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Non-Small Cell Lung Cancer (NSCLC) remains one of the main causes of cancer death worldwide. In the urge of finding an effective approach to treat cancer, enormous therapeutic targets and treatment combinations are explored in clinical studies, which are not only costly, suffer from a shortage of participants, but also unable to explore all prospective therapeutic solutions. Within the evolving therapeutic landscape, the combined use of radiotherapy (RT) and checkpoint inhibitors (ICIs) emerged as a promising avenue. Exploiting the power of quantitative system pharmacology (QSP), we undertook a study to anticipate the therapeutic outcomes of these interventions, aiming to address the limitations of clinical trials. After enhancing a pre-existing QSP platform and accurately replicating clinical data outcomes, we conducted an in-depth study, examining different treatment protocols with nivolumab and RT, both as monotherapy and in combination, by assessing their efficacy through clinical endpoints, namely time to progression (TTP) and duration of response (DOR). As result, the synergy of combined protocols showcased enhanced TTP and extended DOR, suggesting dual advantages of extended response and slowed disease progression with certain combined regimens. Through the lens of QSP modeling, our findings highlight the potential to fine-tune combination therapies for NSCLC, thereby providing pivotal insights for tailoring patient-centric therapeutic interventions. [ABSTRACT FROM AUTHOR]

Checkpoint inhibition (CPI) therapy and adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL-based ACT) are the two most effective immunotherapies for the treatment of metastatic melanoma. While CPI has been the dominating therapy in the past decade, TIL-based ACT is beneficial for individuals even after progression on previous immunotherapies. Given that notable differences in response have been made when used as a subsequent treatment, we investigated how the qualities of TILs changed when the ex vivo microenvironment of intact tumor fragments were modulated with checkpoint inhibitors targeting programmed death receptor 1 (PD-1) and cytotoxic Tlymphocyte-associated protein 4 (CTLA-4). Initially, we show that unmodified TILs from CPI-resistant individuals can be produced, are overwhelmingly terminally differentiated, and are capable of responding to tumor. We then investigate these properties in ex vivo checkpoint modulated TILs finding that that they retain these qualities. Lastly, we confirmed the specificity of the TILs to the highest responding tumor antigens, and identified this reactivity resides largely in CD39+CD69+ terminally differentiated populations. Overall, we found that anti-PD-1 will alter the proliferative capacity while anti-CTLA4 will influence breadth of antigen specificity. [ABSTRACT FROM AUTHOR]

Introduction: Natural killer/T cell lymphoma (NKTL) is an aggressive malignancy associated with poor prognosis. This is largely due to limited treatment options, especially for relapsed patients. Immunotherapies like immune checkpoint inhibitors (ICI) and anti-CD38 therapies have shown promising but variable clinical efficacies. Combining these therapies has been suggested to enhance efficacy. Methods: We conducted a case study on a relapsed NKTL patient treated sequentially with anti-CD38 followed by ICI (anti-PD1) using cytometry analyses. Results and Discussion: Our analysis showed an expected depletion of peripheral CD38+ B cells following anti-CD38 treatment. Further analysis indicated that circulating anti-CD38 retained their function for up to 13 weeks postadministration. Anti-PD1 treatment triggered re-activation and upregulation of CD38 on the T cells. Consequently, these anti-PD1-activated T cells were depleted by residual circulating anti-CD38, rendering the ICI treatment ineffective. Finally, a meta-analysis confirmed this counterproductive effect, showing a reduced efficacy in patients undergoing combination therapy. In conclusion, our findings demonstrate that sequential anti-CD38 followed by anti-PD1 therapy leads to a counterproductive outcome in NKTL patients. This suggests that the treatment sequence is antithetic and warrants re-evaluation for optimizing cancer immunotherapy strategies. [ABSTRACT FROM AUTHOR]

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Introduction: Checkpoint inhibitors, such as PD1 inhibitors, represent an important pillar in the therapy of advanced malignancies of the head and neck region. The most relevant complications are immune-related adverse effects (irAEs), which represent an immense burden for patients. Currently, no sufficient stratification measures are available to identify patients at increased risk of irAEs. The aim of this retrospective study was to examine whether demographic, histopathological, clinical, or laboratory values at the start of CPI therapy represent a risk factor for the later occurrence of autoimmune complications. Material and methods: Data from 35 patients between 2018 and 2021 who received therapy with nivolumab or pembrolizumab for head and neck malignancy were analyzed and assessed for any associations with the subsequent occurrence of irAEs. Results: IrAE developed in 37% of patients, with pneumonitis being the most common form (14%). Pneumonitis was found in patients with an average significantly lower T-stage of primary tumors. An increase in basophilic leukocytes was found in patients with dermatitis later in the course. When thyroiditis developed later, the patients had a higher CPS score and lower monocyte levels. Discussion: Even though individual laboratory values at the beginning of therapy might show a statistical association with the later occurrence of irAEs, neither demographic, histopathological, nor laboratory chemistry values seem to be able to generate a sound and reliable risk profile for this type of complication. Therefore, patients need to be educated and sensitized to irAEs, and regular screening for irAEs should be carried out. [ABSTRACT FROM AUTHOR]

Suppressor of cytokine signaling 1 (SOCS1) is a potent regulator immune cell responses and a proven tumor suppressor. Inhibition of SOCS1 in T cells can boost antitumor immunity, whereas its loss in tumor cells increases tumor aggressivity. Investigations into the tumor suppression mechanisms so far focused on tumor cell-intrinsic functions of SOCS1. However, it is possible that SOCS1 expression in tumor cells also regulate antitumor immune responses in a cell-extrinsic manner via direct and indirect mechanisms. Here, we discuss the evidence supporting the latter, and its implications for antitumor immunity. [ABSTRACT FROM AUTHOR]

Purpose: Immune checkpoint inhibitors (ICI) are then backbone in the therapy of metastatic renal cell carcinoma (RCC). The aim of this analysis was to explore the different expression of the ICI PD-L1, BTLA, and TIM-3 at the different tumor locations of the invasion front and the tumor center. Methods: Large-area sections of the tumor center and invasion front of 44 stage pT1–4 clear cell RCCs were examined immunohistochemically using antibodies against BTLA, TIM-3, and PD-L1 and subsequently correlated with clinicopathologic data. Results: TIM-3 was most strongly expressed at the invasion front (mean ± SD: 84.1 ± 46.6, p = 0.094). BTLA expression was highest in normal tissue, with weak staining in the tumor center and at the invasion front [110.2 vs. 18.6 (p < 0.001) vs. 32.2 (p = 0.248)]. PD-L1 was weakly expressed at the tumor center (n = 5/44) and at the invasion front (n = 5/44). Correlation with clinicopathological parameters revealed significantly higher BTLA expression in ≥ T3 tumors compared to T1/2 tumors (tumor center p = 0.009; invasion front p = 0.005). BTLA-positive tumors at the tumor center correlated with worse CSS (median 48.46 vs. 68.91 months, HR 4.43, p = 0.061). PD-L1 expression was associated with worse CSS (median 1.66 vs. 4.5 years, HR 1.63, p = 0.652). For TIM-3, there were no significant associations with clinicopathological parameters and survival. Conclusion: The present results show heterogeneous intratumoral and intertumoral expression of the investigated checkpoint receptors PD-L1, BTLA, and TIM-3. In the clinical practice tumor sampling should include different tumor locations, and multiple inhibition of different checkpoint receptors seems reasonable to increase the therapeutic success. [ABSTRACT FROM AUTHOR]

Simple Summary: Recurrent and/or metastatic head and neck squamous-cell carcinoma (R/M HNSCC) is a clinically challenging disease with a poor prognosis. Despite advances in survival through the use of immune-checkpoint blockade, only a minority of patients experience benefit from such treatments, and it is difficult to identify the patients most likely to benefit. Machine learning approaches integrating clinical and genomic data can predict response to immune-checkpoint blockade across all cancers; however, the performance of this model in HNSCC has not been examined. Here, we validate this previously described immune-checkpoint blockade response prediction model in R/M HNSCC patients. This model was able to predict response as well as overall survival following immune-checkpoint blockade in patients with R/M HNSCC. Further investigation will be needed to further delineate the importance of HNSCC-specific features. Head and neck squamous-cell carcinoma (HNSCC) is a disease with a generally poor prognosis; half of treated patients eventually develop recurrent and/or metastatic (R/M) disease. Patients with R/M HNSCC generally have incurable disease with a median survival of 10 to 15 months. Although immune-checkpoint blockade (ICB) has improved outcomes in patients with R/M HNSCC, identifying patients who are likely to benefit from ICB remains a challenge. Biomarkers in current clinical use include tumor mutational burden and immunohistochemistry for programmed death-ligand 1, both of which have only modest predictive power. Machine learning (ML) has the potential to aid in clinical decision-making as an approach to estimate a tumor's likelihood of response or a patient's likelihood of experiencing clinical benefit from therapies such as ICB. Previously, we described a random forest ML model that had value in predicting ICB response using 11 or 16 clinical, laboratory, and genomic features in a pan-cancer development cohort. However, its applicability to certain cancer types, such as HNSCC, has been unknown, due to a lack of cancer-type-specific validation. Here, we present the first validation of a random forest ML tool to predict the likelihood of ICB response in patients with R/M HNSCC. The tool had adequate predictive power for tumor response (area under the receiver operating characteristic curve = 0.65) and was able to stratify patients by overall (HR = 0.53 [95% CI 0.29–0.99], p = 0.045) and progression-free (HR = 0.49 [95% CI 0.27–0.87], p = 0.016) survival. The overall accuracy was 0.72. Our study validates an ML predictor in HNSCC, demonstrating promising performance in a novel cohort of patients. Further studies are needed to validate the generalizability of this algorithm in larger patient samples from additional multi-institutional contexts. [ABSTRACT FROM AUTHOR]

Despite high response rates to initial therapy, most patients with ovarian cancer will ultimately recur and go on to develop resistance to standard treatments. Novel therapies have been developed to overcome drug resistance and alter the tumor immune microenvironment by targeting oncogenic pathways, activating the innate immune response, and enhancing drug delivery. In this review, we discuss the current and future roles of chemotherapy, targeted agents such as poly (ADP-ribose) polymerase (PARP) inhibitors, bevacizumab, and mirvetuximab in the treatment of ovarian cancer. We explore the emerging role of therapeutic targets, including DNA repair pathway inhibitors and novel antibody–drug conjugates. Furthermore, we delve into the role of immunotherapeutic agents such as interleukins as well as immune-promoting agents such as oncolytic viruses and cancer vaccines. Innovative combination therapies using these agents have led to a rapidly evolving treatment landscape and promising results for patients with recurrent ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) are an emerging tool in the treatment of brain metastases (BMs), Stereotactic radiosurgery (SRS), traditionally used for BMs, elicits an immune brain response and can act synergistically with ICIs. We aim to investigate the efficacy of ICI administered with SRS and determine the impact of timing on BM response. Methods: A systematical search was performed to identify potential studies concerning BMs managed with SRS alone or with SRS + ICI with relative timing administration (ICI concurrent with SRS, ICI noncon-current with SRS, SRS before ICI, SRS after ICI). The overall survival (OS), 12-month OS, local progression-free survival (LPFS), 12-month local brain control (LBC), distant progression-free survival (DPFS), 12-month distant brain control (DBC), and adverse events (intracranial hemorrhage, radionecrosis) were analyzed using the random-effects model. Results: A total of 16 retrospective studies with 1356 BM patients were included. Compared to noncon-current therapy, concurrent therapy revealed a significantly longer OS (HR= 1.43; p = 0.008) and 12-months LBC (HR = 1.91; p = 0.04), a similar 12-months DBC (HR = 1.12; p = 0.547) and higher complication rate (R = 0.77; p = 0.346). Concurrent therapy leads to a significantly higher OS compared to ICI before SRS (HR = 2.55; p = 0.0003). Conclusion: The combination of SRS with ICI improves patients' clinical and radiological outcomes. The effectiveness of the combination is subject to the identification of an optimal therapeutic window. [ABSTRACT FROM AUTHOR]

AML is a malignant disease of hematopoietic progenitor cells with unsatisfactory treatment outcome, especially in patients that are ineligible for intensive chemotherapy. Immunotherapy, comprising checkpoint inhibition, T-cell engaging antibody constructs, and cellular therapies, has dramatically improved the outcome of patients with solid tumors and lymphatic neoplasms. In AML, these approaches have been far less successful. Discussed reasons are the relatively low mutational burden of AML blasts and the difficulty in defining AML-specific antigens not expressed on hematopoietic progenitor cells. On the other hand, epigenetic dysregulation is an essential driver of leukemogenesis, and non-selective hypomethylating agents (HMAs) are the current backbone of non-intensive treatment. The first clinical trials that evaluated whether HMAs may improve immune checkpoint inhibitors' efficacy showed modest efficacy except for the anti-CD47 antibody that was substantially more efficient against AML when combined with azacitidine. Combining bispecific antibodies or cellular treatments with HMAs is subject to ongoing clinical investigation, and efficacy data are awaited shortly. More selective second-generation inhibitors targeting specific chromatin regulators have demonstrated promising preclinical activity against AML and are currently evaluated in clinical trials. These drugs that commonly cause leukemia cell differentiation potentially sensitize AML to immune-based treatments by co-regulating immune checkpoints, providing a pro-inflammatory environment, and inducing (neo)-antigen expression. Combining selective targeted epigenetic drugs with (cellular) immunotherapy is, therefore, a promising approach to avoid unintended effects and augment efficacy. Future studies will provide detailed information on how these compounds influence specific immune functions that may enable translation into clinical assessment. [ABSTRACT FROM AUTHOR]

Copyright of Die Gynäkologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objectives: Although biomarkers predicting therapy response in first‐line metastatic renal carcinoma (mRCC) therapy remain to be defined, C‐reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. Here, we aimed to assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real‐world first‐line mRCC cohort. Methods: Metastatic renal carcinoma patients treated with IO‐based first‐line therapy within 5 years were retrospectively included in this multicentre study. According to Fukuda et al., patients were defined as 'CRP flare‐responder', 'CRP responder' and 'non‐CRP responder'; according to Ishihara et al., patients were defined as 'normal', 'normalised' and 'non‐normalised' based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression‐free survival (PFS), including multivariable Cox regression analyses. Results: Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare‐ (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non‐CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalised patients had a significantly longer PFS and OS, compared with non‐normalised group. Conclusion: Different early CRP kinetics may predict therapy response in first‐line mRCC therapy in a large real‐world cohort. However, further research regarding the optimal timing and frequency of measurement is needed. [ABSTRACT FROM AUTHOR]

This article explores the potential of non-cellular immunotherapies in treating pediatric cancer. It discusses three strategies for utilizing the immune system to fight cancer, including targeting specific tumor antigens, overriding inhibitory signals from cancer cells, and enhancing tumor-specific immune responses. The authors stress the need for further research and clinical trials to assess the effectiveness and refine the use of non-cellular immunotherapies in pediatric cancer treatment. The document is a list of references for a research article on various topics related to cancer treatment, providing a comprehensive overview of current research and advancements in areas such as CAR immune cells, monoclonal antibodies, immunotherapy, and cancer vaccines. [Extracted from the article]

Introduction: Classical Hodgkin lymphoma (cHL) is the most common pediatric lymphoma. Approximately 10% of patients develop refractory or recurrent disease. These patients are treated with intensive chemotherapy followed by consolidation with radiotherapy or high-dose chemotherapy and autologous stem cell reinfusion. Although this treatment is effective, it comes at the cost of severe long-term adverse events, such as reduced fertility and an increased risk of secondary cancers. Recently, promising results of inducing remission with the immune checkpoint inhibitor nivolumab (targeting PD-1) and the anti-CD30 antibody-drug conjugate Brentuximab vedotin (BV) +/- bendamustine were published. Methods: Here we describe a cohort of 10 relapsed and refractory pediatric cHL patients treated with nivolumab + BV +/- bendamustine to induce remission prior to consolidation with standard treatment. Results and discussion: All patients achieved complete remission prior to consolidation treatment and are in ongoing complete remission with a median follow-up of 25 months (range: 12 to 42 months) after end-of-treatment. Only one adverse event of CTCAE grade 3 or higher due to nivolumab + BV was identified. Based on these results we conclude that immunotherapy with nivolumab + BV +/- bendamustine is an effective and safe treatment to induce remission in pediatric R/R cHL patients prior to standard consolidation treatment. We propose to evaluate this treatment further to study putative long-term toxicity and the possibility to reduce the intensity of consolidation treatment. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the incidence, diagnosis and treatment of immune-related adverse events (e-irAE) of checkpoint inhibition (ICI) in metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma (mRCC). Methods: A retrospective, single-center study was conducted to identify a cohort that received ICI for mUC or mRCC. e-irAE were classified according to the CTCAE V.5.0. Patients received ICI for mUC or mCC between 01/2017 and 03/2021. A retrospective chart review was performed. T-Test, the chi-squared test, and Fisher's exact test were performed. Results: 102 Patients received ICI [mUC: 40 (39%), mRCC: 62 (61%)]. 64 (63%) received an ICI monotherapy, 27 (27%) a dual ICI therapy, 11 (11%) a combination with VEGFi. e-irAE occurred in 19 (19%) patients [grade 1–2: 17 (84%), grade 3: 3 (16%)]. The median time until e-irAE was 42 days (range 11–211 days). 14 Patients developed thyroidism (14%), 4 (4%) a hypophysitis, 1 (1%) an adrenal insufficiency (AI). 7 patients (7%) had to discontinue ICI therapy [hypophysitis (100%), AI (100%), thyroidism (14%)]. 6 (86%) received cortisone. After a median range of 34 days 5 patients (71%) restarted ICI therapy. All patients (n = 4) with hypophysitis continued ICI [4 (100%) prednisone, 3 (75%) levothyroxine]. 11 (79%) presented with hyperthyroidism. 4 (37%) needed therapy (1 (7%) prednisone, 3 (21%) thiamazole, 2 (14%) beta blocker). The 9 (64%) patients with hypothyroidism received levothyroxine. Hypophysitis appears only on dual ICI (CTLA-4/PD-1) inhibition (p 0.007). Conclusion: This study shows the importance of adequate diagnosis and therapy of e-irAEs. [ABSTRACT FROM AUTHOR]

Checkpoint inhibition (CPI) therapy and adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL-based ACT) are the two most effective immunotherapies for the treatment of metastatic melanoma. While CPI has been the dominating therapy in the past decade, TIL-based ACT is beneficial for individuals even after progression on previous immunotherapies. Given that notable differences in response have been made when used as a subsequent treatment, we investigated how the qualities of TILs changed when the ex vivo microenvironment of intact tumor fragments were modulated with checkpoint inhibitors targeting programmed death receptor 1 (PD-1) and cytotoxic Tlymphocyte-associated protein 4 (CTLA-4). Initially, we show that unmodified TILs from CPI-resistant individuals can be produced, are overwhelmingly terminally differentiated, and are capable of responding to tumor. We then investigate these properties in ex vivo checkpoint modulated TILs finding that that they retain these qualities. Lastly, we confirmed the specificity of the TILs to the highest responding tumor antigens, and identified this reactivity resides largely in CD39+CD69+ terminally differentiated populations. Overall, we found that anti-PD-1 will alter the proliferative capacity while anti-CTLA4 will influence breadth of antigen specificity. [ABSTRACT FROM AUTHOR]

Summary: At the turn of the past century, unresectable metastatic melanoma was primarily treated with different chemotherapeutic agents, such as dacarbazine, with only poor efficacy. Immunotherapeutic agents, such as interleukin‑2 or adjuvant interferon alpha, were used with modest results but frequent side effects. In the last 10 years, modern immunotherapy using checkpoint inhibition has dramatically changed the treatment landscape of metastatic melanoma and is now considered the first-line treatment for stage IV melanoma. Consequently, median overall survival has increased from 9.1 months with dacarbazine to up to 72.1 months using the current gold standard ipilimumab + nivolumab first-line. In 2023, in Europe, the anti-PD1 antibodies nivolumab and pembrolizumab are licensed in the adjuvant and metastatic setting and the combination therapies ipilimumab + nivolumab and relatlimab + nivolumab are approved in the metastatic setting. Nevertheless, despite tremendous progress in the last two decades, at least 50% of our patients with stage IV melanoma still die. Currently, research focuses on combining checkpoint inhibition with other drugs such as cancer vaccines, BRAF/MEK inhibition, other tyrosine kinase inhibitors or histone deacetylase inhibitors. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized cancer treatment over the past decade. As it is increasingly introduced into routine clinical practice, immune-related complications have become more frequent. Accurate diagnosis and treatment are essential, with the goal of reduced patient morbidity. This review aims to discuss the various clinical manifestations, diagnosis, treatments, and prognosis of neurologic complications associated with the use of immune checkpoint inhibitors, adoptive T-cell therapies, and T-cell redirecting therapies. We also outline a suggested clinical approach related to the clinical use of these agents. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy based on chimeric antigen receptor (CAR)-engineered Tcells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy has so far been restricted to only a few malignancies, with solid tumors proving to be especially recalcitrant to efficient therapy. Poor intratumor infiltration by T cells and T cell dysfunction due to a desmoplastic, immunosuppressive microenvironment are key barriers for CAR T-cell success against solid tumors. Cancer-associated fibroblasts (CAFs) are critical components of the tumor stroma, evolving specifically within the tumor microenvironment (TME) in response to tumor cell cues. The CAF secretome is a significant contributor to the extracellular matrix and a plethora of cytokines and growth factors that induce immune suppression. Together they form a physical and chemical barrier which induces a T cell-excluding 'cold' TME. CAF depletion in stroma rich solid tumors can thus provide an opportunity to convert immune evasive tumors susceptible to tumor-antigen CAR T-cell cytotoxicity. Using our TALEN-based gene editing platform we engineered non-alloreactive, immune evasive CAR T-cells (termed UCAR T-cells) targeting the unique CAF marker Fibroblast Activation Protein, alpha (FAP). In an orthotopic mouse model of triple-negative breast cancer (TNBC) composed of patient derived-CAFs and tumor cells, we demonstrate the efficacy of our engineered FAP UCAR T-cells in CAF depletion, reduction of desmoplasia and successful tumor infiltration. Furthermore, while previously resistant, pre-treatment with FAP UCAR T-cells now sensitized these tumors to Mesothelin (Meso) UCAR T-cell infiltration and anti-tumor cytotoxicity. Combination therapy of FAP UCAR, Meso UCAR T cells and the checkpoint inhibitor anti-PD-1 significantly reduced tumor burden and prolonged mice survival. Our study thus proposes a novel treatment paradigm for successful CAR T-cell immunotherapy against stroma-rich solid tumors. [ABSTRACT FROM AUTHOR]

Therapy with immune checkpoint inhibitors (ICI) is effective in patients with metastatic mismatch‐repair deficient (dMMR) colorectal cancer (CRC); however, data on treatment with neoadjuvant ICI in patients with locally advanced CRC are limited. From March 2019 to June 2020, five Danish oncological centers treated 10 patients with a treatment‐naïve dMMR CRC with preoperative pembrolizumab, 9 with a nonmetastatic, unresectable colon cancer and 1 with a locally advanced rectum cancer. All 10 patients were evaluated regularly at a multidisciplinary team (MDT) meeting, and they all had a radical resection after a median of 8 cycles (range 2‐13) of pembrolizumab. A microscopic evaluation of the resected tumors revealed no remaining tumor cells in five patients, while five still had tumor cells present. The patients were given no additional therapy. No recurrences were reported after a median follow‐up of 26 months (range 23‐38.5 months). Biopsies from Danish patients with CRC are routinely screened for dMMR proteins. In 2017, data from the Danish Colorectal Cancer Group showed that 19% (565/3000) of the patients with colon cancer and 1.5% (19/1279) of those with rectum cancer had an dMMR tumor. Among the patients with MMR determination, 26% (99/384) patients had a T4 dMMR colon cancer; thus, the 10 patients treated with neoadjuvant pembrolizumab comprised about 9% of the patients with a T4 dMMR colon cancer (9/99) and 5% of patients with dMMR rectal cancer (1/19). Therapy with pembrolizumab was feasible and effective. Larger prospective trials are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells not only are innate effector lymphocytes that directly participate in tumor surveillance but are also essential helpers in the antitumor CD8+ T‐cell response. However, the molecular mechanisms and potential checkpoints regulating NK cell helper functions remain elusive. Here, it is shown that the T‐bet/Eomes‐IFN‐γ axis in NK cells is essential for CD8+ T cell‐dependent tumor control, whereas T‐bet‐dependent NK cell effector functions are required for an optimal response to anti‐PD‐L1 immunotherapy. Importantly, NK cell‐expressed TIPE2 (tumor necrosis factor‐alpha‐induced protein‐8 like‐2) represents a checkpoint molecule for NK cell helper function, since Tipe2 deletion in NK cells not only enhances NK‐intrinsic antitumor activity but also indirectly improves the antitumor CD8+ T cell response by promoting T‐bet/Eomes‐dependent NK cell effector functions. These studies thus reveal TIPE2 as a checkpoint for NK cell helper function, whose targeting might boost the antitumor T cell response in addition to T cell‐based immunotherapy. [ABSTRACT FROM AUTHOR]

Pulmonary blastoma (PB) is a rare and invasive malignancy of the lungs with a poor prognosis. Although the mainstay treatment of PB is surgery, and radiotherapy and chemotherapy have been reported, no standard therapy exists for patients inoperable in advanced stages. Moreover, little is known about driver mutation status and immunotherapy efficacy. This paper presents a male patient diagnosed with classic biphasic PB using CT-guided lung biopsy pathology and immunohistochemistry. The patient’s symptoms included cough, chest pain, shortness of breath, hemoptysis, and hypodynamia. The primary focus of this paper is to discuss the impact of anti-PD-1 immunotherapy on PB. The patient experienced progression-free survival (PFS) of over 27 months following sintilimab second-line anti-PD-1 therapy. The patient has currently survived for nearly 40 months with a satisfactory quality of life. [ABSTRACT FROM AUTHOR]

Checkpoint inhibitors have invigorated cancer immunotherapy research, including cancer vaccination. Classic early phase trial design and endpoints used in developing chemotherapy are not suited for evaluating all forms of cancer treatment. Peripheral T cell response dynamics have demonstrated inconsistency in assessing the efficacy of cancer vaccination. Tumor infiltrating lymphocytes (TILs), reflect the local tumor microenvironment and may prove a superior endpoint in cancer vaccination trials. Cancer vaccines may also promote success in combination immunotherapy treatment of weakly immunogenic tumors. This review explores the impact of TILs as an endpoint for cancer vaccination in multiple malignancies, summarizes the current literature regarding TILs analysis, and discusses the challenges of providing validity and a standardized implementation of this approach. [ABSTRACT FROM AUTHOR]

Opinion statement: Over the last decade in soft tissue sarcoma (STS) research, the shifting landscape towards more precise subtype classification and the increasing study of novel therapeutic strategies has prompted a need to highlight current knowledge of effective subtype specific therapies. Undifferentiated pleomorphic sarcoma (UPS), formerly known as malignant fibrous histiocytoma (MFH), is among the most common subtypes of STS arising in the trunk or extremities of adults. Administration of systemic chemotherapy is the primary management in locally advanced and metastatic UPS. While anthracycline-based chemotherapy continues to be standard of care in this setting, outcomes in locally advanced or metastatic UPS remain poor. Recent studies highlight the unique characteristics of UPS that may contribute to its greater sensitivity to immune checkpoint inhibition (ICI) compared to other STS subtypes. With the promise of benefit from novel therapies, including ICI or ICI plus chemotherapy, for a subset of patients with UPS comes the need to identify biomarkers predictive of response to therapy. Ongoing and future clinical trials should place strong emphasis on correlative biomarker studies to learn more about the unique biology of UPS and to identify patients for whom ICI-based therapy will be effective. [ABSTRACT FROM AUTHOR]

Background: High tumor mutational burden (TMB) is associated with a favorable outcome in metastatic melanoma patients treated with immune checkpoint inhibitors. However, data are limited in the adjuvant setting. As BRAF mutated patients have an alternative with targeted adjuvant therapy, it is important to identify predictive factors for relapse and recurrence-free survival (RFS) in patients receiving adjuvant anti-PD-1 antibodies. Methods: We evaluated 165 melanoma patients who started adjuvant anti-PD-1 antibody therapy at our center between March 2018 and September 2019. The initial tumor stage was assessed at the beginning of therapy according to the 8th edition of the AJCC Cancer Staging Manual. Tumor and normal tissue of the high-risk stages IIIC/D/IV were sequenced using a 700 gene NGS panel. Results: The tumor stages at the beginning of adjuvant anti-PD-1 therapy were as follows: N = 80 stage IIIA/B (48%), N = 85 stage IIIC/D/IV (52%). 72/165 patients (44%) suffered a relapse, 44/72 (61%) with only loco regional and 28/72 (39%) with distant metastases. Sequencing results were available from 83 to 85 patients with stage IIIC/D/IV. BRAF mutation status (HR 2.12, 95% CI 1.12–4.08; p = 0.022) and TMB (HR 7.11, 95% CI 2.19–23.11; p = 0.001) were significant and independent predictive factors for relapse-free survival (RFS). Conclusion: BRAF mutation status and TMB were independent predictive factors for RFS. Patients with BRAF V600E/K mutation and TMB high had the best outcome. A classification based on BRAF mutation status and TMB is proposed to predict RFS in melanoma patients with adjuvant anti-PD-1 therapy. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) constitutes the majority of the lung cancer population and the prognosis is poor. In recent years, immunotherapy has become the standard of care for advanced NSCLC patients as numerous trials demonstrated that immune checkpoint inhibitors (ICI) are more efficacious than conventional chemotherapy. However, only a minority of NSCLC patients benefit from this treatment. Therefore, there is an unmet need for biomarkers that could accurately predict response to immunotherapy. Liquid biopsy allows repeated sampling of blood-based biomarkers in a non-invasive manner for the dynamic monitoring of treatment response. In this review, we summarize the efforts and progress made in the identification of circulating biomarkers that predict immunotherapy benefit for NSCLC patients. We also discuss the challenges with future implementation of circulating biomarkers into clinical practice. [ABSTRACT FROM AUTHOR]

Based upon results of the KEYNOTE-522 trial and following approval by regulatory authorities, the addition of pembrolizumab to chemotherapy is now the standard-of-care for the treatment of early triple-negative breast cancer (eTNBC) (Clinical stage II-III). Pembrolizumab is a programmed cell death protein 1 monoclonal antibody, known to cause immune-related adverse events (irAEs) in a significant subset of patients. Real-world data on incidence, type and treatment strategies of irAEs in the setting of eTNBC treatment are sparse. In this multicenterretrospective analysis, we characterized real-world incidence of irAEs and treatment outcomes such as pathological complete response (pCR) from the combination of pembrolizumab and chemotherapy as neoadjuvant treatment for eTNBC. We found a rate of irAEs of all grades of 63.9% and of 20% for irAEs of grade 3 or higher. In the overall population, a pCR rate of 57.1% was observed. The emergence of irAEs correlated significantly with pCR (72.2% versus 30.8%; p =.03). Discontinuation of neoadjuvant chemotherapy before week 12 correlated significantly with a lower pCR rate. To our knowledge, this is the first study evaluating the real-world efficacy and safety of a neoadjuvant combination of chemotherapy and pembrolizumab in eTNBC, demonstrating a significant correlation between irAEs and pCR. Early discontinuation of neoadjuvant therapy due to AEs resulted in a lower pCR rate. [ABSTRACT FROM AUTHOR]

Immunosuppressive tumor microenvironment (TME) impedes anti-tumor immune responses and contributes to immunotherapy resistance in triple-negative breast cancer (TNBC). ADAM12, a member of cell surface metalloproteases, is selectively upregulated in mesenchymal/claudin-low TNBCs, where its expression is largely restricted to tumor cells. The role of cancer cell-expressed ADAM12 in modulating the immune TME is not known. We show that Adam12 knockout in the T11 mouse syngeneic transplantation model of claudin-low TNBC leads to decreased numbers of tumor-infiltrating neutrophils (TINs)/polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and increased numbers of tumor-infiltrating B cells and T cells. ADAM12 loss in cancer cells increases chemotaxis of B cells in vitro and this effect is eliminated by inhibition of CXCR4, a receptor for CXCL12, or anti-CXCL12 blocking antibody. Importantly, ADAM12 loss in T11 cancer cells sensitizes tumors to anti-PD1/anti-CTLA4 combination therapy, although the initial responsiveness is followed by acquired therapy resistance. Depletion of B cells in mice eliminates the improved response to immune checkpoint blockade of Adam12 knockout T11 tumors. Analysis of gene expression data for claudin-low TNBCs from the METABRIC patient cohort shows significant inverse correlations between ADAM12 and gene expression signatures of several anti-tumor immune cell populations, as well as a significant positive correlation between ADAM12 and gene expression signature of TINs/PMN-MDSCs. Collectively, these results implicate ADAM12 in immunosuppression within the TME in TNBC. [ABSTRACT FROM AUTHOR]

Checkpoint inhibitors (CIs) are now standard of care for late-stage non-small-cell lung cancer (NSCLC); however, only a minority of patients treated with a CI show clinical benefit compared to platinum-based chemotherapy alone, regardless of programmed cell death ligand 1 (PD-L1) expression levels. We describe a case of durable tumor response and disease stabilization in a patient with advanced pretreated squamous NSCLC given a maintenance treatment comprised of nivolumab, docetaxel, and ramucirumab combined with the allogeneic cellular cancer vaccine viagenpumatucel-L over a period of 28 months. Our case suggests that combination strategies that serve to sensitize tumors to checkpoint inhibition, even in patients refractory to available treatment, may lead to improved efficacy. [ABSTRACT FROM AUTHOR]

Background: Oesophageal and gastrooesophageal junction (GOJ) carcinoma frequently present with dysphagia and de novo metastatic disease. There is scope to improve treatment paradigms to both address symptoms and improve survival. One method is integrating immune checkpoint inhibition with novel treatment combinations. Methods: PALEO is a single arm, phase II clinical trial in patients with previously untreated, oligometastatic or locoregionally advanced oesophageal or GOJ carcinoma and dysphagia. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG). Participants receive 2 weeks of therapy with concurrent hypofractionated radiotherapy of 30Gy in 10 fractions to the primary tumour, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m2 and durvalumab 1500 mg q4 weekly, followed by durvalumab monotherapy continuing at 1500 mg q4weekly until disease progression, unacceptable toxicity or 24 months of therapy. A single metastasis is treated with stereotactic radiotherapy of 24Gy in 3 fractions in week 7. The trial primary endpoint is the progression free survival rate at 6 months. Secondary endpoints include duration of dysphagia relief, nutritional status change, quality of life, response rate, toxicity, progression free survival and overall survival. The tertiary endpoint is prediction of outcome based on biomarkers identified from patient serial blood samples collected pre- and post-radiotherapy. Discussion: This unique investigator-initiated clinical trial is designed to simultaneously address the clinically relevant problems of dysphagia and distant disease control. The overarching aims are to improve patient nutrition, quality of life and survival with low toxicity therapy. AGITG PALEO is a multidisciplinary collaboration and will add to the understanding of the relationship between radiotherapy and the anti-tumour immune response. Trial registration: Australian and New Zealand Clinical Trials Registry: ACTRN12619001371189, registered 8 October 2019. [ABSTRACT FROM AUTHOR]

Despite treatment with cisplatin‐based chemotherapy and surgical resection, clinical outcomes of patients with locally advanced urothelial carcinoma (UC) remain poor. We compared neoadjuvant/induction platinum‐based combination chemotherapy (NAIC) with combination immune checkpoint inhibition (cICI). We identified 602 patients who attended our outpatient bladder cancer clinic in 2018 to 2019. Patients were included if they received NAIC or cICI for cT3‐4aN0M0 or cT1‐4aN1‐3M0 UC. NAIC consisted of cisplatin‐based chemotherapy or gemcitabine‐carboplatin in case of cisplatin‐ineligibility. A subset of patients (cisplatin‐ineligibility or refusal of NAIC) received ipilimumab plus nivolumab in the NABUCCO‐trial (NCT03387761). Treatments were compared using the log‐rank test and propensity score‐weighted Cox regression models. We included 107 Stage III UC patients treated with NAIC (n = 83) or cICI (n = 24). NAIC was discontinued in 11 patients due to progression (n = 6; 7%) or toxicity (n = 5; 6%), while cICI was discontinued in 6 patients (25%) after 2 cycles due to toxicity (P =.205). After NAIC, patients had surgical resection (n = 50; 60%), chemoradiation (n = 26; 30%), or no consolidating treatment due to progression (n = 5; 6%) or toxicity (n = 2; 2%). After cICI, all patients underwent resection. After resection (n = 74), complete pathological response (ypT0N0) was achieved in 11 (22%) NAIC‐patients and 11 (46%) cICI‐patients (P =.056). Median (IQR) follow‐up was 26 (20‐32) months. cICI was associated with superior progression‐free survival (P =.003) and overall survival (P =.003) compared to NAIC. Our study showed superior survival in Stage III UC patients pretreated with cICI if compared to NAIC. Our findings provide a strong rationale for validation of cICI for locally advanced UC in a comparative phase‐3 trial. [ABSTRACT FROM AUTHOR]

Nowadays, the impact of the tumor-immune microenvironment (TME) in non-small-cell lung cancer (NSCLC) prognosis and treatment response remains unclear. Thus, we evaluated the expression of PD-L1, tumor-infiltrating lymphocytes (TILs), and transforming growth factor beta (TGF-β) in NSCLC to identify differences in TME, detect possible new prognostic factors, and assess their relationship. We retrospectively analyzed 55 samples from patients who underwent NSCLC surgery and had over a 5-year follow-up. PD-L1 expression was determined by immunohistochemistry following standard techniques. The presence of TILs was evaluated at low magnification and classified into two categories, "intense" and "non-intense". Cytoplasmic TGF-β staining visualization was divided into four categories, and unequivocal nuclear staining in >1% of viable tumor cells was defined as "present" or "absent". Our aim was to identify differences in disease-free survival (DFS) and overall survival (OS). Tumor stage was the only objective prognostic factor for OS. PD-L1 expression and the presence of TILs had no prognostic impact, neither their combination. There seems to be a lower expression of PD-L1 and a higher expression of TILs in early stages of the disease. Our TGF-β nuclear staining analysis was promising, since it was associated with worse DFS, revealing this protein as a possible prognostic biomarker of recurrence for resectable NSCLC. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to test for differences in overall (OS) and progression-free survival (PFS) rates and toxicity in first-line immune checkpoint inhibition (IO) combination therapy in metastatic renal-cell carcinoma (mRCC) patients. Methods: Between November 2017 and April 2021, 104 patients with histologically confirmed mRCC from 6 tertiary referral centers with either IO + IO (nivolumab + ipilimumab, n = 68) or IO + tyrosine kinase inhibitor (TKI) (pembrolizumab + axitinib, n = 36) were included. Kaplan-Meier and Cox regression analyses tested for OS and PFS differences. Results: Of 104 mRCC patients, 68 received IO + IO (65.4%) and 36 IO + TKI (34.6%) therapy, respectively. Median age was 67 years (interquartile range: 57–70.3). Patients receiving IO + TKI were less likely to be poor risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium score (16.7 vs. 30.9%) and presented with lower T-stage, compared to IO + IO treated patients. Median PFS was 9.8 months (CI: 5.3–17.6) versus 12.3 months (CI: 7.7 – not reached) for IO + IO versus IO + TKI treatment, respectively (p = 0.22). Median OS was not reached, survival rates at 12 months being 73.9 versus 90.0% for IO + IO versus IO + TKI patients (p = 0.089). In subgroup analyses of elderly patients (≥70 years, n = 38), IO + TKI treatment resulted in better OS rates at 12 months compared to IO + IO (91.0 vs. 57.0%; p = 0.042). Conclusion: IO + IO and IO + TKI as first-line therapies in mRCC patients were both comparable as for the oncological outcome and toxicity. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is the least survivable gynecological malignancy and presents late. Five‐year survival for OC is around 45% increasing the need for innovative treatments. Checkpoint inhibitors have shown significant clinical efficacy in mismatch repair deficient (MMRd) cancers and could be a powerful treatment in OC. However, their application in OC is limited due to the lack of data on the prevalence of MMRd. The aim of our study was to conduct a systematic review of the literature and meta‐analysis to provide an accurate estimate of the prevalence of MMRd in OC. We followed PRISMA guidelines throughout. Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science followed by citation searching. Studies not written in English were excluded. All studies were reviewed by at least two independent reviewers. Proportions of test positivity were calculated by random and fixed‐effects meta‐analysis models. I2 score was used to assess heterogeneity across studies. In total 54 studies were included with 17 532 analyzed for MMRd. The overall proportions of MMRd by immunohistochemistry and microsatellite instability analysis were 6.7% and 10.4%, respectively. MMRd was reported in all histotypes of epithelial OC but was most common in endometrioid OC. We estimate that on average 46.7% (95% CI: 28.8‐65.4) of ovarian carcinomas showing MMRd by IHC had a germline path_MMR variant identified. OC in those with Lynch syndrome seems to present at an earlier age and stage. Studies however were generally of low quality and there was a high degree of heterogeneity. A significant minority (up to 16%) of OC displays MMRd and, therefore, could be amenable to checkpoint inhibition therapy. However, the current literature base is of limited quality and therefore high‐quality prospective studies exploring MMRd in OC with the use of multimodal testing are required. In addition, trials researching efficacy of checkpoint inhibition in MMRd OC are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: For patients with advanced basal cell carcinoma (aBCC) limited treatment options are available. In this situation, hedgehog inhibitors (HHIs) are approved as first-line treatment. Upon treatment failure or intolerance, a second-line treatment with PD1 inhibitors (PD1i) is an option. However, no third-line treatment is established. Therefore, we collected data of patients with aBCC, who received HHI reinduction following PD1i-failure. In our cohort of 12 patients, initial HHI treatment led to partial response in 8 and disease stabilization in 4 patients. Eventual HHI discontinuation was mostly due to tumor progression. Second-line PD1i resulted in a partial response in only one patient. Four out of the twelve patients responded to HHI reinduction, with the longest follow-up period being 29 months. Thus, a sequential treatment with HHI reinduction can be a feasible treatment option in a subgroup of patients with aBCC after treatment failure of first-line HHIs as well as of second-line PD1i. For patients with advanced basal cell carcinoma (aBCC) first-line treatment with hedgehog inhibitors (HHIs) and second-line treatment with PD1 inhibitors (PD1i) is available, offering combination and sequencing options. Here, we focus on the efficacy and safety of HHI reinduction after PD1i failure. Retrospective data analysis was performed with 12 patients with aBCC (locally advanced (n = 8)/metastatic (n = 4)). These patients (male:female 6:6, median age 68 years) initially received HHIs, leading to complete/partial response (66%) or stable disease (33%). Median treatment duration was 20.8 (2–64.5) months until discontinuation due to progression (n = 8), adverse events (n = 3), or patient request (n = 1). Subsequent PD1 inhibition (pembrolizumab 42%, cemiplimab 58%) yielded a partial response (8%), stable disease (33%), or progression (59%). Median treatment duration was 4.1 (0.8–16.3) months until discontinuation due to progression (n = 9), adverse events (n = 1), patient request (n = 1), or missing drug approval (n = 1). HHI reinduction resulted in complete/partial response (33%), stable disease (50%), or progression (17%). Median treatment duration was 3.6 (1–29) months. Response duration in the four responding patients was 2–29+ months. Thus, a subgroup of patients with aBCC responded to reinduction of HHI following PD1i failure. Therefore, this sequential treatment represents a feasible treatment option. [ABSTRACT FROM AUTHOR]

Background: Prognosis of patients with recurrent or metastatic head and neck cancer is generally poor. Adjuvant immunotherapy (IT) featuring immune checkpoint inhibition (ICI) is standard of care in advanced stage head and neck squamous cell carcinoma (HNSCC) and cutaneous squamous cell carcinoma (CSCC). ICI response rates in CSCC are described as higher than in HNSCC. IT is constantly shifting into earlier disease stages which confronts the surgeon with immunotherapeutically pre-treated patients. It is therefore becoming increasingly difficult to assess which patients with symptomatic tumor disease and a lack of curative surgical option might benefit from salvage surgery. Case presentations: The following 6 cases describe therapeutic decisionmaking regarding ICI and (salvage) surgery in patients with advanced stage HNSCC or CSCC. Cases A and B focus on neoadjuvant ICI followed by salvage surgery. In Cases C and D salvage surgery was performed after short-term stabilization with partial response to ICI. The last two cases (Cases E and F) address the surgical approach after failure of ICI. All cases are discussed in the context of the current study landscape and with focus on individual decisionmaking. For better understanding, a timetable of the clinical course is given for each case. Conclusions: ICI is rapidly expanding its frontiers into the neoadjuvant setting, frequently confronting the surgeon with heavily pretreated patients. Salvage surgery is a viable therapeutic concept despite the rise of systemic treatment options. Decision-making on surgical intervention in case of a salvage surgery remains an individual choice. For neoadjuvant ICI monitoring regarding pathological tumor response or tumor necrosis rate, we suggest correlation between the initial biopsy and the definite tumor resectate in order to increase its significance as a surrogate marker. Scheduling of neoadjuvant ICI should be further investigated, as recent studies indicate better outcomes with shorter time frames. [ABSTRACT FROM AUTHOR]

Introduction: Outcomes for patients with advanced cutaneous squamous cell carcinoma (cSCC) are poor, however recent approvals in programmed death-1 (PD-1) checkpoint inhibition have shown promise. Prior systemic treatments in this patient population included chemotherapy and anti-EGFR directed therapies, with limited long-term benefit. Studies investigating cemiplimab and pembrolizumab have recently revealed significant responses with many cases of sustained benefit in both locally advanced and recurrent and/or metastatic disease. While these treatments have shown improvement in outcomes, there are continued areas of need.Areas Covered: This review focuses on clinical evidence for PD-1 directed checkpoint inhibition in advanced cSCC. Excluded populations and new approaches involving immunotherapy are discussed.Expert Opinion: Immune checkpoint inhibition in advanced cSCC has shown impressive benefit. The clinical trials for both cemiplimab and pembrolizumab demonstrate similar responses and outcomes. Biomarkers for predicting response are an area of need. In addition, these trials excluded immunosuppressed patients due to hematological malignancies or prior organ transplant, which are populations with significantly increased risk of cSCC. Finally, a variety of novel approaches using checkpoint inhibition in cSCC are being investigated, with some encouraging preliminary results. [ABSTRACT FROM AUTHOR]

The aim was to compare treatment outcomes of clear cell metastatic renal cell carcinoma (ccmRCC) versus non-ccmRCC (nccmRCC) patients who received first-line immune combination therapies. Within our retrospective multi-institutional consecutive database of eight tertiary-care centers, we identified mRCC patients treated with first-line immune combination therapies between 11/2017 and 12/2022. Using log-rank analysis and multivariable Cox regression, we tested for differences in overall survival (OS) and progression-free survival (PFS) of nccmRCC versus ccmRCC patients. Covariables consisted of age at diagnosis, sex, International Metastatic Renal Cell Carcinoma Database Consortium risk groups, Eastern Cooperative Oncology Group status, and sarcomatoid feature. Of 289 study patients, 39 (13%) patients harbored nccmRCC. Median OS was 37 months versus not reached for ccmRCC versus nccmRCC patients (P =.6). Median PFS was 13 versus 15 months (P =.9). Multivariable Cox regression models did not identify nccmRCC as an independent predictor of higher overall mortality in mRCC patients (hazard ratio [HR]: 1.23; P =.6) or a higher progression rate (HR: 1.0; P = 1.0). In our real-world multi-institutional study, no differences in OS and PFS between ccmRCC and nccmRCC patients receiving first-line immune combination treatment were observed, even after adjustment for important patient and tumor characteristics. More prospective trials in nccmRCC patients are needed. In our German multi-institutional retrospective study of 289 mRCC patients with 39 (13%) patients harbored nonclear cell metastatic renal cell carcinoma (ccmRCC), no significant overall or progression-free differences were observed between nccmRCC and ccmRCC groups undergoing first-line immune combination therapy, indicating similar outcomes regardless of histological type. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have revolutionized treatment of advanced melanoma, but commonly cause serious immune-mediated complications. The clinical ambition of reserving more aggressive therapies for patients least likely to experience immune-related adverse events (irAE) has driven an extensive search for predictive biomarkers. Here, we externally validate the performance of 59 previously reported markers of irAE risk in a new cohort of 110 patients receiving Nivolumab (anti-PD1) and Ipilimumab (anti-CTLA-4) therapy. Alone or combined, the discriminatory value of these routine clinical parameters and flow cytometry biomarkers was poor. Unsupervised clustering of flow cytometry data returned four T cell subsets with higher discriminatory capacity for colitis than previously reported populations, but they cannot be considered as reliable classifiers. Although mechanisms predisposing some patients to particular irAEs have been described, we are presently unable to capture adequate information from pre-therapy flow cytometry and clinical data to reliably predict risk of irAE in most cases. [ABSTRACT FROM AUTHOR]

High-grade serous ovarian carcinoma (HGSOC) is a genomically unstable malignancy responsible for over 70% of all deaths due to ovarian cancer. With roughly 50% of all HGSOC harboring defects in the homologous recombination (HR) DNA repair pathway (e.g., BRCA1/2 mutations), the introduction of poly ADP-ribose polymerase inhibitors (PARPi) has dramatically improved outcomes for women with HR defective HGSOC. By blocking the repair of single-stranded DNA damage in cancer cells already lacking high-fidelity HR pathways, PARPi causes the accumulation of doublestranded DNA breaks, leading to cell death. Thus, this synthetic lethality results in PARPi selectively targeting cancer cells, resulting in impressive efficacy. Despite this, resistance to PARPi commonly develops through diverse mechanisms, such as the acquisition of secondary BRCA1/2 mutations. Perhaps less well documented is that PARPi can impact both the tumour microenvironment and the immune response, through upregulation of the stimulator of interferon genes (STING) pathway, upregulation of immune checkpoints such as PD-L1, and by stimulating the production of proinflammatory cytokines. Whilst targeted immunotherapies have not yet found their place in the clinic for HGSOC, the evidence above, as well as ongoing studies exploring the synergistic effects of PARPi with immune agents, including immune checkpoint inhibitors, suggests potential for targeting the immune response in HGSOC. Additionally, combining PARPi with epigeneticmodulating drugs may improve PARPi efficacy, by inducing a BRCA-defective phenotype to sensitise resistant cancer cells to PARPi. Finally, invigorating an immune response during PARPi therapy may engage anti-cancer immune responses that potentiate efficacy and mitigate the development of PARPi resistance. Here, we will review the emerging PARPi literature with a focus on PARPi effects on the immune response in HGSOC, as well as the potential of epigenetic combination therapies. We highlight the potential of transforming HGSOC from a lethal to a chronic disease and increasing the likelihood of cure. [ABSTRACT FROM AUTHOR]

LPS challenge is used to model inflammation‐induced organ dysfunction. The effects of T cell activation on LPS‐mediated organ dysfunction and immune responses are unknown. We studied these interactions through in vivo administration of anti‐CD3ε (CD3) T cell activating antibody and LPS. Mortality in response to high‐dose LPS (LPSHi; 600 μg) was 60%; similar mortality was observed with a 10‐fold reduction in LPS dose (LPSLo; 60 μg) when administered with CD3 (CD3LPSLo). LPSHi and CD3LPSLo cohorts suffered severe organ dysfunction. CD3LPSLo led to increased IFNγ and IL12p70 produced by T cells and dendritic cells (cDCs) respectively. CD3LPSLo caused cDC expression of CD40 and MHCII and prevented PD1 expression in response to CD3. These interactions led to the generation of CD4 and CD8 cytolytic T cells. CD3LPSLo responded to IFNγ or IL12p40 blockade, in contrast to LPSHi. The combination of TCR activation and LPS (CD3LPSLo) dysregulated T cell activation and increased LPS‐associated organ dysfunction and mortality through T cell and cDC interactions. [ABSTRACT FROM AUTHOR]

Overall, 33 patients (52%) continued treatment beyond investigator assessed PD and a total of 16 patients received additional concomitant radiotherapy and/or chemotherapy. The majority of patients experiencing PD during or after anti-PD1 treatment received additional therapies (21/37, 57%). Outcomes of anti-programmed death 1 treatment for relapsed/refractory Hodgkin lymphoma: A German Hodgkin Study Group multicentre real-world analysis. [Extracted from the article]

Summary: In this short review article we discuss three key oral presentations from the European Society for Medical Oncology (ESMO) Congress 2021 concerning localised, as well as advanced/metastatic renal cell carcinoma, highlighting their potential implications for the improvement of therapeutic modalities in affected patients. (1) Conditional survival and 5‑year follow-up of CheckMate 214 currently represent the longest available phase III follow-up data in the first-line (combination) treatment of clear cell renal cell carcinoma patients with nivolumab + ipilimumab vs. sunitinib. This analysis demonstrated durable efficacy benefits with the respective combination vs. sunitinib. Moreover, conditional survival results predict an increased probability of durable overall survival, progression-free survival, and response rates with nivolumab + ipilimumab at 2‑ and 3‑year landmarks. (2) The randomised, double-blind, phase III KEYNOTE-564 study, presented as a highlight late-breaking abstract at the ASCO Congress 2021, met its primary endpoint of disease-free survival with post nephrectomy adjuvant pembrolizumab vs. placebo in clear cell renal cell carcinoma patients. At ESMO 2021, the authors presented patient-reported outcomes, whereby no clinically meaningful changes from baseline in health-related quality of life or symptom scores were observed with adjuvant pembrolizumab or placebo. These findings suggest that adjuvant pembrolizumab was tolerable from a patient perspective. (3) A phase II prospective trial of frontline cabozantinib in metastatic collecting ducts carcinoma, namely the BONSAI trial (Meeturo 2), met its primary endpoint objective response rate, showing promising efficacy and acceptable tolerability of cabozantinib in respective patients. Since metastatic collecting ducts carcinoma is biologically poorly characterised and heavily underrepresented in prospective randomised trials, BONSAI gains particular importance. [ABSTRACT FROM AUTHOR]

Immunotherapy has without question revolutionized the treatment of both hematologic and solid malignancies. Over the last several years novel strategies are being developed to incorporate these groundbreaking therapies into the care of patients with AML. Here we present an overview of the recent developments in immunotherapy for AML with a focus on biomarkers of response. Topics reviewed include antibody drug conjugates, BiTEs, DARTs, checkpoint inhibitors, and cellular therapy as well as the development of biomarkers predictive of response in each class. [ABSTRACT FROM AUTHOR]

Background: Immunocompromised people (ICP) and elderly individuals (older than 80 years) are at increased risk for severe coronavirus infections. To protect against serious infection with SARS-CoV-2, ICP are taking precautions that may include a reduction of social contacts and participation in activities which they normally enjoy. Furthermore, for these people, there is an uncertainty regarding the effectiveness of the vaccination. The COVID-19 Contact (CoCo) Immune study strives to characterize the immune response to COVID-19 vaccination in immunocompromised, elderly people, and patients with hematological or oncological diseases. The study uses blood-based screenings to monitor the humoral and cellular immune response in these groups after vaccination. Questionnaires and qualitative interviews are used to describe the level of social participation.Methods: The CoCo Immune Study is a mixed methods prospective, longitudinal, observational study at two large university hospitals in Northern Germany. Starting in March 2021, it monitors anti-SARS-CoV-2 immune responses and collects information on social participation in more than 600 participants, at least 18 years old. Inclusion criteria and subcohorts: Participants with (1) regularly intake of immunosuppressive medication (ICP-cohort) or (2) age ≥ 80 years (80 + -cohort). Additionally, patients with current or former (3) myeloid, (4) lymphatic disease or (5) solid tumor under checkpoint inhibition (3-5: HO-cohort).Exclusion Criteria: (1) refusal to give informed consent, (2) contraindication to blood testing, (3) inability to declare consent. Participants complete a questionnaire at four different time points: prior to full vaccination, and 1, 6 and 12 months after completed vaccination. In addition, participants draw blood samples themselves or through a local health care provider and send them with their questionnaires per post at the respective time points after vaccination. Patients of the HO cohort dispense additional blood samples at week 3 to 12 and at month 6 to 9 after 2nd vaccination to gain additional knowledge in B and T cell responses. Selected participants are invited to qualitative interviews about social participation.Discussion: This observational study is designed to gain insight into the immune response of people with weakened immune systems and to find out how social participation is affected after COVID-19 vaccination.Trial Registration: This study was registered with German Clinical Trial Registry (registration number: DRKS00023972) on 30th December 2020. [ABSTRACT FROM AUTHOR]

In chronic hepatitis B virus (HBV) infection, virus-specific T cells are scarce and partially dysfunctional. Therapeutic vaccination is a promising strategy to induce and activate new virus-specific T cells. In long-term or high-level HBV carriers, however, therapeutic vaccination by itself may not suffice to cure HBV. One reason is the impairment of antiviral T cells by immune checkpoints. In this study, we used small-interfering RNA (siRNA) in combination with a heterologous prime-boost therapeutic vaccination scheme (TherVacB) to interfere with a major immune checkpoint, the interaction of programmed death protein-1 (PD-1) and its ligand (PDL-1). In mice persistently replicating HBV after infection with an adeno-associated virus harboring the HBV genome, siRNA targeting PD-L1 resulted in a higher functionality of HBV-specific CD8+ T cells after therapeutic vaccination, and allowed for a more sustained antiviral effect and control of HBV in peripheral blood and in the liver. The antiviral effect was more pronounced if PD-L1 was down-regulated during prime than during boost vaccination. Thus, targeting PD-L1 using siRNA is a promising approach to enhance the efficacy of therapeutic vaccination and finally cure HBV. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibition is a new standard of targeted therapy in the treatment of advanced or metastatic gastric cancer (GC) and is represented in various combinations with and without chemotherapy in every therapy line within clinical trials. In advanced adenocarcinoma of GC, gastroesophageal junction cancer (GEJC) and esophageal cancer (EC), the combination of nivolumab and chemotherapy in first-line therapy improves overall survival (OS) in PD-L1 (programmed cell death protein 1)-positive patients with approval in Europe (PD-L1 CPS (combined positivity score) ≥ 5), USA and Taiwan (CHECKMATE-649) and pembrolizumab plus chemotherapy for GEJC and EC in Europe (CPS ≥ 10) and the USA (KEYNOTE-590). Furthermore, pembrolizumab plus trastuzumab and chemotherapy show clear benefits in OS and are approved as first-line treatment of Her2 (human epidermal growth factor receptor-2)-positive tumors in the USA (KEYNOTE-811). Nivolumab demonstrates superior OS regardless of PD-L1 expression in third-line therapy with approval in Japan (ATTRACTION-02) and pembrolizumab prolonged the duration of response in PD-L1 positive patients with approval in the USA in PD-L1 CPS ≥ 1 patients (KEYNOTE-059). This review reflects the rationale and current results of phase II and III clinical trials investigating various immune checkpoint inhibitors targeting PD-L1/1 and CTLA (anticytotoxic T-lymphocyte-associated antigen)-4 in combination with and without chemotherapy and Her2-targeted therapy in GC. [ABSTRACT FROM AUTHOR]