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Background Diagnosis of invasive candidiasis (IC) relies on insensitive cultures; the relative utility of fungal biomarkers in children is unclear. Methods This multinational observational cohort study enrolled patients aged >120 days and Results Five hundred participants were enrolled at 22 centers in 3 countries, and IC was diagnosed in 13 (2.6%). Thirteen additional blood specimens were collected and successfully spiked with Candida species, to achieve a 5.0% event rate. Valid T2Candida, Fungitell, Platelia Candida Ag Plus, and Platelia Candida Ab Plus assay results were available for 438, 467, 473, and 473 specimens, respectively. Operating characteristics for T2Candida were most optimal for detecting IC due to any Candida species, with results as follows: sensitivity, 80.0% (95% confidence interval, 59.3%–93.2%), specificity 97.1% (95.0%–98.5%), positive predictive value, 62.5% (43.7%–78.9%), and negative predictive value, 98.8% (97.2%–99.6%). Only T2Candida and Platelia Candida Ag Plus assays met the threshold for combination testing. Positive result for either yielded the following results: sensitivity, 86.4% (95% confidence interval, 65.1%– 97.1%); specificity, 94.7% (92.0%–96.7%); positive predictive value, 47.5% (31.5%–63.9%); and negative predictive value, 99.2% (97.7%–99.8%). Conclusions T2Candida alone or in combination with Platelia Candida Ag Plus may be beneficial for rapid detection of Candida species in children with concern for IC. Clinical Trials Registration NCT02220790.

Supplementary Data from A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Comparing the Tolerability and Efficacy of Ipilimumab Administered with or without Prophylactic Budesonide in Patients with Unresectable Stage III or IV Melanoma

Purpose: Diarrhea (with or without colitis) is an immune-related adverse event (irAE) associated with ipilimumab. A randomized, double-blind, placebo-controlled, multicenter, multinational phase II trial was conducted to determine whether prophylactic budesonide (Entocort EC), a nonabsorbed oral steroid, reduced the rate of grade ≥2 diarrhea in ipilimumab-treated patients with advanced melanoma.Experimental Design: Previously treated and treatment-naïve patients (N = 115) with unresectable stage III or IV melanoma received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) with daily blinded budesonide (group A) or placebo (group B) through week 16. The first scheduled tumor evaluation was at week 12; eligible patients received maintenance treatment starting at week 24. Diarrhea was assessed using Common Terminology Criteria for Adverse Events (CTCAE) 3.0. Patients kept a diary describing their bowel habits.Results: Budesonide did not affect the rate of grade ≥2 diarrhea, which occurred in 32.7% and 35.0% of patients in groups A and B, respectively. There were no bowel perforations or treatment-related deaths. Best overall response rates were 12.1% in group A and 15.8% in group B, with a median overall survival of 17.7 and 19.3 months, respectively. Within each group, the disease control rate was higher in patients with grade 3 to 4 irAEs than in patients with grade 0 to 2 irAEs, although many patients with grade 1 to 2 irAEs experienced clinical benefit. Novel patterns of response to ipilimumab were observed.Conclusions: Ipilimumab shows activity in advanced melanoma, with encouraging survival and manageable adverse events. Budesonide should not be used prophylactically for grade ≥2 diarrhea associated with ipilimumab therapy. (Clin Cancer Res 2009;15(17):5591–8)

This review article considers the physiology, differential diagnosis and immediate management of vasovagal response, vascular injury and carbon dioxide embolism caused during creation of the laparoscopic pneumoperitonium. These pathologies account for over half of all laparoscopic complications and therefore, by taking a systematic approach to these possibly life-threatening events, laparoscopy can become even safer.

Loneliness has been termed a social epidemic, especially when experienced by people with sight challenges. The present study compared how the sight challenged and the blind cope with loneliness, compared to the general population groups, amongst a total of 187 participants. The questionnaire which we used, included 34-items to which a yes/no response was requested, and assessed the various ways that people cope effectively with loneliness. The questionnaire included six subscales of coping strategies, namely, Reflection and acceptance, Self-development and understanding, Social support network, Distancing and denial, Religion faith, and increased activity. As expected, the two populations differed significantly in their subscale scores, with the visually challenged scoring higher than the general population, on Self-development and understanding and the Religion and faith subscales. Interpretation of these results and their implications are discussed in further detail.

We perform a detailed analysis of the vacua of omega-deformed SO(8) supergravity in four dimensions. In particular, using Tensorflow-based numerical methods, we track how the equilibria of the theory change when varying the electric-magnetic deformation parameter omega. Apart from describing various properties of different equilibria (390 in total), we show that as w is deformed, the SO(3), N= 1 vacuum of the de Wit-Nicolai theory becomes equivalent to a critical point in U(4) proportional to R-12 gauged supergravity with a known uplift in IIB supergravity. The procedure employed here to obtain a new gauging with a guaranteed equilibrium is generic and allows one to obtain further admissible noncompact gaugings via omega-deformation, all of which have guaranteed critical points, and some of which may be novel upliftable solutions., Journal of High Energy Physics, 2022 (6), ISSN:1126-6708, ISSN:1029-8479

This datasheet on Oryctolagus cuniculus covers Identity, Overview, Distribution, Dispersal, Biology & Ecology, Impacts, Uses, Prevention/Control, Further Information.

Two persons looking into a field can each say ‘I see the brown cow’ and be conscious of the cow they see. And as there is one thing they see and are talking about, namely the cow, it is assumed that their respective consciousness is also the same. This, very briefly, is what I call the Assumption: that there is one basic kind of consciousness which all human beings have. It is this Assumption which I reject. For the truth, I argue, is that there are two basic kinds of human consciousness, one which is monistic, the other dualistic. I call this the 2 Consciousnesses Theory- or, for short, 2CT. My aim in this chapter is to make clear both the Assumption and the 2CT, and to explain why the former should be rejected and the latter accepted. To do this, I move in different sections between the Assumption and the 2CT, going deeper and deeper into each, providing more and more detail about each and why one is false and the other is true.

My aim in this chapter is to look closely at A. J. Ayer, the philosopher who is the terminus of this work; then to use my understanding of him to point to a number of tangles in twentieth century philosophy and the way they can be untangled. However, first it is necessary to be clear about Ayer’s philosophical position. Nor is this an easy matter, for Ayer wrote many philosophical books and articles after his first and most celebrated work, Language, Truth and Logic [= LTL] was published in 1936, when he was twenty-six. Yet I think his position remained essentially the same even to his last essay, entitled a ‘Defense of Empiricism’, published in 1989, the year of his death. Perhaps the best way of identifying this philosophical position, as he himself suggests in that last essay, is to see what it was not, i.e. the positions which Ayer did not accept, even though he recognized they were held by respected philosophers. One such position was Berkeley’s idealism, which Ayer thought was wrong for, among the reasons, its subjectivist tendency to solipsism. Another position which Ayer thought was mistaken was representationalism, which Ayer rejects for Berkeleian reasons- in short because it supposes that what exists in a non-perceptual realm. But if we do not perceive or experience this realm or the things in it, then how can we know anything about them, or even that that they exist? Hence Ayer sees this position- which was accepted for a time by Russell, who Ayer had enormous respect for- as mistaken.

I can indicate the main aims of this chapter by explaining its title. By ‘Irish Philosophy, Past’, I understand that period when Ireland was at the cutting edge of world philosophy. This was the golden age, which was born with John Toland’s Christianity not Mysterious (1696), grew with the answers to his challenge by Peter Browne, William King and Edward Synge, and culminated in the work of Hutcheson, Burke and especially Berkeley, and then came to a close in the late 1750s.

As indicated in my title, this chapter is about two topics. The first focuses on Hume’s essay ‘Of Miracles’, which in what follows I shall refer to as the ‘essay’. The second topic focusses on Hume’s account of personal identity in his Treatise of Human Nature, Book one, pt iv, sect. vi, and its apparent retraction in the Appendix to the Treatise, Book three.

Carolyn Ellis’ foundational book, Final Negotiations, remains a poignant testament to the role of an individual’s lived experience in the course of scientific discovery. The message, that the human...

Non-muscle-invasive bladder cancer (NMIBC) is more than three times as common in men as it is in women. However, female patients with NMIBC do not respond as well to immunotherapeutic treatments and experience worse clinical outcomes than their male counterparts. The underlying causes of these discrepancies have yet to be fully elucidated. We hypothesized that sexual dimorphism in the tumor immune microenvironment (TIME) may contribute to the inferior clinical outcomes observed in female patients with NMIBC. To test this hypothesis, we investigated immune-associated gene expression in tumors from male (n=357) and female (n=103) patients. High-grade tumors from female patients exhibited significantly increased expression of B cell-associated genes CD40 and CXCL13, and the immune checkpoint genes CTLA4, PDCD1, LAG3, and ICOS. Based on these differences, we utilized multiplexed immunofluorescence to evaluate the density and spatial distribution of 12 immune cell markers (CD79a, CD3, CD8, FoxP3, Ki67, CD103, CD163, GATA3, CK5, IDO1, PD-1, and PD-L1) in tumors from an independent cohort of 332 patients with NMIBC (n=259 males and n=73 females). Tumors from female patients showed significantly higher infiltration of PD-L1+ cells and CD163+ M2-like macrophages compared to tumors from male patients. Notably, increased abundance of CD163+ macrophages and CD79a+ B cells were independently associated with decreased recurrence-free survival. This study has the potential to inform the rational utilization of immunomodulatory treatments for NMIBC based on the TIME of both male and female patients. Furthermore, these novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials.

Introduction: Presentation of dysregulated or neoantigen peptides by human leukocyte antigens (pHLA) are a key source of novel targets for cancer immunotherapy. ImmTAC molecules are a novel class of T cell redirecting bispecific fusion protein that utilize an affinity enhanced TCR to target tumor selective pHLA. Tebentafusp, our lead clinical candidate, is an ImmTAC molecule that targets a gp100-derived peptide presented by HLA-A*02:01. The aim of this study was to investigate whether the gp100 peptide could be presented by other HLA alleles (i.e. alloreactivity), and whether this presentation could be detected by tebentafusp. Experimental procedures: Using mass spectrometry, gp100 presentation in HLA-A*02:01+ and HLA-A*02:01- melanoma cell lines was investigated. T cell redirection assays were performed against gp100+ HLA-A*02:01+ and gp100+ HLA-A*02:01- tumor cells as well as a panel of HLA-A*02:01- B cells with broad HLA allele presentation. X-ray crystallography was used to solve the structure of tebentafusp in complex with HLA-A*02:01-gp100 peptide to understand the mechanisms underpinning target selectivity to tumor cells expressing both gp100 and HLA-A*02:01. Summary of the data: Our data demonstrate that the gp100 peptide targeted by tebentafusp was only detectable on HLA-A*02:01+ tumor cells. Tebentafusp-mediated T cell redirection was only observed on target cells expressing both gp100 and HLA-A*02:01 and recognition of gp100+ HLA-A*02:01- cells could be re-established via lentiviral expression of HLA-A*02:01. Additionally, tebentafusp did not generate a T cell response against a panel of B cells representing major HLA types that cover ~90% of the human population. Further investigation revealed that although gp100 could bind to some other HLA-A*02 subfamily members, tebentafusp was able to discriminate between these pHLA complexes in binding and cellular assays. The 3D crystal structure of tebentafusp in complex with HLA-A*02:01-gp100 peptide revealed the complex was stabilized through specific interactions with residues unique to HLA-A*02:01. Conclusions: The lack of alloreactivity by tebentafusp towards other HLA alleles was driven by both restricted presentation of the target gp100 peptide by HLA-A*02:01 and direct molecular interactions between tebentafusp and unique residues on the HLA-A*02:01 surface. These data have implications for the selection of patient populations that are likely to benefit from treatment with this novel bispecific drug. Citation Format: David Cole, Ross Robinson, Velupillai Srikannathasan, Vijay Karuppiah, Stephen Harper, Charlotte Coles, Viren Patel, Anitha Jevanthan, Jane Harper, David Berman, Alex Powesland. Tebentafusp recognition of melanoma cells is restricted by HLA-A0201 presentation of a gp100 peptide [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2271.

Background: Bispecific immunotherapies have been validated for the treatment of hematologic tumors but none have yet been approved for solid tumor indications, including high prevalent tumors such as non-small-cell lung carcinoma (NSCLC). Immunocore is developing ImmTAC® molecules, a new class of TCR/anti-CD3 bispecific fusion protein, that target intracellularly derived peptides presented at the tumor cell surface in complex with human leukocyte antigen (HLA). The ImmTAC IMC-F106C is in development for the treatment of advanced cancers that are positive for Preferentially Expressed Antigen in Melanoma (PRAME). PRAME is a cancer-testis antigen (CTA) that is highly expressed in normal testis and a range of solid and hematologic malignancies. The aim of this study was to characterise the expression of PRAME in a variety of human malignancies (mRNA and protein) and demonstrate that IMC-F106C can potently redirect T cells to eliminate indication-relevant tumor cells in vitro. Method: FFPE tumor samples were analysed by RT-qPCR and IHC for a number of tumor indications, to determine levels of PRAME mRNA and protein expression in patient samples for each indication. The activity of IMC-F106C was investigated in cellular assays using healthy donor PBMCs as effectors, targeting a variety of indication-relevant tumor cell lines expressing a PRAME-specific peptide complexed with HLA-A*02:01, including NSCLC non-small-cell lung carcinoma, ovarian carcinoma, and acute myeloid leukemia cell lines. T cell activation was assessed by cytokine release and T cell-mediated target-cell killing was evaluated by measurement of cell death (xCELLigence). Results: PRAME mRNA and protein expression was highly prevalent in samples of NSCLC, including both the adenocarcinoma and squamous cell carcinoma subtypes, SCLC, melanoma, ovarian, endometrial carcinoma samples, and in triple negative breast cancer (TNBC). Over 60% of samples demonstrated some level of PRAME expression by IHC and RT-qPCR in these 6 cancer indications. In the PRAME positive HLA-A*02:01 positive cell lines, IMC-F106C redirected donor effector cells to release IFNγ and GrB and kill tumor cells in a dose-dependent manner, with activity demonstrated as low as < 1 pM. By contrast, cell lines negative for PRAME or HLA-A*02:01 expression failed to induce responses < 1 nM of IMC-F106C. Conclusion: These data indicate that PRAME is expressed in a number of solid tumors, and is highly prevalent in lung tumours, irrespective of EGFR status, as well as female-oriented cancers. In conjunction, IMC-F106C efficiently redirects T cell activity against tumor cell lines that express PRAME across a range of tumor indications. Taken together, IMC-F106C could prove to be a highly effective immunotherapy option for HLA*02:01 positive patients with PRAME positive tumors. Citation Format: Sylvie Moureau, Alessio Vantellini, Florence Schlosser, Jacob Robinson, Jane Harper, Athiva Shankar, Greg Dobrynin, Gabrielle Le Provost, Amanda Williams, David Berman, Laure Humbert. IMC-F106C, a novel and potent immunotherapy approach to treat PRAME expressing solid and hematologic tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5572.

Introduction: Bispecific T cell engagers hold promise for effective cancer treatment. The anti-tumor activity of these therapeutics molecules predominantly relies on their capacity to induce direct killing of tumor cells by engaging the cytotoxic machinery of polyclonal CD8+ T cells. However, the impact of additional functionally different T cell populations that can be engaged alongside CD8+ T cells remains unclear. ImmTAC molecules are a novel class of bispecific fusion proteins that use an affinity-enhanced monoclonal TCR to target tumor antigen-derived peptides presented by HLA, and an anti-CD3 monomeric antibody to engage T cells. Tebentafusp, our lead clinical candidate, targets a gp100-derived peptide and is under clinical investigation in metastatic melanoma. Preliminary data revealed T cell activation, trafficking and infiltration into the tumor bed in patients responding to treatment. Importantly not only CD8+ T cells, but also different subsets of CD4+ T cells appeared to be activated, mobilized and redirected to the tumor site following tebentafusp treatment, suggesting a potential contribution of these T cell subsets to the anti-tumor response. The aim of this study was to investigate in vitro the functional capacity of different T cell populations, besides CD8+ T cells, following ImmTAC-mediated redirection toward cancer cells. Methods: Th1, Th2, Th17 CD4+ T cells, γδ T cells and Mucosal-Associated Invariant T cells (MAIT) were isolated from healthy volunteers and their functional response following exposure to ImmTAC in the presence of target cells was analysed. Results: In addition to CD8+ T cells, other T cell populations, were activated in vitro by ImmTAC and elicited a range of effector functions that may differentially contribute to anti-tumor responses. For example, we found that γδ T cells were able to mount rapid and potent cytokine and cytotoxic responses against cancer cells upon redirection with ImmTAC. The mechanisms that underpin our in vitro observations and the potential correlations in patients treated with tebentafusp are under investigation. Conclusions: Multiple T cells populations display functionally distinct responses following ImmTAC-mediated redirection. These results will add valuable insight to our understanding of bispecific T cell engager mechanism of action. In addition, they will help guide rationale for improving the design of these therapeutic molecules and select appropriate combination strategies. Citation Format: Adel Benlahrech, David K. Cole, Christopher J. Holland, Rupert Kenefeck, Rahul C. Khanolkar, Cheryl McAlpine, Sion Lewis, Angela Valerio-Fernandes, Mariantonella Vardeu, David Berman, Marco Lepore. Functionally distinct T cell subsets contribute to ImmTAC-mediated anti-tumor response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4554.

Bladder cancer is a management-intensive disease that leads to ~200, 000 deaths worldwide every year. Upon initial diagnosis, approximately 75% of cases are categorized as non-muscle-invasive bladder cancer (NMIBC). Adjuvant Bacillus Calmette-Guérin (BCG) immunotherapy is the gold standard treatment for high risk NMIBC patients. Despite being used for over 40 years, many BCG patients exhibit tumor recurrence, a subset of which display progression to a muscle-invasive form of the disease that requires undesired bladder removal surgery. We recently demonstrated that the interferon response induced by BCG could be further complemented via synergistic activation of the Stimulator of Interferon Genes (STING) pathway. Towards clinical translation of this combinatorial immunomodulation and in order to determine immune biomarkers associated with response to BCG, we retrospectively investigated the immune transcriptomic profiles of tumors from BCG responders and non-responders. Interestingly, tumors from BCG non-responders showed a higher immune cell abundance and higher immune checkpoint gene expression. To further independently validate the transcriptomic findings at protein levels, we conducted spatial immune profiling of 12 immune cell markers (Ki-67+, CD8+ proliferating T cells, FoxP3+ T regulatory cells, CD79+ B cells, PD-1, PD-L1 and IDO1 immune checkpoints, CD68+ and CD163+ M1 and M2 macrophages) in a cohort of 571 NMIBC tumors. Preliminary findings showed that tumors from BCG non-responders are characterized by infiltration of immunosuppressive T regulatory cells. Findings from this study will have the potential to guide future immune biomarker guided immunomodulatory treatment combinations.

Pregnancy is a time of significant physiologic change that affects the vast majority of organ systems. Pregnant patients occasionally present for nonobstetric surgery, with complication rates of the procedure increased as well as the potential for fetal loss or damage as a result of the underlying disease process. Typical steps in diagnosis (such as imaging modalities) often need to be adjusted in pregnancy, and the medical or surgical treatment of neurologic disease will often change as well. A thorough understanding of pregnancy physiology, pharmacology, and teratogenicity will be important in caring for the pregnant neurosurgical patient.

A method of producing a bit-patterned media on a flexible substrate using a low-cost, hot nanoimprinting process is investigated. Using a topographic master with features as small as 40 nm, a flexible plastic substrate is patterned with high fidelity. Magnetic material is sputter-deposited onto the patterned substrate to produce a magnetic tape media with densities as high as 100 Gigadot/in $^{ {2}}$ . Magnetic recording characteristics of the coated bit-patterned tape is evaluated in an apparatus which slides a recording head on the media with a high-resolution positioning capability.

Background: Achieving high participation of communities representative of all sub-populations is needed in order to ensure broad applicability of biobank study findings. This study aimed to understand potentially mutable attitudes and opinions commonly correlated with biobank participation in order to inform approaches to promote participation in biobanks. Methods: Adults from two University of Maryland (UMD) Faculty Physicians, Inc. outpatient practices were invited to watch a video and complete a survey about a new biobank initiative. We used: Chi-square to assess the relationship between willingness to join the biobank and participant characteristics, other potentially mutable attitudes and opinions, and trust in the UMD. We also used t-test to assess the relationship with trust in medical research. We also prioritize proposed actions to improve attitudes and opinions about joining biobanks according to perceived responsiveness. Results: 169 participants completed the study, 51% of whom indicated a willingness to join the biobank. Willingness to join the biobank was not associated with age, gender, race, or education but was associated with respondent comfort sharing samples and clinical information, concerns related to confidentiality, potential for misuse of information, trust in UMD, and perceived health benefit. In ranked order, potential actions we surveyed that might alleviate some of these concerns include: increase chances to learn more about the biobank, increase opportunities to be updated, striving to put community concerns first, including involving community members as leaders of biobank research, and involving community members in decision making. Conclusions: This study identified several attitudes and opinions that influence decisions to join a biobank, including many concerns that could potentially be addressed by engaging community members. We also demonstrate our method of prioritizing ways to improve attitudes and opinions about joining a biobank according to perceived responsiveness.

Purpose To provide a more precise estimate of long-term survival observed for ipilimumab-treated patients with advanced melanoma, we performed a pooled analysis of overall survival (OS) data from multiple studies. Methods The primary analysis pooled OS data for 1,861 patients from 10 prospective and two retrospective studies of ipilimumab, including two phase III trials. Patients were previously treated (n = 1,257) or treatment naive (n = 604), and the majority of patients received ipilimumab 3 mg/kg (n = 965) or 10 mg/kg (n = 706). We also conducted a secondary analysis of OS data (n = 4,846) with an additional 2,985 patients from an expanded access program. OS rates were estimated using the Kaplan-Meier method. Results Among 1,861 patients, median OS was 11.4 months (95% CI, 10.7 to 12.1 months), which included 254 patients with at least 3 years of survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. Three-year survival rates were 22%, 26%, and 20% for all patients, treatment-naive patients, and previously treated patients, respectively. Including data from the expanded access program, median OS was 9.5 months (95% CI, 9.0 to 10.0 months), with a plateau at 21% in the survival curve beginning around year 3. Conclusion To our knowledge, this is the largest analysis of OS to date for ipilimumab-treated patients with advanced melanoma. We observed a plateau in the survival curve, beginning at approximately 3 years, which was independent of prior therapy or ipilimumab dose. These data add to the evidence supporting the durability of long-term survival in ipilimumab-treated patients with advanced melanoma.

The discovery and increased understanding of the complex interactions regulating the immune system have contributed to the pharmacologic activation of antitumor immunity. The activity of effector cells, such as T and NK cells, is regulated by an array of activating and attenuating receptors and ligands. Agents that target these molecules can modulate immune responses by exerting antagonistic or agonistic effects.Several T- or NK-cell modulators have entered clinical trials, and two have been approved for use. Ipilimumab (Yervoy®, Bristol-Myers Squibb) and nivolumab (OPDIVO, Ono Pharmaceutical Co., Ltd./Bristol-Myers Squibb) were approved for the treatment of metastatic melanoma, in March 2011 in the United States, and in July 2014 in Japan, respectively.The clinical activity of these two antibodies has not been limited to tumor types considered sensitive to immunotherapy, and promising activity has been reported in other solid and hematologic tumors.Clinical development of ipilimumab and nivolumab has presented unique challenges in terms of safety and efficacy, requiring the establishment of new evaluation criteria for adverse events and antitumor effects. Guidelines intended to help oncologists properly manage treatment in view of these non-traditional features have been implemented.The introduction of this new modality of cancer treatment, which is meant to integrate with or replace the current standards of care, requires additional efforts in terms of optimization of treatment administration, identification of biomarkers and application of new clinical trial designs. The availability of immune modulators with different mechanisms of action offers the opportunity to establish immunological combinations as new standards of care.