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ZusammenfassungFortschritte in der onkologischen Therapie von nicht heilbaren Tumorpatienten machen die Einschätzung einer korrekten Prognose schwieriger. Mittels molekularer Marker unterteilen sich die diversen Tumorerkrankungen in immer kleinere Subgruppen mit unterschiedlichen Prognosen. Eine Vorstellung im interdisziplinären Tumorboard sollte Standard sein. Um übersteigerte und unrealistische Erwartungen am Lebensende zu minimieren, bedarf es optimaler Aufklärung und der Integration einer frühen palliativen Betreuung in den weiteren Behandlungsverlauf.

Immunotheranostics will be an important development in the future of nuclear medicine and medical oncology. It describes the synergy of theranostic procedures in nuclear medicine and immune oncology (IO) treatment. In brief, it takes advantage of molecular imaging and subsequent targeted modulation of the-in most cases immunosuppressive-tumor microenvironment (TME) by diagnostic and therapeutic radioisotopes. This is of high importance since only a fraction of patients receiving IO is currently being cured by this exciting therapy option. We therefore envision the concept of immunotheranostics as a powerful mean to augment the success of IO treatment in the future and thus the urgent need to further develop the interaction and joint action of nuclear medicine and medical oncology for substantially improved therapy outcome for cancer patients.

Various strategies for cancer therapy have been devised over the past decade. Cancer immunotherapy has been an emerging technology that activates the host's immune systems to efficiently recognize and kill tumor cells. Despite the revolutionary development in the field of immunooncology, only a small fraction of patients have had beneficial results as many tumors possess the innate characteristic of immune evasion. Ideally, the immune system should be spatiotemporally regulated to augment the therapeutic index of these therapies. One method of enabling codelivery of immune-stimulatory molecules, improve pharmacokinetics and specificity to target sites, and reprogram tumor microenvironments is the utilization of nanoparticles. They have been shown to elicit enhanced antitumor immune responses that cannot be achieved by treating naked anticancer drugs. Immunotherapy harmonized with nanotechnology provides the tremendous opportunity to enhance the therapeutic effectiveness by delivering immunostimulatory molecules, adjuvantizing immune cells, and/or enabling specific targeting while minimizing side effects. Herein, we highlight how the convergence of cancer immunotherapy and nanotechnology overcomes the critical limitations of conventional treatments and increases the possibility for clinical translation in cancer treatments.

As a biochemist developing antibody therapies at a major pharmaceutical company, Li Peng spent years fixated on membrane proteins. But every now and then, she wondered if she and her colleagues were missing something. Proteins carry out a cell’s work, yet whether and where they act often depend on another type of biomolecule—glycans. These sugars that coat the surface of a protein can influence a drug’s structure and stability and even dictate if it works at all. “In the back of my mind, I always felt we had overlooked glycobiology,” says Peng, who worked for nearly a decade at MedImmune, AstraZeneca’s biologics research arm. “But I didn’t have the resources or the tools or the power to make a big initiative.” In the summer of 2016, Peng received an intriguing email from the CEO of a Boston-area start-up. He hoped to interest her in an entirely new approach to cancer

Background. Urothelial cancer ranks 7th and 17th of all the malignant tumors in males and females, respectively. Development of new immunotherapeutic drugs provides new possibilities in treatment of such patients, especially the patient population in whom platinum‑based therapy is contraindicated. Administration of immunooncology drugs requires determination of PD-L1, for which various diagnostic systems are used. The question regarding correlation of results of determination of PD-L1 expression remains of concern.Materials and Methods. The study was performed on 100 samples of surgical and biopsy samples of urothelial cancer. Two clones of 22C3 and SP142 with corresponding detection systems were used for the study. PD-L1 expression was assessed in tumor and immune cells.Results. The study demonstrated a high correlation of negative PD-L1 tumor status determined using both diagnostic agents (92 % and 97 %) and low correlation of results of positive PD-L1 status (67 % and 43 %).Conclusions. Thus, if a negative result of PD-L1 status of urothelial cancer is obtained using any of the diagnostic agents studied, repeated test with the other antibody is not required. If positive status is obtained in one test, the patient may have a negative status in the other test, which allows recommending a repeated testing in borderline cases using a test, recommended for the medicinal product untended for treatment.

Bone metastases are common in men with metastatic castrate-resistant prostate cancer (mCRPC), occurring in 30% of patients within 2 years of castrate resistance and in >90% of patients over the disease course. There are 6 US Food and Drug Administration-approved therapies for mCRPC with demonstrated survival benefit. Of these, only radium-223 (Ra-223) specifically targets bone metastases, delays development of skeletal-related events, and improves survival. This review discusses key data from the ALSYMPCA trial, which contributed to the approval of Ra-223. Data from other trials are highlighted to provide further insight into which patients might benefit from Ra-223. Special patient populations are described, as well as other considerations for the administration of Ra-223. Finally, ongoing trials of Ra-223 combined with other therapies for mCRPC are discussed. These include combining Ra-223 with sipuleucel-T or immunooncology agents, to enhance immune responses, and trials in mildly symptomatic or asymptomatic patients. To date, the optimal timing, sequence, and combinations of Ra-223 with other agents are yet to be determined. The goals of this review are to provide insight into practical aspects of patient selection for Ra-223 treatment and to discuss key therapeutic strategies using the 6 approved mCRPC agents in patients with bone metastases. Results from ongoing trials should help guide the practitioner in using Ra-223 in patients with mCRPC.

Significance On-target, off-tumor toxicity of anti-CTLA4 checkpoint inhibitors leads to severe adverse events, restricting therapeutic efficacy. We engineered anti-CTLA4 antibodies and generated a new class of antibodies referred to as conditionally active biologic (CAB) antibodies using physiological chemicals (bicarbonate, hydrogen sulfide) as protein-associated chemical switches (PaCS) to reduce binding under normal physiological conditions, while maintaining binding in the tumor. PaCS add a new dimension to drug discovery. PaCS can be applied to a variety of targets and drug formats, improving safety, increasing the number of targets, allowing the development of new therapies, and enhancing the tolerability of existing therapeutics. The PaCS mechanism can be used to tune the binding activity for disease-related microenvironments, including cancer, infection, inflammation, and cellular senescence., Anticytotoxic T lymphocyte-associated protein 4 (CTLA4) antibodies have shown potent antitumor activity, but systemic immune activation leads to severe immune-related adverse events, limiting clinical usage. We developed novel, conditionally active biologic (CAB) anti-CTLA4 antibodies that are active only in the acidic tumor microenvironment. In healthy tissue, this binding is reversibly inhibited by a novel mechanism using physiological chemicals as protein-associated chemical switches (PaCS). No enzymes or potentially immunogenic covalent modifications to the antibody are required for activation in the tumor. The novel anti-CTLA4 antibodies show similar efficacy in animal models compared to an analog of a marketed anti-CTLA4 biologic, but have markedly reduced toxicity in nonhuman primates (in combination with an anti-PD1 checkpoint inhibitor), indicating a widened therapeutic index (TI). The PaCS encompass mechanisms that are applicable to a wide array of antibody formats (e.g., ADC, bispecifics) and antigens. Examples shown here include antibodies to EpCAM, Her2, Nectin4, CD73, and CD3. Existing antibodies can be engineered readily to be made sensitive to PaCS, and the inhibitory activity can be optimized for each antigen’s varying expression level and tissue distribution. PaCS can modulate diverse physiological molecular interactions and are applicable to various pathologic conditions, enabling differential CAB antibody activities in normal versus disease microenvironments.

Sialoscintigraphy has been used in nuclear imaging for almost sixty years. It allows functional assessment and quantification of all large salivary glands. Physiological function of the salivary glands is essential for the preservation of the oral mucosa, the sense of taste and dental health. Impaired salivary gland function may lead to reduced or even absent salivation resulting in various complaints such as loss of taste reducing quality of life. During the recent years clinical relevance of assessment of salivary gland function has been rising. As novel radiopharmaceuticals such as 225Ac-PSMA or 177Lu-PSMA may cause damage to the salivary glands in a subset of patients, reliable methods for quantification of salivary gland function are vital for therapy planning and follow-up. Standardized protocols for the implementation and interpretation of this procedure are necessary to achieve comparable results from individual theranostic centers and to facilitate multicenter trials. Sialocintigraphy is also of clinical relevance for immunooncology. Treatments with checkpoint inhibitors such as Ipilimumab or Nivulomab frequently cause autoimmune disorders affecting the salivary glands that may lead to reduced production of saliva and finally loss of taste. Therefore, standardized procedure protocols for sialoscintigraphy are also important for general oncology.Here we suggest a protocol for sialoscintigraphy that may be used as standard in centers for theranostics or immunooncology and discuss the potential future role of this traditional procedure.Die Sialoszintigrafie wird seit fast sechzig Jahren in der nuklearmedizinischen Bildgebung eingesetzt. Sie ermöglicht die funktionelle Beurteilung und Quantifizierung aller großen Speicheldrüsen. Die physiologische Funktion der Speicheldrüsen ist für die Erhaltung der Mundschleimhaut, des Geschmackssinns und der Zahngesundheit von wesentlicher Bedeutung. Eine beeinträchtigte Speicheldrüsenfunktion kann zu vermindertem oder sogar fehlendem Speichelfluss führen, was verschiedene Beschwerden wie z. B. den Verlust des Geschmacksempfindens zur Folge hat und somit die Lebensqualität verringert. In den letzten Jahren hat die klinische Relevanz der Beurteilung der Speicheldrüsenfunktion zugenommen. Da neuartige Radiopharmazeutika wie 225Ac-PSMA oder 177Lu-PSMA bei einer Untergruppe von Patienten Schäden an den Speicheldrüsen verursachen können, sind zuverlässige Methoden zur Quantifizierung der Speicheldrüsenfunktion für die Therapieplanung und das Follow-Up von entscheidender Bedeutung. Standardisierte Protokolle für die Durchführung und Interpretation dieser Methode sind notwendig, um vergleichbare Ergebnisse von einzelnen Theranostikzentren zu erzielen und um multizentrische Studien zu ermöglichen. Die Sialozintigrafie ist auch für die Immunonkologie von klinischer Bedeutung. Behandlungen mit Checkpoint-Inhibitoren wie Ipilimumab oder Nivulomab verursachen häufig Autoimmunerkrankungen mit Beeinträchtigung der Speicheldrüsen, was zu einer verminderten Speichelproduktion und schließlich zu einem Verlust des Geschmacksinns führen kann. Daher sind standardisierte Protokolle für die Sialoszintigrafie auch in der allgemeinen Onkologie wichtig.Wir schlagen hier ein Protokoll für die Sialoszintigrafie vor, das als Richtlinie in Zentren für Theranostik oder Immunonkologie angewandt werden kann, und diskutieren die mögliche zukünftige Rolle dieser herkömmlichen Methode.

In der Kopf-Hals-Onkologie gewinnen immuntherapeutische Konzepte an Bedeutung und wurden bei dem diesjahrigen amerikanischen Krebskongress in relevanter Anzahl prasentiert. In dieser Arbeit sollen die interessantesten Studien und Studienergebnisse der Immuntherapie von Kopf-Hals-Tumoren zusammengefasst werden. Alle ASCO Abstracts und Prasentationen zur Immuntherapie von Kopf-Halstumoren wurden beurteilt und die interessantesten Studien aufgearbeitet. Auch wenn unmittelbar praxisverandernde Ergebnisse groser Phase-III-Studien ausblieben, wurden einige nennenswerte Ansatze und neue Erkenntnisse fur die Immuntherapie von Kopf-Hals-Tumoren prasentiert. Neoadjuvante Immuntherapiestudien, Ergebnisse zur Immuntherapie im Alter, zum prognostischen Einfluss immunvermittelter Nebenwirkungen und neue Immuntherapiekombinationen werden hier zusammengefasst. Die Rolle der Immuntherapie erreicht in der Behandlung von Kopf-Hals-Tumoren einen zunehmenden Stellenwert. Viele wegweisende Studien befinden sich derzeit in der Durchfuhrung, Auswertung oder Planung.

The treatment landscape in advanced and metastatic renal cell carcinoma (RCC) is moving from the inhibition of tyrosine kinases (TKI) and the mammalian target of rapamycin (mTOR) inhibitors to specific immunooncology agents like immune checkpoint inhibitors (ICI). The review focus on the recent immunooncology developments and available trial results within the last 12 months.ICI as monotherapy (nivolumab) or immunooncology and immunooncology combinations (nivolumab and ipilimumab) demonstrated positive results on prolonged overall survival in phase III trials. The combination of ICI (atezolizumab) and bevacizumab provided positive signals in prolonged PFS in the PD-L1 positive subgroup. Combinations of ICI and TKI are promising in early phase I and phase II trials. Results are currently expanded in larger phase III studies. The combination of vaccine and TKI in mRCC has not provided beneficial results so far.The current treatment landscape in mRCC is shifting towards immunooncology agents, which already gained ground in the clinic as ICI monotherapy (nivolumab) or is likely to do in the near future as ICI combination (nivolumab and ipilimumab). The future will hold promise of new combinations with TKIs and ICI or other immunooncology agents like vaccines and metabolic immune checkpoint inhibitors.

Over the last forty years, recombinant antibodies have been transformed from an unproven experimental approach to a therapeutic modality with multiple success stories in the treatment of cancer, inflammation, infections and cardiometabolic diseases. Owing to their high affinity and selectivity for the target antigen, their multimodal tunable mode of action, their modular nature and long half-life, antibodies now hold prominent positions in the pipelines of major biopharmaceutical companies. In this brief report, I aim to highlight the themes that have shaped the therapeutic antibody engineering as it exists today and to offer a personal perspective on its future developments. Distinct antibody engineering history, developments and trends in Russian Federation will not be discussed since they are detailed elsewhere in this journal issue.

The paradigms for treating head and neck squamous cell carcinoma are changing as new subgroups are defined. The technical successes of improved radiation therapy are many; however, the success of novel combined therapies are few. With the emergence of human papillomavirus and the development of immunooncology agents, such as checkpoint inhibitors, are we ready to reevaluate how we use radiation and chemotherapy for locally advanced and metastatic disease-will we remain the fire or become the fire starter?

Immuncheckpoint-Inhibitoren etablieren sich derzeit als neue systemische Therapieoption (neben der Chemotherapie und der targeted Therapie) bei metastasierten Tumoren. Uber eine (Re-)Aktivierung des Immunsystems konnen diese Antikorper zu eindrucksvollen, teils lang anhaltenden Remissionen fuhren. Bei den urologischen Tumoren wurden in diesem Jahr der PD-1-Antikorper Nivolumab (Opdivo ® ) beim fortgeschrittenen Nierenzellkarzinom nach Vortherapie und in den USA Atezolizumab (Tecentriq ® ) beim metastasierten Urothelkarzinom nach platinbasierter Chemotherapie zugelassen. Fur Nivolumab wurden nach antiangiogenetischer Vortherapie eine hohere Remissionsrate (25 vs. 5%) und eine Verlangerung des Gesamtuberlebens um 5,4 Monate im Vergleich zu Everolimus nachgewiesen. Fur das Urothelkarzinom nach platinbasierter Vortherapie zeigt sich im indirekten Vergleich zur Chemotherapie eine hohere Remissionsrate (15%) und 1-Jahres-Uberlebensrate (37%) fur Atezolizumab. Daruber hinaus zeichnen sich diese Therapien durch vergleichsweise geringe Nebenwirkungen aus. Bei einem Teil der Patienten kommt es aber zu sogenannten immunvermittelten Nebenwirkungen die rechtzeitig erkannt und behandelt werden mussen. Derzeit werden Immuncheckpoint-Inhibitoren in zahlreichen Phase-3-Studien gepruft und haben das Potenzial, die bisherigen Erstlinien-Standardtherapien bei metastasierten Tumoren, u. a. dem Urothel- und Nierenzellkarzinom abzulosen. Dabei werden auch Kombinationen aus PD-1/PD-L1-Antikorpern und CTLA4-Immuncheckpoint-Inhibitoren bzw. einer antiangiogenetischen Therapie gepruft. Auch die adjuvante Situation ist Gegenstand zulassungsrelevanter Studien.

During the 11th Breast-Gynecological and Immunooncology International Cancer Conference (BGICC), which was held on 17 and 18 January 2019, in Cairo, Egypt, around 100 international, regional and national experts from every continent presented the latest updates in breast cancer, gynaecological cancers and immunotherapy in oncology. Through this report, we highlight the important data and consensus issues that were discussed during the conference.

Oncology treatment has been revolutionized by the introduction of immune checkpoint inhibitor drugs, which enable 20–40% of patients to generate anti-tumor immune responses. Combination treatment approaches with chemotherapeutic drugs may enable responses in the remaining patient cohorts. In this regard, a handful of drugs are promising due to their ability to induce immunogenic cell death in target cells. However, these agents are systemically delivered and indiscriminately cytotoxic to proliferating cells. By contrast, antibody-drug conjugates can selectively deliver a cytotoxic payload to a tumor, sparing most healthy cells. The ability of antibody-drug conjugates to induce immunogenic cell death in target cells has not yet been determined, although preclinical in vivo studies suggest this possibility. Here, we describe for the first time production of the in vitro hallmarks of immunogenic cell death – ecto-calreticulin and secreted ATP and HMGB1 protein – by cells in response to treatment with antibody-drug conjugates bearing a maytansine payload.

The introduction of checkpoint inhibitors revolutionized immuno-oncology. The efficacy of traditional immunotherapeutics, like vaccines and immunostimulants was very limited due to persistent immune-escape strategies of cancer cells. Checkpoint inhibitors target these escape mechanisms and re-direct the immune system to anti-tumor toxicity. Phenomenal results have been reported in entities like melanoma, where no other therapy was able to demonstrate survival benefit, before the introduction of immunotherapeutics. The first experience in ovarian cancer (OC) was reported for nivolumab, a fully human anti-programmed cell death protein 1 (PD1) antibody, in 2015. While the data are extraordinary for a mono-immunotherapeutic agent and very promising, they do not match up to the revolutionary results in entities like melanoma. The key to exceptional treatment response in OC, could be the identification of the most immunogenic patients. We hypothyse that BRCA mutation could be a predictor of improved response in OC. The underlying DNA-repair-deficiancy should result in increased immunogenicity because of higher mutational load and more neoantigen presentation. This hypothesis was not tested to date and should be subject to future trials. The present article gives an overview of the immunologic background of checkpoint inhibition (CI). It presents current data on nivolumab and other checkpoint-inhibitors in solid tumors and OC specifically and depicts important topics in the management of this novel substance group, such as side effect control, diagnostic PD-1/programmed cell death-ligand 1 (PD-L1) expression assessment and management of pseudoprogression.

Immunotherapies are set to become part of the therapeutic repertoire for breast cancer in the near future. Active vaccination is a promising strategy, especially in tumors that have a specific tumor-associated antigen. Although cellular immunotherapies have not yet shown efficacy, new technologies are on the way to improve this approach. Given the recent Food and Drug Administration approval of chimeric antigen receptor (CAR) T cells for leukemia, it is only a question of time before solid tumors will follow. However, not all breast cancer patients will respond to cellular or other immunotherapy. Hence, we must define subpopulations of breast cancer patients who benefit from this new approach.

Non–small cell lung cancer (NSCLC) is the leading cause of cancer related mortality worldwide. Many patients present with metastatic disease and traditional CT treatment fails to provide long- term benefit for most patients. Patients with driver mutations demonstrate substantially better response rate and progressionfree survival when the appropriate targeted agents are used, but only approximately 25%-30% of patients with NSCLC have actionable mutations. Novel treatment options are clearly needed for patients with lung cancer. Immuno-oncology recently has been identified as effective second line therapy of NCSLC. Almost all of this progress has been due to the development of PD‑1 and PD-L1 inhibitors. In this review, we explore the data currently available for these agents.

Urothelial carcinoma of the bladder is a heterogeneous disease with many challenges for clinicians and patients alike. However, for the most part of the last three decades, treatment and outcomes for patients with this disease have not changed a lot. With recent advances in immunooncology leading to the approval of multiple agents for the metastatic setting, the treatment landscape started to change. With the emergent data from landmark multi-institutional sequencing projects as well as molecular data from recent trials, our understanding of the underlying disease biology, response patterns as well as definition of molecular subtypes has evolved tremendously. This review aims to summarize the currently available concepts of mutational profiles and molecular subtypes as well as their implications for management of urothelial carcinoma.

We live in a scientific golden age. Never has the pace of discovery been so rapid, the range of achievements so broad, and the changing nature of our understanding so revolutionary. Science today has extraordinary powers. It reveals fundamental phenomena of our universe, catalyzes new technologies, powers new businesses, fosters new industries, and improves lives. This month's annual meeting of the American Association for the Advancement of Science (AAAS, the publisher of Science ) in Austin, Texas, celebrates this golden age. More than 10,000 scientists, students, teachers, business people, journalists, philanthropists, science enthusiasts, government officials, and others will come together to hear and discuss talks by experts on such topics as immunooncology, exoplanets, election polling, and much more. Today's advances and innovations presage a future that most of us have not yet imagined.

Cancer immunotherapy has shown impressive clinical results in the last decade, improving both solid and hematologic cancer patients' overall survival. Nevertheless, most of the molecular aspects underlying the response to this approach are still under investigation. miRNAs in particular have been described as regulators of a plethora of different immunologic processes and thus have the potential to be key in the future developments of immunotherapy. In this review, we summarize and discuss the emerging role of miRNAs in the diagnosis and therapeutics of the four principal cancer immunotherapy approaches: immune checkpoint blockade, adoptive cell therapy, cancer vaccines, and cytokine therapy. In particular, this review is focused on potential roles for miRNAs to be adjuvants in soluble factor- and cell-based therapies, with the aim of helping to increase specificity and decrease toxicity, and on the potential for rationally identified miRNA-based diagnostic approaches to aid in precision clinical immunooncology.

Gliomas are incurable diffusely infiltrating intrinsic brain tumors with a particular medical need as standard of care has not moved beyond surgery and radiochemotherapy despite profound efforts with targeted agents. Immunotherapy of gliomas is a particularly challenging field in immunooncology as these tumors grow in an immune-privileged site and—particularly in glioblastomas, the most malignant type of gliomas—create an immunosuppressive microenvironment. Preclinical animal models and case reports applying checkpoint inhibitors and CAR T cells indicate that the central nervous system per se does not represent a barrier for translating an effective antitumor immune response to gliomas. Rather, human gliomas are generally poorly immunogenic as also indicated by the comparatively low mutational load. Current challenges include the definition of appropriate antigens and the reversal of the tumor-associated immune suppression. This review summarizes current preclinical and phase I–III concepts in glioma immunooncology and aims at describing a path forward for the development of successful immunotherapies, which will likely encompass combinatorial approaches aiming at inducing an antigen-specific immune response and reversal of glioma immunosuppression.

As the ACS national meeting wound down, medicinal chemists flocked to a massive ballroom to hear the stories of eight potential drugs at the start of their likely years-long journey through the clinic to one day reach patients—or so drugmakers hope. Always a highly anticipated event, the “First-Time Disclosure of Clinical Candidates” session rewards curious chemists with glimpses of drug-compound structures not previously made public. This year’s session was organized by Erin DiMauro, Merck & Co.’s executive director of discovery chemistry. Half of the talks in the lineup revealed immuno-oncology compounds that enlist humans’ immune system to combat tumors. Other presenters discussed drug-development programs tackling diabetes, resistant bacterial infections, and Parkinson’s disease. Read our full story online to find out more about these drug candidates, including their structures at cenm.ag/drugdisclosuresorlando.

Vitamin D deficiency is frequently observed in human cancer patients and a prognostic relevance could be shown for some entities. Additionally, it is known that vitamin D can stimulate the patients' antitumor immunity. However, valid epidemiological data for head and neck squamous cell carcinoma (HNSCC) patients are sparse and functional studies on a possible connection between vitamin D and the patients' immune system are missing. 25-OH vitamin D serum levels were analyzed in 231 HNSCC patients and 232 healthy controls and correlated with clinical data and patient survival. Intra- and peritumoral infiltration with T-cell, NK-cell and macrophage populations was analyzed in 102 HNSCC patients by immunohistochemistry. In 11 HNSCC patients, NK-cells were isolated before and after vitamin D substitution and analyzed for their cytotoxic activity directed against a HNSCC cell line. Vitamin D serum levels were significantly lower in HNSCC patients compared with healthy controls. Low vitamin D levels were associated with lymphatic metastasis and a negative HPV status and were a significant predictor of poor overall survival. HNSCC patients with severe vitamin D deficiency showed significantly altered intra- and peritumoral immune cell infiltrate levels. After vitamin D substitution, the patients' NK cells showed a significant rise in cytotoxic activity. Taken together, we could show that Vitamin D deficiency is highly prevalent in HNSCC patients and is a predictor of poor survival. Vitamin D substitution used as an adjuvant in immune therapies such as cetuximab and nivolumab treatment could support antitumorigenic immune responses, thus contributing to the improvement of the patients' prognosis in the context of a multimodal therapy.

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found.

Immunotherapeutic concepts in neurooncology have been developed for many decades but have mainly been hampered by poor definition of relevant antigens and selective measures to target the central nervous system. Independent of the recent remarkable successes in clinical immunooncology with checkpoint inhibitors and vaccines, immunotherapy of brain tumors in general and gliomas in particular has evolved with novel neurooncology-specific concepts over the past years providing new phase 1 approaches of individualized immunotherapy to first phase three clinical trials. These concepts are driven by a high medical need in the absence of approved targeted therapies and refute the classic dogma that the central nervous system is immune-privileged and hence inaccessible to potent antitumor immunity. Instead, measures have been taken to improve the odds for successful immunotherapies, including rational targeting of relevant antigens and integration of immunotherapies into standard of care primary radiochemotherapy to increase the efficacy of antitumor immunity in a meaningful time window. This review highlights concepts and challenges associated with epitope discovery and selection and trial design.

2543 Background: Trials using randomized designs have been conducted for decades to demonstrate efficacy of novel anti-cancer drugs (NACD). Recently, several NACD have shown high antitumor activity in early phase studies, prompting suggestions that NRCT could expedite drug development. We sought to determine what changes have occurred in numbers of NACD RCT vs NRCT conducted from 2004-2016. Methods: We reviewed a database of NACD clinical trials conducted by INC (excluding phase I and I/II trials) and classified them by RCT vs NRCT, grouped by year (≤ 2010 or > 2010). We queried Citeline Trialtrove database for industry sponsored, phase 2 trials (P2T) initiated from 2006-2016 and examined numbers of RCT vs NRCT by year.A more detailed analysis of non-small cell lung cancer (NSCLC) clinical trials based on drug type category - Immunooncology (IO) vs. all other mechanims of action (NIO) was performed. Results: 190 INC-conducted trials were reviewed. 58 trials (31%) were performed ≤ 2010 and 132 trials (69%) > 2010. Over this period, NRCT (n = 107, 56%) outnumbered RCT (n = 83, 44%). Whereas RCT outnumbered NRCT from 2004-2010 (74% vs 52%), after 2010, NRCT outnumbered RCT (58% vs 42%). Citeline Trialtrove search revealed 4776 industry sponsored P2T initiated from 2006-2016. The total number of P2T started annually was highest in 2007 (n = 621), decreasing to a low of 375 in 2016. The proportion of phase 2 RCT demonstrated an increase from 27% (n = 166) in 2006 to a peak plateau of 37-39% from 2011-2014, followed by a drop to 33% in 2015 and 29% in 2016. Among IO studies, RCT declined in 2015-6 vs. previous years, and a decreased for all NACD in 2016 vs. previous years also was noted. For studies in NSCLC, declines in RCT were evident from 2015-6 vs. previous years ( 45% in 2007-14 vs. 25% in 2015-6). Conclusions: Our data indicate a trend toward fewer trials of NACD using randomized designs and more studies using non-randomized designs, with overall fewer P2T initiated in the past year. This change reflects shifts in NACD development pathways, related to a better understanding of cancer biology, drive to develop personalized treatment and a more flexible regulatory drug approval process.

Cancer immunotherapy has been one of the dominant topics in oral presentations and abstracts during the 2015 annual meeting of the American Society of Clinical Oncology (ASCO). The renewed interest in immunotherapy is explained by the wide spectrum of activity, the durability of tumor responses and the rapid clinical development of immune-checkpoint targeted monoclonal antibodies. These new drugs are currently revolutionizing the field of oncology. Here we highlight what were to us the most important results announced during the annual meeting of ASCO held in Chicago, IL from May, 29th to June, 2nd 2015. In addition, we searched all the posters/published abstracts pertinent to the field of immunooncology from this year conference. Among more than 400 published abstracts on this topic, we have grouped and briefly summarized the most relevant ones.