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BACKGROUND: Metastatic melanoma to the small bowel is an aggressive disease often accompanied by obstruction, abdominal pain, and gastrointestinal bleeding. With advancements in melanoma treatment, the role for metastasectomy continues to evolve. Inclusion of novel immunotherapeutic agents, such as checkpoint inhibitors, into standard treatment regimens presents potential survival benefits for patients receiving metastasectomy. CASE PRESENTATION: We report an institutional experience of 15 patients (12 male, 3 female) between 2014-2022 that underwent small bowel metastasectomy for metastatic melanoma and received perioperative systemic treatment. Median age of patients was 64 years (range: 35-83 years). No patients died within 30 days of their surgery, and the median hospital length of stay was 5 days. Median overall survival in these patients was 30.1 months (range: 2-115 months). Five patients died from disease (67 days, 252 days, 426 days, 572 days, 692 days postoperatively), one patient died of non-disease related causes (1312 days postoperatively), six patients are alive with disease, and three remain disease free. CONCLUSIONS: This case series presents an updated perspective of the utility of metastasectomy for small bowel metastasis in the age of novel immunotherapeutic agents as standard systemic treatment. Small bowel metastasectomy for advanced melanoma performed in conjunction with perioperative systemic therapy is safe and appears to promote long-term survival and enhanced quality of life.

Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer, with the tumor microenvironment (TME) playing a pivotal role in modulating the immune response. CD47, a cell surface protein, has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy. However, the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood. This comprehensive review aims to provide an overview of CD47's multifaced role in TME regulation and immune evasion, elucidating its impact on various types of immunotherapy outcomes, including checkpoint inhibitors and CAR T-cell therapy. Notably, CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes, especially when combined with other immunotherapeutic approaches. The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47. Despite the demonstrated effectiveness of CD47-targeted therapies, there are potential problems, including unintended effects on healthy cells, hematological toxicities, and the development if resistance. Consequently, further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches, ultimately improving cancer treatment outcomes. Overall, this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.

Regulatory T cells (Tregs), a subset of CD4+T cells marked by the expression of the transcription factor forkhead box protein 3 (Foxp3), are pivotal in maintaining immune equilibrium and preventing autoimmunity. In our review, we addressed the functional distinctions between Foxp3+Tregs and other T cells, highlighting their roles in autoimmune diseases and cancer. We uncovered the dual nature of Tregs: they prevented autoimmune diseases by maintaining self-tolerance while contributing to tumor evasion by suppressing anti-tumor immunity. This study underscored the potential for targeted therapeutic strategies, such as enhancing Treg activity to restore balance in autoimmune diseases or depleting Foxp3+Tregs to augment anti-tumor immune responses in cancer. These insights laid the groundwork for future research and clinical applications, emphasizing the critical role of Foxp3+Tregs in immune regulation and the advancement of next-generation immunotherapies. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores the association of immune-related adverse events during atezolizumab therapy with better outcomes for patients with advanced non-small-cell lung cancer who had already received chemotherapy in previous lines of treatment. This study found that patients who experienced an immune-related adverse event while undergoing atezolizumab treatment had longer median progression-free survival compared to those who did not. Specifically, patients that experienced side effects had a median progression-free survival of 13.03 months, compared to just 3.4 months for those without side effects. Additionally, these side effects were more common in patients who were in better overall health when they started the treatment. The findings suggest that immune-related adverse events could be predictive in this patient population. Immune checkpoint inhibitors (ICIs) are pivotal in managing metastatic non-oncogene addicted non-small-cell lung cancer (NSCLC). They have unique toxicities known as immune-related adverse events (irAEs). Previous studies have linked irAEs during atezolizumab-based first-line treatments in advanced NSCLC with improved outcomes. This study explored the association between irAEs and the efficacy of atezolizumab in advanced NSCLC patients who had previously received platinum-based chemotherapy. The study involved 105 advanced NSCLC patients who received atezolizumab monotherapy after progressing on at least one line of platinum-based chemotherapy from a single academic institution in Serbia. Data were obtained from a hospital lung cancer registry. Among the participants, 63.8% were male, with the majority being current (53.3%) or former smokers (37.1%). About half had a good performance status (ECOG PS 0–1) at the start of atezolizumab treatment. irAEs occurred in 23 patients (21.9%). The median progression-free survival (mPFS) was significantly longer for patients with irAEs (13.03 months) compared to those without (3.4 months) (HR 0.365 [95% CI, 0.195–0.681], p = 0.002). irAEs and ECOG PS 0–1 were predictors of longer mPFS, with irAEs being more common in patients with good performance status (p = 0.01). irAEs were linked to improved mPFS in NSCLC patients treated with atezolizumab after multiple lines of platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

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AbstractRichter’s transformation (RT) is defined as the evolution of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. This complication is rare and aggressive, with poor prognosis and dismal survival. Clonal relationship with the underlying CLL/SLL, observed in ∼80% of cases, represents one of the main factors affecting prognosis. Treatment has been historically based on chemoimmunotherapy, but frequent mutations in genes involved in cell survival and proliferation—such as TP53, NOTCH1, MYC, CDKN2A—confer resistance to standard treatments. During the last years, advances in the knowledge of the biological mechanisms underlying RT allowed to identify genetic and molecular lesions that can potentially be targeted by novel selective agents. Pathway and checkpoint inhibitors, bispecific antibodies and CAR T-cell therapy are currently under investigation and represent promising treatment options. This review summarizes current biological evidence and available data on novel therapeutic agents. [ABSTRACT FROM AUTHOR]

Background: The prognostic implications of tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are poorly studied in hematologic malignancies. Objectives: This study aimed to better understand the characteristics and prognostic value of TMB and PD-1/PD-L1 in hematologic malignancies. Design: This real-world study was conducted among patients with hematologic malignancies who had next-generation sequencing (NGS) (Foundation Medicine) at the University of California San Diego Moores Cancer Center (2014–2018). Methods: TMB was measured by NGS. PD-L1 expression (tumor proportion score, TPS) was measured by immunohistochemistry (classified as high (⩾50%), low (1–49%), and negative (<1%)). Data was curated from the electronic medical records. Results: In 388 evaluable patients, the most common diagnoses were B-cell non-Hodgkin lymphoma (NHL) (35%) and Philadelphia chromosome-negative myeloproliferative disorders (16%). Median TMB was 1.6 mutations/Mb (range, 0–46.83). Forty-eight patients (12%) had TMB ⩾10 mutations/Mb, 90% of which were B-cell or T-cell NHL. In 85 samples with available PD-L1 scores, 11 were high; 26, low; and 48, no tumor cell expression. PD-L1 TPS positive (⩾1%) was most common in T-cell NHL (7/9 (77%) cases) followed by B-cell NHL (21/51 (41%) cases). TMB ⩾4 mutations/Mb and PD-L1 score ⩾1% were significantly associated with shorter overall survival (OS) from diagnosis, with hazard ratio (HR) = 1.46 (p = 0.02, 95% confidence interval (CI) 1.05–2.03) and HR = 2.11 (p = 0.04, 95% CI 1.04–4.30), respectively; the relationship was more pronounced when PD-L1 ⩾50% versus <50% was used (HR = 2.80, p = 0.02, 95% CI 1.19–6.59). Higher TMB and higher PD-L1 positivity correlation were significant but weak (Pearson correlation coefficient R 2 = 0.04, p = 0.04). Conclusion: TMB ⩾4 mutations/Mb and positive PD-L1 TPS are poor prognostic factors, correlating with shorter OS across hematologic malignancies. Trial registration: ClinicalTrials.gov NCT02478931. [ABSTRACT FROM AUTHOR]

Cancer is one of the most complex and challenging human diseases, with rising incidences and cancer-related deaths despite improved diagnosis and personalized treatment options. Targeted alpha therapy (TαT) offers an exciting strategy emerging for cancer treatment which has proven effective even in patients with advanced metastatic disease that has become resistant to other treatments. Yet, in many cases, more sophisticated strategies are needed to stall disease progression and overcome resistance to TαT. The combination of two or more therapies which have historically been used as stand-alone treatments is an approach that has been pursued in recent years. This review aims to provide an overview on TαT and the four main pillars of therapeutic strategies in cancer management, namely external beam radiation therapy (EBRT), immunotherapy with checkpoint inhibitors (ICI), cytostatic chemotherapy (CCT), and brachytherapy (BT), and to discuss their potential use in combination with TαT. A brief description of each therapy is followed by a review of known biological aspects and state-of-the-art treatment practices. The emphasis, however, is given to the motivation for combination with TαT as well as the pre-clinical and clinical studies conducted to date. [ABSTRACT FROM AUTHOR]

Opinion Statement: Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies that arise from the epithelium of the biliary tract. Most patients present with locally advanced or metastatic disease at the time of diagnosis. For patients with unresectable BTC, the survival advantage provided by systemic chemotherapy was limited. Over the last decade, immunotherapy has significantly improved the therapeutic landscape of solid tumors. There is an increasing number of studies evaluating the application of immunotherapy in BTC, including immune checkpoint inhibitors (ICIs), cancer vaccines and adoptive cell therapy. The limited response to ICIs monotherapy in unselected patients prompted investigators to explore different combination therapy strategies. Early clinical trials of therapeutic cancer vaccination and adoptive cell therapy have shown encouraging clinical results. However, there still has been a long way to go via validation of therapeutic efficacy and exploration of strategies to increase the efficacy. Identifying biomarkers that predict the response to immunotherapy will allow a more accurate selection of candidates. This review will provide an up-to-date overview of the current clinical data on the role of immunotherapy, summarize the promising biomarkers predictive of the response to ICIs and discuss the perspective for future research direction of immunotherapy in advanced BTC. [ABSTRACT FROM AUTHOR]

Purpose of Review: Given the rapid development of multiple targeted and immune therapies for patients with advanced melanoma, it can be challenging to select a therapy based on currently available data. This review aims to provide an overview of frontline options for metastatic melanoma, with practical guidance for selecting a treatment regimen. Recent Findings: Recently reported data from randomized trials suggests that the majority of patients with unresectable melanoma should receive a PD-1 checkpoint inhibitor as part of their first line therapy, irrespective of BRAF mutation status. Additional data also suggests that combination immunotherapies result in improved outcomes compared to single agent, albeit at the cost of increased toxicity, though to date no biomarker exists to help guide treatment selection. Summary: As the number therapeutic options continue to grow for patients with advanced melanoma, there is likely to be a continued focus on combination strategies. Defining the optimal treatment approach in order to maximize efficacy while minimizing toxicity remains an area of active investigation. [ABSTRACT FROM AUTHOR]

Despite the success of immunotherapies for melanoma in recent years, there remains a significant proportion of patients who do not yet derive benefit from available treatments. Immunotherapies currently licensed for clinical use target the adaptive immune system, focussing on Tcell interactions and functions. However, the most prevalent immune cells within the tumor microenvironment (TME) of melanoma are macrophages, a diverse immune cell subset displaying high plasticity, to which no current therapies are yet directly targeted. Macrophages have been shown not only to activate the adaptive immune response, and enhance cancer cell killing, but, when influenced by factors within the TME of melanoma, these cells also promote melanoma tumorigenesis and metastasis. We present a review of the most up-to-date literatureavailable on PubMed, focussing on studies from within the last 10 years. We also include data from ongoing and recent clinical trials targeting macrophages in melanoma listed on clinicaltrials.gov. Understanding the multifaceted role of macrophages in melanoma, including their interactions with immune and cancer cells, the influence of current therapies on macrophage phenotype and functions and how macrophages could be targeted with novel treatment approaches, are all critical for improving outcomes for patients with melanoma. [ABSTRACT FROM AUTHOR]

Background: Liver cancer, particularly hepatocellular carcinoma (HCC), is a significant gastrointestinal disease with a mortality rate as high as nearly 80% within five years. The disease's pathophysiology involves deranged immune responses and bile acid metabolism, with the gut microbiota (GM) playing a crucial role. Recent research highlights the potential of GM in influencing HCC treatment outcomes, especially regarding immune checkpoint inhibitors (ICIs). However, few patients currently benefit from ICIs due to a lack of effective response biomarkers. Aims and methods: This review aimed to explore the literature on HCC treatment issues, focusing on immune response, bile acid metabolism, and GM dysbiosis. This review included studies from PubMed, Medline, and major gastroenterology and hepatology meetings, using keywords like gut microbiota, immune system, liver cancer, and checkpoint inhibitors. Results: GM dysbiosis significantly impacts immune response and bile acid metabolism, making it a promising biomarker for ICI response. Modulating GM can enhance ICI treatment efficacy, although more research is needed to confirm its direct therapeutic benefits for HCC. Conclusions: GM dysbiosis is integral to liver cancer pathogenesis and treatment response. Its modulation offers promising therapeutic avenues for improving HCC prognosis and response to immunotherapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel anticancer therapy using autologous or allogeneic T-cells. To date, six CAR-T therapies for specific B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphomas (NHL), and multiple myeloma (MM) have been approved by the Food and Drug Administration (FDA). Significant barriers to the effectiveness of CAR-T therapy include cytokine release syndrome (CRS), neurotoxicity in the case of Allogeneic Stem Cell Transplantation (Allo-SCT) graft-versus-host-disease (GVHD), antigen escape, modest antitumor activity, restricted trafficking, limited persistence, the immunosuppressive microenvironment, and senescence and exhaustion of CAR-Ts. Furthermore, cancer drug resistance remains a major problem in clinical practice. CAR-T therapy, in combination with checkpoint blockades and bispecific T-cell engagers (BiTEs) or other drugs, appears to be an appealing anticancer strategy. Many of these agents have shown impressive results, combining efficacy with tolerability. Biomarkers like extracellular vesicles (EVs), cell-free DNA (cfDNA), circulating tumor (ctDNA) and miRNAs may play an important role in toxicity, relapse assessment, and efficacy prediction, and can be implicated in clinical applications of CAR-T therapy and in establishing safe and efficacious personalized medicine. However, further research is required to fully comprehend the particular side effects of immunomodulation, to ascertain the best order and combination of this medication with conventional chemotherapy and targeted therapies, and to find reliable predictive biomarkers. [ABSTRACT FROM AUTHOR]

Breast cancer is a disease encompassing a spectrum of molecular subtypes and clinical presentations, each with distinct prognostic implications and treatment responses. Breast cancer has traditionally been considered an immunologically "cold" tumor, unresponsive to immunotherapy. However, clinical trials in recent years have found immunotherapy to be an efficacious therapeutic option for select patients. Breast cancer is categorized into different subtypes ranging from the most common positive hormone receptor (HR+), human epidermal growth factor receptor 2 (HER2)—negative type, to less frequent HER2− positive breast cancer and triple-negative breast cancer (TNBC), highlighting the necessity for tailored treatment strategies aimed at maximizing patient outcomes. Despite notable progress in early detection and new therapeutic modalities, breast cancer remains the second leading cause of cancer death in the USA. Moreover, in recent decades, breast cancer incidence rates have been increasing, especially in women younger than the age of 50. This has prompted the exploration of new therapeutic approaches to address this trend, offering new therapeutic prospects for breast cancer patients. Immunotherapy is a class of therapeutic agents that has revolutionized the treatment landscape of many cancers, namely melanoma, lung cancer, and gastroesophageal cancers, amongst others. Though belatedly, immunotherapy has entered the treatment armamentarium of breast cancer, with the approval of pembrolizumab in combination with chemotherapy in triple-negative breast cancer (TNBC) in the neoadjuvant and advanced settings, thereby paving the path for further research and integration of immune checkpoint inhibitors in other subtypes of breast cancer. Trials exploring various combination therapies to harness the power of immunotherapy in symbiosis with various chemotherapeutic agents are ongoing in hopes of improving response rates and prolonging survival for breast cancer patients. Biomarkers and precise patient selection for the utilization of immunotherapy remain cardinal and are currently under investigation, with some biomarkers showing promise, such as Program Death Lignat-1 (PDL-1) Combined Positive Score, Tumor Mutation Burden (TMB), and Tumor Infiltrating Lymphocytes (TILs). This review will present the current landscape of immunotherapy, particularly checkpoint inhibitors, in different types of breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: Checkpoint inhibitors (CPI) are widely used in cancer treatment with a potential of causing immune-related adverse events (IRAEs). Several studies have reported a positive correlation between development of IRAEs and improved survival outcome. However, few studies have focused on the potential role of multiple IRAEs on treatment effectiveness. This study aimed at investigating the association between multiple IRAEs and treatment effectiveness in terms of progression-free survival (PFS) and overall survival (OS) in advanced cancer patients. Methods: We performed a retrospective cohort study at three Swedish centers. All patients (n=600) treated with PD-L1 or PD-1 inhibitor, in monotherapy or in combination for advanced cancer between January 2017 and December 2021 were included. Multiple IRAEs were defined as IRAEs involving more than one organ system either simultaneously or sequentially. Time-depending Cox-regression model to mitigate the risk for immortal time bias (ITB) was applied. Results: The major tumor types were non-small cell lung cancer (205 patients; 34.2%) and malignant melanoma (196 patients; 32.7%). Of all patients,32.8% developed single IRAE and 16.2% multiple IRAEs. Patients with multiple IRAEs showed significantly improved PFS (Hazard Ratio, HR=0.78 95% Confidence Interval, CI: 0.57–0.98) and OS (HR=0.65 95% CI: 0.44–0.95) compared to patients with single IRAE or no IRAE (HR=0.46 95% CI:0.34–0.62 for PFS vs HR=0.41 95% CI: 0.28-0.60 for OS). Conclusion: In conclusion, our data supports a stronger association between development of multiple as opposed to single IRAEs and clinical effectiveness in advanced cancer patients treated with CPIs. [ABSTRACT FROM AUTHOR]

Simple Summary: In the past few years, the endometrial cancer field has been revolutionized, following the integration of molecular classification into clinical practice. Endometrial carcinoma is currently molecularly categorized into four main subgroups: POLE-mutated, mismatch repair-deficient, p53-mutated, and no specific molecular profile. The POLE-mutated subgroup is characterized by an excellent prognosis notwithstanding bad conventional prognostic factors, including high-grade and TP53 mutations. On the other hand, the p53-mutated subgroup demonstrates the worst outcome. However, the remaining subgroups are more prevalent and display variable clinical outcomes. In this review, we describe the evolution of the endometrial carcinoma classification, its strengths and limitations, clinical implications, and foreseen perspectives. Endometrial carcinoma (EC) is the most frequent gynecological cancer, with an increasing incidence and mortality in recent times. The last decade has represented a true revolution with the development of the integrated histo-molecular classification of EC, which allows for the stratification of patients with morphologically indistinguishable disease into groups with different prognoses. Particularly, the POLE-mutated subgroup exhibits outstanding survival. Nevertheless, the indiscriminate application of molecular classification appears premature. Its prognostic significance has been proven mainly in endometrioid EC, the most common histotype, but it has yet to be convincingly confirmed in the other minor histotypes, which indeed account for a relevant proportion of EC mortality. Moreover, its daily use both requires a mindful pathologist who is able to correctly evaluate and unambiguously report immunohistochemical staining used as a surrogated diagnostic tool and is hampered by the unavailability of POLE mutation analysis. Further molecular characterization of ECs is needed to allow for the identification of better-tailored therapies in different settings, as well as the safe avoidance of surgery for fertility preservation. Hopefully, the numerous ongoing clinical trials in the adjuvant and metastatic settings of EC will likely produce evidence to refine the histo-molecular classification and therapeutic guidelines. Our review aims to retrace the origin and evolution of the molecular classification for EC, reveal its strengths and limitations, show clinical relevance, and uncover the desired future developments. [ABSTRACT FROM AUTHOR]

Background: Bone metastases (BoMs) are prevalent in patients with metastatic non-small-cell lung cancer (NSCLC) however, there are limited data detailing how BoMs respond to immune checkpoint inhibitors (ICIs). The purpose of this study was to compare the imaging response to ICIs of BoMs against visceral metastases and to evaluate the effect of BoMs on survival. Materials and methods: A retrospective, multicentre cohort study was conducted in patients with NSCLC treated with nivolumab or pembrolizumab in Alberta, Canada from 2015 to 2020. The primary endpoint was the real-world organ specific progression free survival (osPFS) of bone versus visceral metastases. Visceral metastases were categorized as adrenal, brain, liver, lung, lymph node, or other intra-abdominal lesions. The secondary outcome was overall survival (OS) amongst patients with and without BoMs. Results: A total of 573 patients were included of which all patients had visceral metastases and 243 patients (42.4%) had BoMs. High PD-L1 expression was identified in 268 patients (46.8%). No significant difference in osPFS was observed between bone, liver, and intra-abdominal metastases (p=0.20 and p=0.76, respectively), with all showing shorter osPFS than other disease sites. There was no difference in the osPFS of extra-thoracic sites of disease in patients with high PD-L1 expression. There was significant discordance between visceral disease response and bone disease response to ICI (p=0.047). The presence of BoMs was an independent poor prognostic factor for OS (HR 1.26, 95%CI: 1.05-1.53, p=0.01). Conclusion: Metastatic bone, liver, and intra-abdominal lesions demonstrated inferior clinical responses to ICI relative to other sites of disease. Additionally, the presence of bone and liver metastases were independent poor prognostic factors for overall survival. This real-world data suggests that BoMs respond poorly to ICI and may require treatment adjuncts for disease control. [ABSTRACT FROM AUTHOR]

We previously reported that dendritic cell (DC)-based vaccines targeting antigens expressed by tumor-associated vascular endothelial cells (VECs) and pericytes effectively control tumor growth in translational mouse tumor models. In the current report, we examined whether the therapeutic benefits of such tumor blood vessel antigen (TBVA)-targeted vaccines could be improved by the cotargeting of tumor antigens in the s.c. B16 melanoma model. We also evaluated whether combination vaccines incorporating anti-PD-L1 checkpoint blockade and/or a chemokine-modulating (CKM; IFNα + TLR3-L [rintatolimod] + Celecoxib) regimen would improve T cell infiltration/functionality in tumors yielding enhanced treatment benefits. We report that DC–peptide or DC–tumor lysate vaccines coordinately targeting melanoma antigens and TBVAs were effective in slowing B16 growth in vivo and extending survival, with superior outcomes observed for DC–peptide-based vaccines. Peptide-based vaccines that selectively target either melanoma antigens or TBVAs elicited a CD8+ T cell repertoire recognizing both tumor cells and tumor-associated VECs and pericytes in vitro, consistent with a treatment-induced epitope spreading mechanism. Notably, combination vaccines including anti-PD-L1 + CKM yielded superior therapeutic effects on tumor growth and animal survival, in association with the potentiation of polyfunctional CD8+ T cell reactivity against both tumor cells and tumor-associated vascular cells and a pro-inflammatory TME. [ABSTRACT FROM AUTHOR]

Background: Immune check point inhibitors (ICIs) have an established role in Microsatellite- Instability--High (MSI-H) and Combined Positive Score (CPS) high advanced gastric/ gastroesophageal (G/GE) adenocarcinomas, but there is limited real world data with regard to practice patterns, and efficacy of standard doses (SD-ICIs) and alternative lower doses (LD-ICIs). Methods: A retrospective study of patients with advanced G/GE adenocarcinomas receiving ICIs was conducted. The primary endpoint of the study was 12-month overall survival (OS), which was computed by Kaplan-Meier method. Results: A total of 91 patients were available for analysis during the study period. Seventy- four patients (81%) received nivolumab, while the remaining received pembrolizumab. Fifteen patients (16%) had MSI-H status and had a 12-month OS of 60% and median OS of 15 months (median follow-up -- 38.3 months). In the Microsatellite-Stable (MSS) cohort (84%; n = 76), ICIs (combined with chemotherapy) were used predominantly in pre-treated patients (54%; n = 41). Patients with CPS ≥5 (72%; n = 55) had improved survival compared to patients with CPS <5 (28%; n = 21) (12-month OS: 52% vs. 26%; Median OS: 12.8 months vs. 3.2 months; p = 0.005). There was no difference in survival between patients who received SD-ICIs (54%; n = 41) and LD-ICIs (46%; n = 35) (12-month OS: 42% vs. 48%; Median OS: 8.7 months vs. 11 months; p = 0.44). Conclusions: Patients with advanced G/GEJ adenocarcinomas in the real world predominantly received ICIs during later lines of therapy as opposed to first line therapy. Using a CPS cutoff of ≥5 as opposed to CPS <5 predicts for improved survivals in MSS patients and patients receiving low dose ICIs have similar survival outcomes to patients receiving standard dose ICIs within the confines of a heterogenous study cohort. [ABSTRACT FROM AUTHOR]

Except the widely accepted use of immune Checkpoint inhibitors in the treatment of microsatellite instability-high (MSI-H) mismatch repair-deficient (MMRd) CRCs representing about 5% of all metastatic (m)CRC patients, new strategies are applied to cure MMR-proficient (MMRp) mCRC patients. Tumor microenvironment (TME) is decisive for cancer development. The determination of some immunoeffective and immunosuppressive immune cells and some cytokines, chemokines and growth factors in the TME gives Information about the use of immune Checkpoint inhibitors in MMRp CRCs. The increased level of IL-6 in the serum and increased number of IL-6+ immune cells in TME, the increased number of IL-17+ Th17 cells, and of FoxP3+ cells are used to determine the use of anti-IL-6 antibody and of anti-FoxP3 antibody for treatment. The determination of high CD8+, high PD-1 expression and little or no Th17 cells appoint better response to anti-PD-1 therapy. The used combination therapies are: combination of immunotherapy with chemotherapy, with radiation therapy, with targeted therapy, with vaccines, oncolytic viruses and bispeeifie antibodies. Classical treatment of CRC patients has included chemotherapy, radiotherapy and surgery. Recently, immunotherapy has been added as a mainstay for therapy of CRC. The main checkpoint inhibitors used in CRC immunotherapy are pembrolizumab and nivolumab (anti-PD-1), durvalumab (anti-PD-L1), ipilimumab (anti-CTLA-4), favezelimab (anti-LAG3), etc. They are applied after fluorapyrimidine, oxaliplain, and irinotecan therapy. In conclusion, we may state that the future treatment of MSS CRC is in combination therapies, i.e. conventional and immunotherapies. We consider that immune infiltrate in TME must be assessed in order to determine combination therapies.

Introduction: Basal cell carcinoma (BCC) is treated with local surgery or noninvasive treatment modalities. If a BCC remains untreated, it can develop into a locally advanced BCC or a metastatic BCC. Case Presentation: Here we report in detail the management of three complex advanced BCC (aBCC) after treatment failure with vismodegib. On all tumors, next generation DNA sequencing in the Center for Personalized Cancer Treatment-02 (CPCT-02) study was performed; subsequently, patients were included in the Drug Rediscovery Protocol (DRUP) trial, in which treatment was started with commercially available targeted anticancer drugs based on the molecular tumor profile. All patients showed partial response or stable disease following treatment with second line PD-1 inhibitors with an average duration of response of 12.3 months. Discussion/Conclusion: Immunotherapy can be a treatment option for aBCC resistant to hedgehog pathway inhibitor treatment. However, despite the high tumor mutational burden of aBCCs, immunotherapy does not always lead to a long response. Rechallenge or combining treatment of hedgehog inhibitors and PD-1 inhibitors by parallel or alternating cycles may be a strategy to lengthen the treatment response.

Immune-mediated diarrhea represents a serious complication of checkpoint inhibitor therapy, especially following ipilimumab-based treatment. Efficient diagnosis and control of diarrhea remains an ongoing challenge. We developed an accelerated management paradigm for patients with ipilimumab-induced diarrhea. Patients who developed significant diarrhea (>five loose stools/day) were presumed to be developing immune colitis. Therapy was interrupted and patients were treated with a methylprednisolone dose pack. If diarrhea was not completely resolved, high-dose steroids and infliximab were promptly added. Only non-responding patients underwent further evaluation for infection or other causes of diarrhea. A total of 242 patients were treated with ipilimumab-based regimens. Forty-six developed significant diarrhea (19%) and thirty-four (74.4%) had a rapid resolution of diarrhea following glucocorticosteroid and infliximab treatment. The median time to resolution of diarrhea was only 8.5 ± 16.4 days. Accelerated treatment for presumed immune-mediated diarrhea resulted in the rapid control of symptoms in the majority of patients. There were no intestinal complications or deaths. Immunosuppressive therapy for diarrhea did not appear to decrease the remission rate or survival. After the control of diarrhea, most patients were able to continue their planned immunotherapy. Further testing in 11/46 patients with unresponsive diarrhea revealed additional diagnoses, allowing their treatment to be adjusted.

Abstract Angiosarcomas are rare, aggressive tumours with a propensity for the head and neck region. Surgery is the mainstay of treatment of localised angiosarcoma, but in unresectable or metastatic disease, the treatment is much more challenging. Traditionally, chemotherapy (Paclitaxel in particular) has been the treatment of choice. Evidence from case reports and small trials shows that PD1 inhibitors have activity against angiosarcomas, despite the lack of a large clinical trial data demonstrating definitive efficacy. The present case exemplifies the susceptibility of this malignancy to anti‐PD1 agents. We report a 77‐year‐old male patient with an advanced, multifocal angiosarcoma of the frontotemporal and malar region. The patient was pretreated using the association of Propranolol and Endoxan and then Paclitaxel. Because of the lack of efficacy, the patient was started on Nivolumab as the third line of therapy. After five cycles of immunotherapy, an excellent response was achieved, with complete remission of the cutaneous lesions as well as a partial remission of the hepatic nodules. The duration of response is currently 14 months, the patient being still alive at the present time. This case suggests that immune checkpoint inhibitors may represent a viable therapeutic option that needs further exploration for the treatment of locally advanced, unresectable or metastatic cases of cutaneous angiosarcoma.

Introduction: Basal cell carcinoma (BCC) is treated with local surgery or noninvasive treatment modalities. If a BCC remains untreated, it can develop into a locally advanced BCC or a metastatic BCC. Case Presentation: Here we report in detail the management of three complex advanced BCC (aBCC) after treatment failure with vismodegib. On all tumors, next generation DNA sequencing in the Center for Personalized Cancer Treatment-02 (CPCT-02) study was performed; subsequently, patients were included in the Drug Rediscovery Protocol (DRUP) trial, in which treatment was started with commercially available targeted anticancer drugs based on the molecular tumor profile. All patients showed partial response or stable disease following treatment with second line PD-1 inhibitors with an average duration of response of 12.3 months. Discussion/Conclusion: Immunotherapy can be a treatment option for aBCC resistant to hedgehog pathway inhibitor treatment. However, despite the high tumor mutational burden of aBCCs, immunotherapy does not always lead to a long response. Rechallenge or combining treatment of hedgehog inhibitors and PD-1 inhibitors by parallel or alternating cycles may be a strategy to lengthen the treatment response. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B cell lymphoma is the most common type of B cell neoplasm, and can be cured by traditional chemoimmunotherapy in 60–70% of cases. Relapsed/refractory patients usually have a dismal prognosis and most of them finally succumb to lymphoma. In the last decade, several new innovative therapies have been approved against DLBCL, targeting both surface antigens and the intracellular pathways of neoplastic B cells. Compared to standard chemotherapy, new monoclonal antibodies and engineered T cells have shown an increased response rate, progression-free survival and overall survival, but, on the other side of the coin, patients have been experiencing new kinds of toxicities, previously unknown, that clinicians have been learning to manage. Here, we review new drugs that are already approved or under investigation for DLBCL and the corresponding molecular target on lymphoma cells. Since the introduction of rituximab in the late 1990s, significant progress has been made in advancing targeted therapies for B cell lymphomas, improving patients' chance of being cured and clinicians' therapeutic armamentarium. A better understanding of disease biology and pathogenic pathways, coupled with refinements in immunophenotypic and molecular diagnostics, have been instrumental in these achievements. While traditional chemotherapy remains fundamental in most cases, concerns surrounding chemorefractoriness and cumulative toxicities, particularly the depletion of the hemopoietic reserve, underscore the imperative for personalized treatment approaches. Integrating targeted agents, notably monoclonal antibodies, alongside chemotherapy has yielded heightened response rates and prolonged survival. A notable paradigm shift is underway with innovative-targeted therapies replacing cytotoxic drugs, challenging conventional salvage strategies like stem cell transplantation. This review examines the landscape of emerging targets for lymphoma cells and explores innovative therapies for diffuse large B cell lymphoma (DLBCL). From Chimeric Antigen Receptor-T cells to more potent monoclonal antibodies, antibody–drug conjugates, bispecific antibodies, checkpoint inhibitors, and small molecules targeting intracellular pathways, each modality offers promising avenues for therapeutic advancement. This review aims to furnish insights into their potential implications for the future of DLBCL treatment strategies. [ABSTRACT FROM AUTHOR]

Globally, the efforts to find the best cancer treatment are demanding and very intensive. Immunotherapy has gained an important role as a second or sometimes first line of treatment for various types of cancer. PD-1/PD-L1 checkpoint inhibitors are an impending category of immunotherapy, and their mechanism, as well as their interaction with T cells, are well studied. However, our knowledge about any possible effect(s) of immunotherapy on B cells is limited. In this prospective study, we asked the question of any possible alterations of circulating B cells (numbers and subsets) occurring during immunotherapy in patients with cancer and of the potential correlation of such changes with the outcomes and with development of immune-related adverse events (irAEs). We enrolled 20 cancer patients who received PD-1 checkpoint inhibitors and 8 healthy donors (HD). Patients underwent regular clinical assessment and imaging using the iRECIST criteria for 6 months following immunotherapy. Peripheral blood samples were collected before and during PD-1 checkpoint inhibitor therapy, and flow cytometry analysis of peripheral blood mononuclear cells (PBMCs) was performed, evaluating various circulating B cell subset phenotypes, including mature naïve B cells, memory B cells, regulatory B cells (Bregs), antibody-secreting cells (ASCs), and age-related B cells (ABCs). Statistical analysis was employed to compare the differences of B cells between different groups and among sequential data within the same group. Total circulating CD19+ B cell counts remained stable across both groups (responders (R), nonresponders (NR)) and timepoints. However, there was a significant rise in mature naïve B cells and decline in memory B cells at the initiation of the treatment in the R group compared to healthy donors and to the NR group. Such changes were correlated with a good response to immunotherapy. On the contrary, higher numbers of ABCs at baseline were seen in the NR group and were correlated with resistance to treatment. As far as immune-related adverse events are concerned, no significant changes were recorded among the different B cell subpopulations evaluated in both groups. Our study provides preliminary data suggesting that B cell subset changes during immunotherapy may correlate with immune checkpoint inhibitor-induced clinical responses in patients with neoplasia. Further investigations to delineate the potential role(s) of B cells in patients undergoing immunotherapy are needed. [ABSTRACT FROM AUTHOR]

Background: Epidemiological data reveal that 45% of persons with multiple sclerosis (PwMS) in France are more than 50 years. This population more than 50 is more susceptible to cancer, and this risk may be increased by frequent use of immunosuppressive drugs. Consequently, concerns have arisen about the potential increased risk of cancer in PwMS and how patients should be screened and managed in terms of cancer risk. Objective: To develop evidence-based recommendations to manage the coexistence of cancer and multiple sclerosis (MS). Methods: The French Group for Recommendations in MS collected articles from PubMed and university databases covering the period January 1975 through June 2022. The RAND/UCLA method was employed to achieve formal consensus. MS experts comprehensively reviewed the full-text articles and developed the initial recommendations. A group of multidisciplinary health care specialists then validated the final proposal. Results: Five key questions were addressed, encompassing various topics such as cancer screening before or after initiating a disease-modifying therapy (DMT), appropriate management of MS in the context of cancer, recommended follow-up for cancer in patients receiving a DMT, and the potential reintroduction of a DMT after initial cancer treatment. A strong consensus was reached for all 31 recommendations. Conclusion: These recommendations propose a strategic approach to managing cancer risk in PwMS. [ABSTRACT FROM AUTHOR]

Immune-mediated diarrhea represents a serious complication of checkpoint inhibitor therapy, especially following ipilimumab-based treatment. Efficient diagnosis and control of diarrhea remains an ongoing challenge. We developed an accelerated management paradigm for patients with ipilimumab-induced diarrhea. Patients who developed significant diarrhea (>five loose stools/day) were presumed to be developing immune colitis. Therapy was interrupted and patients were treated with a methylprednisolone dose pack. If diarrhea was not completely resolved, high-dose steroids and infliximab were promptly added. Only non-responding patients underwent further evaluation for infection or other causes of diarrhea. A total of 242 patients were treated with ipilimumab-based regimens. Forty-six developed significant diarrhea (19%) and thirty-four (74.4%) had a rapid resolution of diarrhea following glucocorticosteroid and infliximab treatment. The median time to resolution of diarrhea was only 8.5 ± 16.4 days. Accelerated treatment for presumed immune-mediated diarrhea resulted in the rapid control of symptoms in the majority of patients. There were no intestinal complications or deaths. Immunosuppressive therapy for diarrhea did not appear to decrease the remission rate or survival. After the control of diarrhea, most patients were able to continue their planned immunotherapy. Further testing in 11/46 patients with unresponsive diarrhea revealed additional diagnoses, allowing their treatment to be adjusted. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) has become one of the leading causes of cancer-related morbidity and mortality worldwide. Immune checkpoint inhibitors (ICIs) and adoptive cell therapy (ACT) have been recently added to the clinical armamentarium of stage II/III diseases. Moreover, the improvement of a patient's telomere status may have a synergistic effect along with ICIs/ACT. This can be achieved either via lifestyle modifications with increased physical activity or with new promising treatments such as those acting on telomerase. Therefore, this review aims to comprehensively summarize the current data on immunotherapy in order to facilitate clinicians' familiarity with this relatively new therapeutic approach. Cancer of the colon and rectum (CRC) has been identified among the three most prevalent types of cancer and cancer-related deaths for both sexes. Even though significant progress in surgical and chemotherapeutic techniques has markedly improved disease-free and overall survival rates in contrast to those three decades ago, recent years have seen a stagnation in these improvements. This underscores the need for new therapies aiming to augment patient outcomes. A number of emerging strategies, such as immune checkpoint inhibitors (ICIs) and adoptive cell therapy (ACT), have exhibited promising outcomes not only in preclinical but also in clinical settings. Additionally, a thorough appreciation of the underlying biology has expanded the scope of research into potential therapeutic interventions. For instance, the pivotal role of altered telomere length in early CRC carcinogenesis, leading to chromosomal instability and telomere dysfunction, presents a promising avenue for future treatments. Thus, this review explores the advancements in CRC immunotherapy and telomere-targeted therapies, examining potential synergies and how these novel treatment modalities intersect to potentially enhance each other's efficacy, paving the way for promising future therapeutic advancements. [ABSTRACT FROM AUTHOR]

The DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication. MMR-deficiency (MMR-D) leads to microsatellite instability (MSI) associated with an increased mutation rate, driving cancer development. This is particularly relevant in endometrial cancer (EC) as 25%-30% of tumors are of MMR-D/MSI-high (MSI-H) phenotype. Comprehensive assessment using immunohistochemistry (IHC) and sequencing-based techniques are necessary to fully evaluate ECs given the importance of molecular subtyping in staging and prognosis. This also influences treatment selection as clinical trials have demonstrated survival benefits for immune checkpoint inhibitors (ICIs) alone and in combination with chemotherapy for MMR-D/MSI-H EC patients in various treatment settings. As a portion of MMR-D/MSI-H ECs are driven by Lynch syndrome, an inherited cancer predisposition syndrome that is also associated with colorectal cancer, this molecular subtype also prompts germline assessment that can affect at-risk family members. Additionally, heterogeneity in the tumor immune microenvironment and tumor mutation burden (TMB) have been described by MMR mechanism, meaning MLH1 promoter hypermethylation versus germline/somatic MMR gene mutation, and this may affect response to ICI therapies. Variations by ancestry in prevalence and mechanism of MMR-D/MSI-H tumors have also been reported and may influence health disparities given observed differences in tumors of Black compared to White patients which may affect ICI eligibility. These observations highlight the need for additional prospective studies to evaluate the nuances regarding MMR-D heterogeneity as well as markers of resistance to inform future trials of combination therapies to further improve outcomes for patients with EC. [ABSTRACT FROM AUTHOR]

Simple Summary: Corticosteroid use for the treatment of immune related adverse events (irAEs) after immune checkpoint inhibitor (ICI) use comes with concerns of side effects and the potential abrogation of antitumor immunity. Relatedly, the impact of steroid-sparing immunosuppressive agents (SSIAs) for treatment of irAEs on tumor outcomes is not well known, and current literature on this topic is limited by study design and issues around immortal time bias. This retrospective case-control study accounts for immortal time bias via strategic statistical methodology. Our results suggest that SSIAs used for irAE treatment may not negatively impact cancer outcomes in malignant melanoma and non-small cell lung cancer. For patients with melanoma, our results demonstrated better progression free survival for patients treated with infliximab compared to patients treated with corticosteroid monotherapy for irAEs. This study supports the safety for utilizing SSIAs for irAE treatment in patients receiving immune checkpoint inhibitors. Our study also encourages accounting for immortal time bias in the design of other observational studies in this space to accurately convey results and draw clinically meaningful conclusions. Background: The effects of steroid-sparing immunosuppressive agents (SSIAs), used for the treatment of immune-related adverse events (irAEs), on immune checkpoint inhibitor (ICI) antitumor activity is not well known. We compared tumor outcomes of patients who received corticosteroid monotherapy (CS) versus a corticosteroid plus SSIA (CS-SSIA) for irAE treatment, using statistical methods to address immortal time bias. Methods: We conducted a retrospective case-control study on patients ≥ 18 years with melanoma or non-small-cell lung cancer (NSCLC) treated with ≥1 ICI at a quaternary care center between 1 January 2016 and 11 January 2021. Patients were divided into two cohorts: CS or CS-SSIA. We used propensity score nearest-neighbor matching to match on tumor type, stage, and prior lines of therapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included the time from the start of the irAE treatment to the irAE resolution. Hazard ratios (HRs) for PFS and OS were calculated using the Cox proportional hazard regression method with both (1) the time to the steroid and SSIA as time-varying covariates and (2) a binary exposure classification not accounting for the time to the treatment. Results: A total of 167 patients were included after matching (132 in the CS cohort and 35 in the CS-SSIA cohort). Sixty-six percent of all the patients had melanoma. The most common irAEs requiring treatment were gastroenterocolitis and hepatitis. In an adjusted analysis not accounting for immortal time bias, there were no significant differences in PFS (HR 0.75, 95% CI [0.46–1.23]) or OS (HR 0.82, 95% CI [0.46–1.47]). In analyses using a time-varying treatment indicator, there was a trend toward improved PFS in patients treated with SSIAs (HR 0.54, CI 0.26–1.10). There was no difference in OS (HR 1.11, CI 0.55–2.23). Patients with melanoma who specifically received infliximab had improved PFS compared to patients with CS only, after adjusting for immortal time bias (HR 0.32, CI 0.24–0.43). Conclusions: The use of SSIAs with CS did not have worse outcomes than CS monotherapy. In melanoma, our findings showed improved PFS for the use of infliximab versus steroid monotherapy for irAEs. Large, prospective, randomized controlled trials are needed to confirm these findings and guide the optimal treatment of irAEs. [ABSTRACT FROM AUTHOR]

Primary liver cancer, represented mainly by hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA), is one of the most common and deadliest tumors worldwide. While surgical resection or liver transplantation are the best option in early disease stages, these tumors often present in advanced stages and systemic treatment is required to improve survival time. The emergence of immune checkpoint inhibitor (ICI) therapy has had a positive impact especially on the treatment of advanced cancers, thereby establishing immunotherapy as part of first-line treatment in HCC and CCA. Nevertheless, low response rates reflect on the usually cold or immunosuppressed tumor microenvironment of primary liver cancer. In this review, we aim to summarize mechanisms of resistance leading to tumor immune escape with a special focus on the composition of tumor microenvironment in both HCC and CCA, also reflecting on recent important developments in ICI combination therapy. Furthermore, we discuss how combination of ICIs with established primary liver cancer treatments (e.g. multikinase inhibitors and chemotherapy) as well as more complex combinations with state-of-the-art therapeutic concepts may reshape the tumor microenvironment, leading to higher response rates and long-lasting antitumor immunity for primary liver cancer patients. [ABSTRACT FROM AUTHOR]

Summary: Immune checkpoint blocking therapy targeting the PD‐1/PD‐L1 inhibitory signalling pathway has produced encouraging results in the treatment of a variety of cancers. Durvalumab (Imfinzi®) targeting PD‐L1 is currently used for immunotherapy of several tumour malignancies. The Fc region of this IgG1 antibody has been engineered to reduce FcγR interactions with the aim of enhancing blockade of PD‐1/PD‐L1 interactions without the depletion of PD‐L1‐expressing immune cells. Here, we used Nicotiana benthamiana to produce four variants of Durvalumab (DL): wild‐type IgG1 and its 'Fc‐effector‐silent' variant (LALAPG) carrying further modifications to increase antibody half‐life (YTE); IgG4S228P and its variant (PVA) with Fc mutations to decrease binding to FcγRI. In addition, DL variants were produced with two distinct glycosylation profiles: afucosylated and decorated with α1,6‐core fucose. Plant‐derived DL variants were compared to the therapeutic antibody regarding their ability to (i) bind to PD‐L1, (ii) block PD‐1/PD‐L1 inhibitory signalling and (iii) engage with the neonatal Fc receptor (FcRn) and various Fcγ receptors. It was found that plant‐derived DL variants bind to recombinant PD‐L1 and to PD‐L1 expressed in gastrointestinal cancer cells and are able to effectively block its interaction with PD‐1 on T cells, thereby enhancing their activation. Furthermore, we show a positive impact of Fc amino acid mutations and core fucosylation on DL's therapeutic potential. Compared to Imfinzi®, DL‐IgG1 (LALAPG) and DL‐IgG4 (PVA)S228P show lower affinity to CD32B inhibitory receptor which can be therapeutically favourable. Importantly, DL‐IgG1 (LALAPG) also shows enhanced binding to FcRn, a key determinant of serum half‐life of IgGs. [ABSTRACT FROM AUTHOR]

Purpose of Review: Immune checkpoint inhibitor (ICI) use has been on the rise for treatment of many different malignancies. Subsequently, more has been learned about immune-related adverse events (irAEs) that occur up to 12 months after treatment. This review summarizes the latest findings and management of neuro-ophthalmic associated irAEs. Recent Findings: irAEs can affect the afferent and efferent neuro-ophthalmic pathways, thereby targeting central and peripheral nervous systems. As more cases are being reported, it is becoming apparent that neuro-ophthalmic irAEs often present with atypical features when compared to their spontaneous autoimmune counterparts. These neuro-ophthalmic presentations can also be signs of a more extensive inflammatory process that spans other organ systems, such as myopathies, endocrinopathies, and paraneoplastic syndromes. Summary: Awareness of neuro-ophthalmic irAEs and their atypical presentations can lead to early detection, termination of ICI treatment, and immunosuppressant therapy initiation. [ABSTRACT FROM AUTHOR]

Objective To conduct a multicenter case series characterizing the clinical characteristics at presentation and pancreatic volume changes of patients with checkpoint inhibitor-associated autoimmune diabetes (CIADM). Research Design and Methods Electronic medical records were reviewed with 36 consecutive patients identified with CIADM, as defined by (1) previous immune checkpoint inhibitor (ICI) therapy, (2) new-onset hyperglycemia (blood glucose level ≥ 11.1 mmol/L and/or glycosylated hemoglobin ≥ 6.5%), and (3) insulin deficiency [C-peptide <0.4 nmol/L or diabetic ketoacidosis (DKA)] within 1 month of presentation. Pancreatic volume was available and measured using computed tomography volumetry for 17 patients with CIADM and 3 sets of control patients: 7 with ICI-related pancreatitis, 13 with asymptomatic ICI-related lipase elevation, and 11 ICI-treated controls for comparison. Results All patients had either anti-programmed cell death protein 1 or anti-programmed cell death ligand 1 therapy. Median time from ICI commencement to CIADM diagnosis was 15 weeks. At presentation, 25 (69%) had DKA, 27 (84%) had low C-peptide, and, by 1 month, 100% had low C-peptide. Traditional type 1 diabetes autoantibodies were positive in 15/35 (43%). Lipase was elevated in 13/27 (48%) at presentation. In 4 patients with longitudinal lipase testing, elevated levels peaked 1 month prior to CIADM diagnosis. Pancreatic volume was lower pre-ICI in CIADM patients compared with controls and demonstrated a mean decline of 41% from pretreatment to 6 months post-CIADM diagnosis. Conclusion Pronounced biochemical and radiologic changes occur during CIADM pathogenesis. Rapid loss of C-peptide is a distinct characteristic that can be used to aid diagnosis as autoantibodies are often negative. [ABSTRACT FROM AUTHOR]

Drug-induced myopathies are a common cause of muscle pain, and the range of drugs that can cause muscle side effects is constantly expanding. In this article, the authors comprehensively discuss the diagnostic and therapeutic process in patients with myalgia, and present the spectrum of drug-induced myopathies. The review provides a detailed analysis of the literature on the incidence of myopathy during treatment with hypolipemic drugs, beta-blockers, amiodarone, colchicine, glucocorticosteroids, antimalarials, cyclosporine, zidovudine, and checkpoint inhibitors, a group of drugs increasingly used in the treatment of malignancies. The article considers the clinical course of the different types of myopathies, their pathogenesis, histopathological features, and treatment methods of these disorders. The aim of this paper is to gather from the latest available literature up-to-date information on the course, pathophysiology, and therapeutic options of drug-induced myopathies, to systematize the knowledge of drug-induced myopathies and to draw the attention of internists to the fact that these clinical issues are an important therapeutic problem. [ABSTRACT FROM AUTHOR]

Over the past three decades, the treatment of lymphoproliferative disorders has undergone profound changes, notably due to the increasing availability of innovative therapies with the potential to redefine clinical management paradigms. A major impact is related to the development of monoclonal antibodies, checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T (CAR-T) cell therapies. This review discusses the current landscape of clinical trials targeting various hematological malignancies, highlighting promising early-phase results and strategies to overcome resistance. Lymphoproliferative disorders encompass a range of conditions: while in Hodgkin lymphoma (HL) the goal is to reduce chemotherapy-related toxicity by integrating immunotherapy into the frontline setting, peripheral T cell lymphoma (PTCL) lacks effective targeted therapies. The review emphasizes a shifting therapeutic landscape towards precision medicine and treatment modalities that are less toxic yet more effective. [ABSTRACT FROM AUTHOR]

Interleukin-21 (IL-21) is an immunostimulatory cytokine which belongs to the common gamma-chain family of cytokines. It plays an import role in the development, differentiation, proliferation, and activation of immune cells, in particular T and natural killer (NK) cells. Since its discovery in 2000, IL-21 has been shown to regulate both adaptive and immune responses associates with key role in antiviral and antitumor responses. Recent advances indicate IL-21 as a promising target for cancer treatment and encouraging results were obtained in preclinical studies which investigated the potency of IL-21 alone or in combination with other therapies, including monoclonal antibodies, checkpoint inhibitory molecules, oncolytic virotherapy, and adoptive cell transfer. Furthermore, IL-21 showed antitumor effects in the treatment of patients with advanced cancer, with minimal side effects in several clinical trials. In the present review, we will outline the recent progress in IL-21 research, highlighting the potential of IL-21 based therapy as single agent or in combination with other drugs to enhance cancer treatment efficiency. [ABSTRACT FROM AUTHOR]

The incidence and prevalence of drug-induced liver injury appear to be increasing globally, for example, with the introduction of checkpoint inhibitors. Several reviews have been published in the last decade on the epidemiology of DILI, both among hospitalized patients and in the general population, as well as from retrospective and prospective studies on DILI. Most of these reviews have not focused on newly recognized agents that have recently changed the landscape of DILI. Apart from liver injury associated with antibiotics, oncological agents, particularly checkpoint inhibitors, are increasingly being recognized as causing liver injury. The type of liver injury associated with these agents is not idiosyncratic but rather an indirect type of injury. Furthermore, recently, COVID-19 vaccines and green tea extract have been found to lead to liver injury. Checkpoint inhibitors have revolutionized the treatment of many malignancies, such as malignant melanoma, lung cancer, and renal cancer. Via the activation of T cells, they can increase immune activity against malignant cells, but at the same time, they can decrease immune tolerance and therefore lead to immune-related adverse effects in many organs. The most common adverse effect in clinical practice is liver injury. A recent prospective study demonstrated an 8% frequency of DILI due to the use of checkpoint inhibitors among patients with malignant melanoma and renal cancer. This rate is much higher than observed with drugs, leading to idiosyncratic liver injury. Shortly after the implementation of the worldwide vaccination program against COVID-19, several case reports were published on suspected vaccination-induced autoimmune-like hepatitis occurring shortly after the vaccination. At first, these reports were met with skepticism, but currently, around 100 reports have been published, and cases of positive recurrence have been reported. The clinical, biochemical, immunological, and histological features are indistinguishable from classic autoimmune hepatitis (AIH). These reactions are very similar to drug-induced autoimmune-like hepatitis (DI-ALH) due to drugs such as nitrofurantoin, minocycline, and infliximab, which do not relapse after a short course of corticosteroids, which is the general rule in classic autoimmune hepatitis (AIH). Green tea extract has been found to be a well-documented cause of acute hepatocellular liver injury with jaundice. A strong HLA association has been reported, showing a high prevalence of HLA-B*35:01 among patients suffering from green tea-induced liver injury. Overall, 3% of patients recruited in the DILIN study were supplemented with green tea extract as one of the ingredients. In a prospective population-based study from Iceland, green tea was implicated in approximately 8% of patients with DILI. [ABSTRACT FROM AUTHOR]

The International Immunosuppression and Transplant Skin Cancer Collaborative (ITSCC) and its European counterpart, Skin Care in Organ Transplant Patients-Europe (SCOPE) are comprised of physicians, surgeons, and scientist who perform integrative collaborative research focused on cutaneous malignancies that arise in solid organ transplant recipients (SOTR) and patients with other forms of long-term immunosuppression. In October 2022, ITSCC held its biennial 4-day scientific symposium in Essex, Massachusetts. This meeting was attended by members of both ITSCC and SCOPE and consisted of specialists including Mohs micrographic and dermatologic oncology surgeons, medical dermatologists, transplant dermatologists, transplant surgeons, and transplant physicians. During this symposium scientific workshop groups focusing on consensus standards for case reporting of retrospective series for invasive squamous cell carcinoma (SCC), defining immunosuppressed patient status for cohort reporting, development of multi-institutional registry for reporting rare tumors, and development of a KERACON clinical trial of interventions after a SOTRs' first cutaneous SCC were developed. The majority of the symposium focused on presentation of the most up to date research in cutaneous malignancy in SOTR and immunosuppressed patients with specific focus on chemoprevention, immunosuppression regimens, immunotherapy in SOTRs, spatial transcriptomics, and the development of cutaneous tumor registries. Here, we present a summary of the most impactful scientific updates presented at the 2022 ITSCC symposium. [ABSTRACT FROM AUTHOR]

Immuno-oncology (IO) therapies have changed the cancer treatment landscape. Immune checkpoint inhibitors (ICIs) have improved overall survival in 20–40% of patients with malignancies that were previously refractory. Due to the uniqueness in biology, modalities and patient responses, drug development strategies for IO differed from that traditionally used for cytotoxic and target therapies in oncology, and quantitative pharmacology utilizing modeling approach can be applied in all phases of the development process. In this review, we used case studies to showcase how various modeling methodologies were applied from translational science and dose selection through to label change, using examples that included anti-programmed-death-1 (anti-PD-1), anti-programmed-death ligand-1 (anti-PD-L1), anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), and anti-glucocorticoid-induced tumor necrosis factor receptor-related protein (anti-GITR) antibodies. How these approaches were utilized to support phase I–III dose selection, the design of phase III trials, and regulatory decisions on label change are discussed to illustrate development strategies. Model-based quantitative approaches have positively impacted IO drug development, and a better understanding of the biology and exposure–response relationship may benefit the development and optimization of new IO therapies. [ABSTRACT FROM AUTHOR]

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Context Few meta-analyses on incidence of endocrine immune-related adverse effects (eirAEs) have been published and many trials have been published since. Objective We performed a comprehensive meta-analysis with updated literature to assess risk and incidence of eirAEs of any grade and grade 3 to 5 by immune checkpoint inhibitor (ICI) monotherapy or combination therapy in solid tumors. Methods An electronic search using PubMed/Medline, Embase, and the Cochrane Library was performed. Randomized controlled studies (RCTs) assessing eirAEs under ICI monotherapy or ICI combination therapy were selected. Stata software (v17) was used for statistical analyses and risk of bias was evaluated using Review Manager version 5.3. Results A total of 69 RCTs with 80 independent reports, involving 42 886 patients, were included in the study. Meta-analysis revealed the following pooled estimates for risk ratio and incidence, respectively: for any grade hypothyroidism 7.81 (95% CI, 5.68-10.74, P <.0001) and 7.64% (95% CI, 6.23-9.17, P <.0001); significantly increased also for hyperthyroidism, hypophysitis/hypopituitarism, and adrenal insufficiency; and for insulin-dependent diabetes mellitus 1.52 (95% CI, 1.07-2.18, P =.02), and 0.087% (95% CI, 0.019-0.189, P =.0006), respectively. Meta-regression showed that combination of ICIs (nivolumab plus ipilimumab; durvalumab plus tremelimumab) is an independent risk factor for any grade hypophysitis/hypopituitarism, and that ICI agent is an independent factor of risk for adrenal insufficiency, but that cancer type is not an independent risk factor for eirAEs. Conclusion We showed that risk, independent from cancer type, and incidence of eirAEs are substantially increased with ICI therapy. Combination of ICIs increases risk for eirAEs, especially for hypophysitis/hypopituitarism. [ABSTRACT FROM AUTHOR]