by activation of an antitumor immune response is now a widely practiced and well-accepted approach to therapy. However, despite dramatic responses in some patients, the high proportion of unresponsive patients points to a considerable unmet medical need. Although antibody therapies have led the way, small molecule immuno-oncology agents are close behind. This perspective provides an overview of some of the many small molecule approaches being explored. It encompasses small molecule modulators of validated targets such as programed cell death 1 (PD-1) as well as novel approaches still to be proven clinically.     

International Meeting “Immunotherapy of Cancer: Challenges and Needs”

The main aims of the international meeting “Immunotherapy of Cancer: Challenges and Needs” were to review the state of the art of cancer immunotherapy and to identify critical issues which deserve special attention for promoting progress of research in this field, with a particular focus on the perspectives of clinical research. Novel concepts and strategies for identifying, monitoring and predicting effective responses to cancer immunotherapy protocols were presented, focused on the use of adjuvants (CpG oligonucleotides) or cytokines (IFN-alpha) to enhance the efficacy of cancer vaccines. Moreover, the possible advantages of using different types of dendritic cells (for active immunization strategies) or T cells (for adoptive immunotherapy protocols) were debated. A consensus was achieved on the need for enhancing the efficacy of cancer vaccines or adoptive cell immunotherapy by combining these strategies with other anti-cancer treatments, including chemotherapy. Finally, initiatives for promoting clinical research by establishing a strategic cooperation in the field of cancer immunotherapy based on the active participation of all the relevant actors, including public institutions responsible of Public Health, National Cancer Institutes, industry, representatives of regulatory bodies, and patients’ organizations were proposed.     

Current concepts in clinical radiation oncology

Based on its potent capacity to induce tumor cell death and to abrogate clonogenic survival, radiotherapy is a key part of multimodal cancer treatment approaches. Numerous clinical trials have documented the clear correlation between improved local control and increased overall survival. However, despite all progress, the efficacy of radiation-based treatment approaches is still limited by different technological, biological, and clinical constraints. In principle, the following major issues can be distinguished: (1) The intrinsic radiation resistance of several tumors is higher than that of the surrounding normal tissue, (2) the true patho-anatomical borders of tumors or areas at risk are not perfectly identifiable, (3) the treatment volume cannot be adjusted properly during a given treatment series, and (4) the individual heterogeneity in terms of tumor and normal tissue responses toward irradiation is immense. At present, research efforts in radiation oncology follow three major tracks, in order to address these limitations: (1) implementation of molecularly targeted agents and ‘omics’-based screening and stratification procedures, (2) improvement of treatment planning, imaging, and accuracy of dose application, and (3) clinical implementation of other types of radiation, including protons and heavy ions. Several of these strategies have already revealed promising improvements with regard to clinical outcome. Nevertheless, many open questions remain with individualization of treatment approaches being a key problem. In the present review, the current status of radiation-based cancer treatment with particular focus on novel aspects and developments that will influence the field of radiation oncology in the near future is summarized and discussed.     

Cancer immunotherapy: moving beyond current vaccines

Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.