Recent Immunotherapy Research Articles

Immunotherapy in gynecological cancers: where are we?

This manuscript discusses the clinical evidence on immunotherapy for ovarian, endometrial, and cervical cancer. We report here the results of the clinical trials and present the ongoing trial in this area. Immunotherapy has become a pillar of cancer treatment improving the prognosis of many patients with a broad variety of solid malignancies. Unfortunately, until recently the progress achieved in some other tumors has not been seen in the majority of patients with gynecological cancer. Except for some subgroups of endometrial cancers the immune checkpoint inhibitors in monotherapy have shown unsatisfactory results. However, several combinations of immunotherapy with other drugs are under investigation and are very promising. It is essential, to develop tools to select the patients who will response best to immunotherapy. Combined immune checkpoint inhibitors with targeted therapies are awaited in gynecological cancers and could provide additional benefit.

Ultraviolet Radiation and Melanomagenesis: From Mechanism to Immunotherapy.

Melanoma is the deadliest form of skin cancer, and nearly 90% of melanomas are believed to be caused by ultraviolet radiation (UVR), mainly from sunlight. UVR induces DNA damage, forming products such as cyclobutane pyrimidine dimers (CPD) and 6-4-pyrimidone photoproducts (6-4PP) in a wavelength-dependent manner and causes oxidative DNA damage. These DNA lesions lead to DNA mutations and contribute to the formation of melanoma. In this review, we discuss the protective role of melanocytes against UV-induced DNA damage and how genetic variations, including those in p53 and melanocortin-1 receptor (MC1R), or epigenetic histone modifications in melanocytes result in a tendency toward melanoma. We also provide a summary of prevention and treatment strategies against melanoma, including the most recent immunotherapies. Collectively, this work contributes to the understanding of the molecular pathogenesis of UV-induced melanoma.

Research progress of immunotherapy alone and in combination for liver cancer

Presently, the incidence of hepatocellular carcinoma (HCC) ranks fourth among common malignant tumors in China, and the mortality rate ranks second. The preferred method of clinical treatment for HCC is early surgical resection at this time, but most patients have reached to mid-advanced stage at the time of diagnosis, so surgery cannot be performed. Traditional radiotherapy and chemotherapy have poor prognosis and many adverse reactions, which make the current clinical treatment of HCC in China full of challenges. Therefore, new treatment strategies are urgently needed to improve the quality of life of liver cancer patients. With the advancement of modern medicine, the treatment of liver cancer is no longer limited to traditional treatments. Immunotherapy as a new treatment has become an important treatment for liver cancer. In recent years, immunotherapy and new targeted drugs for liver cancer have become a research hotspot, and many achievements have been made in the treatment of liver cancer. In this paper, the current situation and progress of single or combined immunotherapy for liver cancer of recent years are briefly reviewed.

Activity of PD1 inhibitor therapy in advanced sarcoma: a single-center retrospective analysis

BackgroundSarcomas constitute a heterogeneous group of tumors with different clinical behaviors and variable responses to systemic therapies. Recent immunotherapy studies with PD1 inhibitors (PD1i) show promising results with use in certain soft-tissue sarcomas; however, the clinical and molecular features that best predict response to PD1i remain unclear.MethodsDemographic, imaging, histologic, and genetic sequencing data was collected for sarcoma patients who received nivolumab or pembrolizumab (PD1i) treatment at our institution between January 1st 2015 and April 23rd 2018. The primary objective was to determine progression-free survival (PFS) in patients with advanced sarcomas receiving PD1i. Secondary objectives included determining overall survival (OS) and assessment of characteristics associated with response to PD1i. Fifty-six patients who were treated with PD1i therapy met inclusion criteria for this study.ResultsPartial response towards PD1i treatment was seen in 3 in 26 evaluable patients, but no complete responses were observed (overall response rate 11.5%). Within this group of patients, the 90 day PFS was found to be 48.8%. In patients in whom PD1 expression was known, there was a statistically significant positive correlation between expression of PD1 and longer PFS and OS rates. Patients that were treated with more than four cycles of PD1i therapy were also more likely to have a greater OS.ConclusionsThis study suggests activity of PD1i in a pretreated cohort of advanced sarcoma patients, particularly for the subset of patients with PD1 positive tumors. Our results highlight the importance of further research to better target the optimal patient population and markers of response.

Exclusion rates of patients living with HIV from cancer immunotherapy clinical trials.

e19035 Background: Although patients living with HIV are at increased risk for developing several cancers, they have often been excluded from practice-changing immunotherapy clinical trials across many tumor types. Emerging retrospective and prospective studies indicate that immunotherapies can be safe and effective in patients with HIV. ASCO and Friends of Cancer Research have supported the inclusion of patients with HIV in cancer clinical trials. We determined the rate of HIV exclusion from recent cancer immunotherapy clinical trials according to tumor type, immunotherapy treatment, and phase of trial. Methods: We compiled trials on the ClinicalTrials.gov database with study start dates from January 1, 2019 to October 10, 2020, using the search term “cancer” for disease, and the following intervention terms: “immunotherapy, PD-1, PD-L1, CTLA-4, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab, ipilimumab, tremelimumab, sintilimab, spartalizumab.” Observational studies and trials not offering immune checkpoint inhibitors (ICIs) or cellular immunotherapy were excluded. Eligibility criteria for each trial were reviewed to determine rate of exclusion for HIV, human immunodeficiency virus, acquired immunodeficiency, or immune deficiency. Cellular immunotherapies were defined as modified T cell, dendritic cell, NK cell, or other peripheral blood leukocyte treatments. Results: Of 1090 analyzed trials, 795 (72.9%) specifically excluded patients with HIV, and another 80 (7.3%) trials included patients with HIV only if certain criteria were met (e.g. undetectable viral load, minimum CD4+ T cell count). By tumor type, the rate of HIV exclusion ranged from 60.9% (renal cancer) to 85.7% (cervical cancer), with hematologic malignancies having a significantly higher rate of HIV exclusion than solid tumor trials (85.2% vs. 73.3%, p = 0.015). Trials combining ICIs with cellular immunotherapies were more likely to exclude HIV (N = 22, 90.9% exclusion) than trials with ICIs alone (N = 1003, 71.4% exclusion, p = 0.044). Phase I (N = 271, 73.1% exclusion, p = 0.0012), I/II (N = 165, 70.9% exclusion, p = 0.010), and II trials (N = 519, 77.5% exclusion, p < 0.0001) had higher rates of exclusion than phase III trials (N = 101, 55.4% exclusion). Conclusions: Despite ASCO and Friends of Cancer Research recommendations to include patients with HIV in cancer clinical trials, the vast majority of immunotherapy clinical trials in 2019 exclude patients with cancer and HIV.

PH-Sensitive Carbon Dots for Enhancing Photomediated Antitumor Immunity.

Recent cancer immunotherapy has attracted much attention due to high specificity and recurrence prevention of tumor. Nevertheless, its therapeutic effects are still challenging in solid cancer. To establish superior antitumor immunity, chlorin e6 (Ce6)-loaded pH sensitive carbon dots were investigated (Ce6@IDCDs). At tumoral pH 6.5, Ce6 was released four times compared with the release at physiological pH 7.4 due to an imbalance between hydrophilic and hydrophobic forces via protonation of imidazole groups in Ce6@IDCDs. This result led to the superior singlet oxygen generating activity of Ce6@IDCDs without Ce6 quenching. The maturation effects of dendritic cells after co-incubation with supernatant media obtained from Ce6@IDCDs with laser-treated cells at pH 6.5 were much higher than at physiological pH. Furthermore, Ce6@IDCDs following a laser at pH 6.5 significantly promoted calreticulin exposure and high-mobility group box 1 release, as major immunogenic cell death markers. In bilateral CT-26-bearing mice model, the Ce6@IDCDs elicited significant antitumoral effects at laser treated-primary tumor regions via therapeutic reactive oxygen species. Furthermore, Ce6@IDCDs upon laser irradiation induced a large amount of activated CD8+ T cells, natural killer cells, and mature dendritic cells recruitment into tumoral tissue and hampered tumor growth even at untreated sites approximately four-fold compared with those of others. Overall, this pH-sensitive immunoinducer can accomplish primary and distant tumor ablation via photomediated cancer immunotherapy.

Immune escape mechanisms in head and neck squamous cell carcinoma and implication for new immunotherapy approach.

The aim of this review is to describe the major steps leading to the immunosuppressive tumor microenvironment and to summarize some of the new immunotherapies that interfere with these mechanisms. Immunotherapy has improved the outcome of relapsed/metastatic head and neck squamous cell carcinoma (HNSCC). However, most patients still do not respond to treatment and median overall survival remains short with a modest rate of long-term survivors. There is a growing awareness that tumor immune-escape is a complex process that involves many redundant mechanisms other than immune check-points. They interfere with the innate immune response, activation of adaptive immune response, homing of effector T cells, their clonal expansion, viability, and efficiency. This abundance of immunosuppressive mechanisms explains the limited results achieved by immune checkpoint inhibitors. Combined treatments targeting different mechanisms of escape are in development to further improve the outcome of patients with HNSCC. Many mechanisms favor tumor immune-escape. Each tumor exploits preferably some of them and the challenge is to understand which are the best targets in each tumor. This knowledge is an important tool to design future combination strategies based on strong biological rationales, which could offer better results than simple empirical combinations.

Not Yet Another Negative Trial-ReACTing on Recent Glioblastoma Trials.

The present ReACT trial provides data from a small randomized controlled vaccination trial that in addition to other recent immunotherapy trials in glioblastoma allows sketching a rational, advanced trial design for the development of (immune) therapies in glioblastoma elaborating on but not restricting to biological monitoring and endpoints.See related article by Reardon et al., p. 1586.

Integrated immune gene expression signature and molecular classification in gastric cancer: New insights.

Gastric cancer (GC) is characterized by extreme heterogeneity due to histopathological differences, molecular characteristics, and immune gene expression signature. Until recently, several targeted therapies failed due to this complexity. The recent immunotherapy resulted in more effective and safe approaches in several malignancies. All tumors could be considered potentially immunogenic and the new knowledge regarding the interactions among tumor cells, immune cells, and tumor microenvironment (TME) allowed to reverse possible immune resistance. The immune response is a complex multisteps process that finely regulates the balance between the recognition of non-self and the prevention of autoimmunity. Cancer cells can use these pathways to suppress tumor immunity as a major mechanism of immune resistance. The recent molecular classifications of GCs by The Cancer Genome Atlas (TCGA) and by the Asian Cancer Research (ACRG) networks, together with the identification of multiple biomarkers, open new perspectives for stratification of patients who might benefit from a long-term immune checkpoint therapy. One of the major processes that contribute to an immunosuppressive microenvironment is represented by tumor angiogenesis. The cellular mechanisms inducing both angiogenesis and immunosuppressive responses are often reached by the same cell types and soluble factors, such as vascular endothelial growth factor A (VEGFA). Recent studies point out that combinatorial strategies should be adapted as useful therapeutic approach to reverse the immunosuppressive status of microenvironment occurring in a relevant percentage of gastric tumors.

Modulation of Immune and Anti-Tumor Effects of Cancer Immunotherapy with Anti-Pd-1 Monoclonal Antibodies by the Pineal Hormone Melatonin: Preliminary Clinical Results

The recent cancer immunotherapy with inhibitors of the expression of PD-1 and its ligands represents one of the most promising strategies in cancer cure. Then, the main question is how to enhance its therapeutic efficacy, which could potentially achieved by its association with chemotherapy, Il-2 immunotherapy, and anti-angiogenic strategies. By taking into consideration that the immune system is physiologically under a neuroendocrine regulation, another possible strategy to enhance the efficacy of cancer immunotherapy could consist of a neuro immune approach, namely by the pineal hormone melatonin (MLT), which at present constitutes the most investigated endogenous neuroendocrine molecule provided by immune stimulatory anticancer properties. On these bases, a study was planned to evaluate the effects of a concomitant administration of high-dose MLT in metastatic cancer patients treated by the anti-PD-1 monoclonal antibody Nivolumab (NIVO). The study included 14 patients, and the results were compared to those observed in a control group of 50 patients. No small cell lung cancer and melanoma were the most frequent tumor histo types. MLT was given orally at 100 mg/day during the dark period of the day, and NIVO was injected i.e. at 3 mg/kg b.w. at 15-day intervals. The percentage of both objective tumor regressions and disease control (DC) were higher in patients concomitantly treated by MLT, even though the only difference in DC was statistically significant. This evidence was associated with a significantly higher increase in lymphocyte-to-monocyte ratio (LMR) in MLT group, by suggesting that MLT may be successfully associated with anti-PD-1 monoclonal antibodies to pilot the immune response in an antitumor way by stimulating lymphocyte proliferation and inhibiting macrophage-induced inflammatory status, which suppresses the antitumor immunity.

CAR-T Cell Therapy in Cancer: Tribulations and Road Ahead.

Chimeric antigen receptor- (CAR-) T cell therapy is one of the most recent innovative immunotherapies and is rapidly evolving. Like other technologies, CAR-T cell therapy has undergone a long development process, and persistent explorations of the actions of the intracellular signaling domain and make several improvements have led to the superior efficacy when anti-CD19 CAR-T cell treatments in B cell cancers. At present, CAR-T cell therapy is developing rapidly, and many clinical trials have been established on a global scale, which has great commercial potential. This review mainly describes the toxicity of CAR-T cell therapy and the challenges of CAR-T cells in the treatment of solid tumors, and looks forward to future development and opportunities for immunotherapy and reviews major breakthroughs in CAR-T cell therapy.

Can we change autoimmunity in Type 1 Diabetes via insulin injection or oral insulin?

This article reviews recent immunotherapy studies of Type 1 Diabetes (T1D) which is an autoimmune disease. Researchers show that injecting human proinsulin peptides can safely modulate the immune system and affect beta-cell function in Type 1 Diabetes, but oral insulin consumption does not reduce the onset of Type 1 Diabetes in individuals at the early stage of the disease.

Role of myeloid cells in the immunosuppressive microenvironment in gliomas.

Glioma is the most common primary brain cancer, and half of patients present a diagnosis of glioblastoma (GBM), its most aggressive and lethal form. Conventional therapies, including surgery, radiotherapy, and chemotherapy, have not resulted in major ameliorations in GBM survival outcome, which remains extremely poor. Recent immunotherapy improvements for other tumors, coupled with growing knowledge of the complex interactions between malignant glioma cells and the immune system, led to an exponential increase in glioma immunotherapy research. However, immunotherapeutic strategies in GBM have not yet reached their full potential, mainly due to the limited understanding of the strong immunosuppressive microenvironment (TME) characterizing this tumor. Glioma-associated macrophages and microglia (GAMs) are key drivers of the local immunosuppression promoting tumor progression and its resistance to immunomodulating therapeutic strategies. Together with other myeloid cells, such as dendritic cells and neutrophils, GAMs actively shape glioma TME, modulate anti-tumoral immune response and support angiogenesis, tumor cell invasion and proliferation. In this review, we discuss the role of myeloid cells in the complex TME of glioma and the available clinical data on therapeutic strategies focusing on approaches that affect myeloid cells activity in GBM.

In Vitro Evaluation of CMV Specific CD8+T Cells Function in CMV+ Colorectal Cancer Patients Compared to Healthy Controls.

The oncogenic role of human cytomegalovirus (HCMV) has been recently shown in different cancers like colorectal cancer (CRC). According to the recent immunotherapy approach to target the CMV-expressing tumor cells, we investigated the CMV peptide-stimulated CD8+T cells functions in CRC patients compared to healthy individuals.All sixteen patients and seven controls were CMV seropositive. Blood samples were obtained from patients without chemotherapy and radiotherapy before surgery. Cytotoxic CD8+ T cells were generated using 14-day culture of PBMCs in the presences of CMV peptide epitopes and rhIL-2. In addition to the supernatant evaluations for TNF-α and IFN-γ, the functionality of CD8+ T cells was examined by detecting CD107a and intracellular IFN-γ using flow cytometry. CMV DNA was detected in tissues by Real Time PCR. CMV DNA was found in 31% of tumor tissues, while it was not seen in the adjacent non-tumor tissues. There was a close association between CMV in tumor tissue and tumor grade. Surface expression of CD107a and intracellular IFN-γ in CMV-stimulated CD8+T cells and the level of IFN-γ production in patient and control groups increased significantly after culture. The number of functions increased in patients (p<0.05) and healthy individuals after culture. Followingstimulation, expressions of CD107a and intracellular IFN-γ were elevated in tumor CMV positive patients while the TNF-α secretion was decreased. In vitro stimulation of PBMC in the presence of CMV peptide epitopes and IL-2 can be an applicable method to generate cytotoxic CD8+ T cells in CRC patients for future T cell therapy.

Abstract 4467: Survival of patients with microsatellite instable (MSI) metastatic colorectal cancer (mCRC) upon systemic non-immunotherapy

Abstract Introduction: Data on survival of patients with MSI mCRC treated with systemic non-immunotherapy are scarce, which complicates the interpretation of recent immunotherapy trials. Our study examined survival in MSI mCRC patients in a retrospective observational cohort. Methods: We performed a study involving 186 mCRC MSI patients (n=54 from the phase 3 CAIRO, CAIRO2 and CAIRO3 trials and n=132 from The Netherlands Cancer Registry 2015 and 2016). Overall survival from diagnosis of mCRC (OS), from start of first-line (OS1) and second-line therapy (OS2) to death of any cause were examined. Progression-free survival from start of first line (PFS1) and second-line therapy (PFS2) to progression or death of any cause were examined. Results: Of the 186 patients, 57% were females, median age 67 years, 19% had liver-only metastasis, 31% peritoneal metastasis and 23% underwent metastasectomy. In 113 patients with known BRAF status, 51% had BRAF mutated tumors. The proportion of patients receiving first, second and third-line systemic treatment was 68%, 27% and 7%, respectively. For all patients, median OS was 13.8 months (95% confidence interval [C.I.] 11.8 - 16.3). In patients receiving at least one line of treatment median OS was 15.6 months (13.8 - 19.3), OS1 was 13.9 months (11.6-16.6) and PFS1 was 6.4 months (5.5 - 9.2). In the 48 patients receiving second-line therapy, median OS was 16.5 months (13.9 - 21.5), OS2 was 6.1 months (5.4 - 9.7) and PFS2 was 2.2 months (1.9 - 4.2). Patients starting second-line treatment with a performance score of 0-1, thus eligible for CHECKMATE-142, had an OS2 of 6.7 months (5.0 - 12.1). Discussion: A direct comparison between our cohort and the CHECKMATE-142 cohort is not possible due to key differences in the patient populations: CHECKMATE-142 patients often received more than one therapy line prior to inclusion and displayed fewer BRAF mutant tumors. However, the survival from start of second-line in our cohort of approximately 7 months is inferior to the published CHECKMATE-142 results, where median OS was not reached after a median follow-up of 1 year in the nivolumab and the nivolumab and ipilimumab cohorts. Conclusion: We present data on systemic non-immunotherapy in the largest cohort of trial and population-based mCRC MSI patients to date. Our results suggest that immunotherapy may offer a survival benefit for mCRC MSI patients. Citation Format: G. E. Wensink, M. A. Elferink, A. M. May, L. Mol, P. A. Hamers, C. J. Punt, G. R. Vink, J. M. Roodhart, M. Koopman. Survival of patients with microsatellite instable (MSI) metastatic colorectal cancer (mCRC) upon systemic non-immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4467.

Evaluation of a Fully Automated Idylla Test System for Microsatellite Instability in Colorectal Cancer

BackgroundMicrosatellite instability (MSI) is a phenotype commonly observed in colorectal cancer, and is caused by a deficient mismatch repair system. Determining MSI status greatly aids tumor prognosis and treatment plans in colorectal cancer, and plays a critical role in recent United States Food and Drug Administration-approved immunotherapies. As recognition of its importance grows, MSI has been identified in more types of cancers, underscoring the importance of accurate assays for determining MSI status in tumor cells. Currently, tumor MSI status is detected via polymerase chain reaction-based methods or immunohistochemistry. Materials and MethodsIn this study, we tested a new, fully automated MSI detection system (Idylla MSI detection kit) released by Biocartis. We evaluated 42 formalin-fixed paraffin-embedded tumor tissues, which were clinically tested for MSI status using the polymerase chain reaction or immunohistochemistry method, with the Idylla MSI detection system. ResultsThe Idylla MSI detection system showed an overall 97.62% concordance rate with previously used methods. Moreover, this fully automated system requires less than 5 minutes “hands on” preparation time and 150 minutes total run time per sample. ConclusionThe Biocartis Idylla MSI kit proves a powerful tool to accurately detect MSI status in tumor cells in a rapid and almost labor-free manner.

Immune mechanisms and possible immune therapy in testicular germ cell tumours.

Testicular germ cell tumours (GCTs) are the only universally curable solid malignancy. The long-term cure rate of >95% is attributed to the extraordinary sensitivity to cisplatin-based treatment but a proportion of patients die due to a progression of the chemotherapy-refractory disease. While treatment of a variety of solid cancers was significantly improved with recent immune therapies, the immunology and immunotherapy remained underinvestigated in GCTs. In this narrative review, we summarize evidence about immune-related mechanisms and possible immune therapies in GCTs and provide insights and implications for future research and clinical practice. We performed a comprehensive search of PubMed/MEDLINE to identify original and review articles reporting on immune mechanisms and immunotherapy in GCTs. Review articles were further searched for additional original articles. Clear link of immune surveillance and the presence of GCT have been identified with several novel immune-related prognostic biomarkers published recently. Several case reports, case series, and preliminary results from phase I-II studies are emerging to report on the efficacy of immune checkpoint inhibitors. Newly discovered immune biomarkers provide an evidence supporting the role of immune environment in the GCT biology. While these discoveries provide only an initial insight into the immunobiology, strong correlation with prognosis is evident. This provided a premise to investigate the treatment efficacy of novel immunotherapy. Some efficacy of these treatments has been reported in clinical setting; however, the results of published studies with immune checkpoint inhibitor monotherapy seem to be disappointing. Immune-related mechanisms and efficacy of immune checkpoint blockade in GCTs should be further investigated in preclinical and clinical studies.

Characteristics and outcomes of oncology unit patients requiring admission to an Australian intensive care unit.

Patients with advanced malignancies have historically been considered poor candidates for admission to the intensive care unit (ICU); however, prognosis is continually improving, and requirements for ICU access are increasing. To understand the characteristics and outcomes of oncology unit patients admitted to an Australian ICU and identify potential prognostic factors. A single-centre, retrospective, cohort study conducted at a tertiary public hospital with a quaternary ICU in Sydney, Australia. All patients admitted under the medical oncology team requiring ICU admission between June 2014 and June 2016 were evaluated. Clinical outcomes were determined including mortality, ICU requirements (ventilation, dialysis, vasopressors, infection) and prognostic scores (Acute Physiologic and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) score). There were 96 patients with mean age 61 years, 58% were male and 76% had metastatic disease. Most were receiving palliative treatment (89%), with recent chemotherapy (43%), immunotherapy (10%) and other therapies (5%). Of the 10 patients with recent immunotherapy, three (all with melanoma) required ICU admission due to immunotoxicity; 13% were admitted due to an oncological emergency. Mean APACHE II score was 17 (standard deviation (SD) 5.33), mean SOFA score was 3.99 (SD 2.70), ICU mortality was 5% and hospital mortality was 22%. Using multivariate logistic regression analysis, cancer stage, infection during ICU admission, intracranial mass effect on ICU admission and SOFA score were associated with 30-day mortality. Our patient population had good short-term survival outcomes despite most receiving palliative treatment. Cancer patients can achieve positive outcomes after ICU admission, and appropriate selection of patients is crucial.

Does neutrophil to lymphocyte ratio correlate with toxicities and outcome of patients with genitourinary cancers treated with checkpoint inhibitors?

e16032 Background: Few data are available concerning the role of neutrophil and lymphocyte counts in predicting toxicities and outcome in patients (pts) with genitourinary cancer treated with recent immunotherapy. Methods: We retrospectively reviewed the clinical charts of all pts with metastatic renal cell (RCC) or urothelial cancer (UC) treated at our Institute with immunotherapy(Nivolumab with or without Ipilimumab, Atezolizumab, Durvalumab, Pembrolizumab), having at least one response assessment after starting treatment. Results: We identified 117 pts treated from May 2015 onwards, median age: 68 years (range 39-84), 72% males, 53% with UC. Incidence of G3/4 toxicities was 17%, while 23.9% of pts needed an high dose steroid treatment because of immune-related toxicities (IrT). Median PFS and OS were 7.0 and 24.1 months, respectively for RCC, and 2.8 and 7.1 months, respectively for UC. 56 pts had progressive disease at best response. Baseline value of neutrophils or lymphocytes does not correlate with IrT (t test, p = 0.399, p = 0.728, respectively). In the IrT events, no significant increase of lymphocytes was detected (p = 0.160). The incidence of a IrT which needed steroid treatment positively impact in PFS (p = 0.03) but not in OS (p = 0.74). The use of steroid therapy was not associated with a different outcome in terms of OS (p = 0.49 for UC and p = 0.18 for RCC) and associated with a better PFS in RCC (p = 0.018). Steroid use was associated with the probability of non-progressive disease at first assessment (Chi-squared test, p = 0.015). In our cohort, baseline neutrophil to lymphocyte ratio (NLR) ≥ 3 correlate with a shorter PFS and OS in UC (p = 0.026 and p = 0.003 respectively), while it does not in RCC (p = 0.104 and p = 0.678 respectively). In our cohort, baseline neutrophil to lymphocyte ratio (NLR) ≥ 3 correlate with a shorter PFS and OS in UC (p = 0.026 and p = 0.003 respectively), while it does not in RCC (p = 0.104 and p = 0.678 respectively). In UC, the positivization of NLR after 2 cycles predicts a shorter PFS for UC (p = 0.008) and a trend for OS. Conclusions: In our retrospective single-center experience, NLR confirms its role in UC even in a cohort treated with immunotherapy and its variation predicts shorter outcome, while neutrophils or lymphocytes do not relate with IrT. The use of steroid for IrT is safe since it does not impact on survival and is associated with a higher probability of non-progressive disease at first assessment.

The Quest for an Ideal Neoadjuvant Systemic Therapy in Cisplatin-Ineligible Patients with Muscle-Invasive Localized Urothelial Carcinoma.

This commentary reviews current progress in neoadjuvant immunotherapy for muscle‐invasive localized urothelial carcinoma, highlighting opportunities and challenges with recent neoadjuvant immunotherapy trials.