Systemic Immunotherapy Research Articles

Characterization of Immune Infiltrates Associated with Radiation Necrosis in the Setting of Brain Metastases Following Stereotactic Radiosurgery and Immunotherapy

<h3>Purpose/Objective(s)</h3> Radiation necrosis (RN) represents an inflammatory sequel and hyalinization secondary to radiotherapy (RT). The impact of immunotherapy on immune cellular microenvironment in patients with brain metastasis (BM) is unknown. The objective of this study was to characterize the inflammatory microenvironment in the setting of RN compared to recurrent tumor and determine whether immunotherapy treatment affects cellular infiltrates. <h3>Materials/Methods</h3> Adult patients with BM from solid tumors who received both systemic immunotherapy (IO) and radiotherapy (RT) who then underwent resection for progressively enlarging abnormality following IO+RT were retrospectively analyzed. A group of BM patients who developed RN confirmed by surgery and who did not receive IO was reviewed as control. Surgical specimens were stained for immune and inflammatory components and reviewed by a neuro-pathologist who remained blinded during the analysis. The presence or absence of lymphocytes, cuffing, plasma cells, macrophages, and fibrinoid were used as surrogates of immune infiltrate and were characterized in a semiquantitative manner. <h3>Results</h3> A total of 18 patients were categorized into 1 of 3 groups: (1) Necrosis, IO+RT (2) Tumor, IO+RT (3) Necrosis, RT. The median age was 61.5 years (range 37-82 years). 77% of primary cancers were melanoma. Review of surgical specimens demonstrated a higher but not statistically significant extent of immune infiltrates in the groups with RN when compared to the group with tumor recurrence. Higher lymphocytes, cuffing, and macrophages were found in "Necrosis, IO+RT" patients compared to "Tumor, IO+RT" patients (83.3% and 16.7%, respectively). Further analysis demonstrated 100% of "Necrosis, IO+RT" patients have quantifiable cell counts while 83.3% of "Tumor, IO+RT" patients do not have quantifiable cell counts. <h3>Conclusion</h3> The immune microenvironment of BM following radiotherapy and immunotherapy shows higher levels of cell infiltrates in the RN setting versus recurrent tumor setting. Lower level of presence of immune cells in tumor recurrence following IO+RT may suggest an environment lacking primed immune cells with implication to potential decreased efficacy in immunotherapy.

Clinical Factors Associated with Radionecrosis Following Stereotactic Radiosurgery in the Era of Modern Systemic Therapy

<h3>Purpose/Objective(s)</h3> Stereotactic radiosurgery (SRS) is commonly utilized in the treatment of brain metastases; however, radiation necrosis (RN) is a dose-limiting toxicity. Systemic therapy has greatly improved in recent years with the advent of immunotherapy and targeted therapy leading to increased overall survival. Here, we examined the impact of clinical factors on development of RN after SRS for brain metastasis in the era of modern systemic therapy. <h3>Materials/Methods</h3> We retrospectively reviewed patients treated with Linac-based SRS at a single institution from 2015-2020. Overall survival was calculated using the Kaplan-Meier method. Univariable (UVA) and multivariable (MVA) analysis was performed using Cox proportional hazards modeling. Covariates included age, sex, race, ethnicity, ECOG, primary cancer site, neurologic deficits at diagnosis, seizures, number/size of tumors, benign vs. malignant disease, prior systemic therapy, post-op vs. intact SRS, whole brain radiotherapy before or after SRS, edema at diagnosis, receipt and timing of immunotherapy/targeted therapy. Concurrent therapy was defined as within 30 days of SRS. <h3>Results</h3> 412 patients treated with SRS to 950 lesions were identified at a median follow-up of 8 months. Median age was 63 (interquartile range [IQR] 54-70) with 90% ECOG 0-1. At presentation, 53% had neurologic deficits and 7.6% had seizures. 82% were treated for malignant disease. 30% received post-op SRS. Prior to SRS, treatment included 1-9 lines of systemic therapy (58%), immunotherapy (24%), and WBRT (7.4%). SRS was given for 1-5 lesions in 91% of patients. Median tumor diameter was 2.0 cm (IQR 1.2-2.8). Median OS was 35 months (95% confidence interval [CI] 21-50); 1- and 2-year OS were 68% (95% CI 75-84) and 54% (95% CI 63-73). 17% developed radiographic RN with a median time to RN of 10 months (95% CI 9-13). Of 68 patients who developed RN, those with clinical symptoms (65%) were successfully treated with steroids (65%), laser interstitial thermal therapy (47%), bevacizumab (10%), and craniotomy (21%). On UVA, factors predictive of time to RN included post-op SRS (HR 1.84, 95% CI 1.12-3.00, p=0.015), number of treated lesions (HR 1.11, 95% CI 1.03-1.21, p=0.011), size of largest lesion (HR 1.46, 95% CI 1.17-1.81, p=0.001), malignant tumor (HR 4.17, 95% CI 1.49-11.11, p=0.006), prior systemic therapy (HR 1.7, 95% CI 1.1-2.86, p=0.046), and vasogenic edema at diagnosis (HR 1.97, 95% CI 1.19-3.26, p=0.008). On MVA, for every 1 cm increase in diameter of the largest lesion, the likelihood of developing RN was increased 1.45-fold (95% CI 1.12-1.88, p=0.005). Timing of systemic therapy did not impact RN rate. <h3>Conclusion</h3> Our data demonstrate that RN occurs in ∼17% of patients at a median of 10 months following SRS and can be successfully managed with medical and surgical therapies. The strongest predictor of RN was the size of the treated tumor. Our findings highlight the need for continued clinical surveillance as improved systemic therapy leads to increased long-term survival.

Pembrolizumab (Keytruda)

&#x0D; CADTH recommends that Keytruda should be reimbursed by public drug plans for the adjuvant treatment of adult patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions if certain conditions are met.&#x0D; Keytruda should only be covered to treat patients aged 18 years and older with RCC of clear cell subtype and previous nephrectomy, with or without surgery to remove 1 or more metastases, who are at intermediate-high or high risk of the tumour returning, and without prior systemic therapy for advanced RCC. Patients should also be in relatively good health.&#x0D; Keytruda should only be reimbursed if prescribed by a clinician with experience in RCC management, in specialized clinics with expertise in systemic treatment and immunotherapy delivery, and if the price of Keytruda is reduced. Keytruda should not be used in combination with other adjuvant cancer treatments.&#x0D;

Gastrointestinal toxicity of systemic oncology immunotherapy

Systemic anti-cancer immunotherapy provides a substantial progress in options of current oncology treatment. Yet, this therapeutic approach is potentially associated with a significant gastrointestinal toxicity. The purpose of this paper is to provide a comprehensive review on pathogenesis, clinical features, dia gnostics and therapy of these toxicities. Review of current knowledge: Check-point inhibitors brought a major progress in anti-cancer immunotherapy and improved significantly prognosis of several malignancies (e. g. metastatic malignant melanoma, non-small-cell lung cancer, gastric and colorectal cancers in high-risk population associated with presence of pathogenic mutations, renal cell carcinoma, squamous cell carcinoma of the head and neck and urothelial carcinoma). They include monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4; e. g. ipilimumab, tremelimumab), programmed death-1 receptor (PD-1; e. g. pembrolizumab, nivolumab) and its ligand PD-L1 (e. gatezolizumab, avelumab). Chimeric antigen receptor (CAR) T-cell therapy is another new option for haematological malignancies and metastatic colorectal cancer. Major symptoms of gastrointestinal toxicity caused by systemic immunotherapy include diarrhoea (20-50%), entero-colitis (1-10%) and laboratory or clinical signs of hepatopathy (~10%). Anti-cancer immunotherapy can be also complicated by infections (Clostridium difficile, Mycoplasma and/ or cytomegalovirus). There is no data on other possible complications so far. However, it can be assumed that these will also include bile acid malabsorption as well as small intestinal bacterial overgrowth syndrome. Treatment of gastrointestinal complications of immunotherapy should be graded according to their severity. It includes symptomatic medications (e. g. loperamide), systemic glucocorticoids and anti-TNF monoclonal antibodies (alone or together with mycofenolate mofetil or tacrolimus in the most severe cases). Awareness of possible complications of systemic anti-cancer immunotherapy is crucial for patients safety. It is mandatory to consider immune-related adverse events, complicating infections, bile acids malabsorption and small intestinal bacterial overgrowth syndrome. Prompt proper dia gnostics and immediate vigorous therapy infl uence the outcome of patients signifi cantly. A strictly individualized approach is indispensable.

Liver Metastasis Modulate Responses of Suppressive Macrophages and Exhausted T Cells to Immunotherapy Revealed by Single Cell Sequencing.

Liver metastasis is associated with immunotherapy resistance, although the underlying mechanisms remain incompletely understood. By applying single cell RNA-sequencing to a concurrent subcutaneous and liver tumor murine model to recapitulate liver metastases, it is identified that subsets within tumor-infiltrating exhausted CD8+ T (Tex) cells and immunosuppressive tumor-associated macrophages (TAMs) display opposite responses to concurrent liver tumors and anti-PD-1 treatment, suggesting a complex immune regulating network. Both angiogenic and interferon-reactive TAMs show increased frequencies in implanted liver tumors, and anti-PD-1 treatment further elevates the frequencies of angiogenic TAMs. Such TAMs frequencies negatively correlate with the proportions of cytotoxic T cell subsets. Further, expression of interferon-stimulated genes in TAMs is dramatically reduced under effective anti-PD-1 treatment, while such tendencies are diminished in mice with implanted liver tumors. Therefore, the study indicates that liver metastases could increase immunosuppressive TAMs frequencies and inhibit Tex responses to PD-1 blockade, resulting in compromised systemic antitumor immunity and limited immunotherapy efficacy.

Activating Innate Immunity by a STING Signal Amplifier for Local and Systemic Immunotherapy.

The number of patients who benefit from acquired immunotherapy is limited. Stimulator of interferon genes (STING) signal activation is a significant component to enhance innate immunity, which has been used to realize broad-spectrum immunotherapy. Here, M@P@HA nanoparticles, as a STING signal amplifier, are constructed to enhance innate immunotherapy. Briefly, when M@P@HA was targeted into tumor cells, the nanoparticles decomposed with Mn2+ and activated the release of protoporphyrin (PpIX). Under light irradiation, the generated reactive oxygen species disrupt the cellular redox homeostasis to lead cytoplasm leakage of damaged mitochondrial double-stranded (ds) DNA, which is the initiator of the STING signal. Simultaneously, Mn2+ as the immunoregulator could significantly increase the activity of related protein of a STING signal, such as cyclic GMP-AMP synthase (cGAS) and STING, to further amplify the STING signal of tumor cells. Subsequently, the STING signal of tumor-associated macrophages (TAM) is also activated by capturing dsDNA and Mn2+ that escaped from tumor cells, so as to enhance innate immunity. It is found that, by amplifying the STING signal of tumor tissue, M@P@HA could not only activate innate immunity but also cascade to activate CD8+ T cell infiltration even in a tumor with low immunogenicity.

A Systematic Review and Meta-Analysis of the Role of Immune Checkpoint Inhibitors (ICI) as Adjuvant Treatment for Localized High-Risk Muscle-Invasive Urothelial Carcinoma (MIUC).

Nivolumab, a PD-1 ICI has been recently approved for the adjuvant treatment of high-risk MIUC patients. However, conflicting data from another randomized controlled trial (RCT) with atezolizumab makes the benefit of this treatment uncertain. We performed a systematic review and study-level meta-analysis to evaluate the benefit in terms of disease-free survival (DFS) with ICI adjuvant treatment for patients with high-risk MIUC. Considering the Preferred Reporting Items for Systematic Review statement, a systematic search was performed in PUBMED/MEDLINE, Scopus and EMBASE up to October 30, 2021. The statistical analysis was performed by RevMan 5.4 software in intention-to-treat (ITT) population and in predetermined subgroups. Two RCTRCT, with a total of 1518 patients, met the inclusion criteria. Systemic immunotherapy was atezolizumab for 406 patients and nivolumab for 353 patients. In the ITT population there was a nonsignificant benefit with the systemic adjuvant immunotherapy (HR:0.79, 95% CI 0.62-1.00; z=2.00) but with high heterogeneity (I2=65%). Regarding the subgroups, there was no benefit in PD-L1 negative (HR:0.81, 95% CI 0.70-1.00; z=1.96, I2=0%) and in non-neoadjuvant chemotherapy (HR:0.95, 95% CI 0.78-1.15; z=0.56, I2=0%). Adjuvant treatment with ICI to patients with high-risk MIUC reveals a nonsignificant impact in DFS. The lack of clinical benefit was demonstrated in all subgroups. These data reinforce the need for a careful selection of patients before offering this approach in daily practice.

S2542 A Rare Case of Renal Cell Carcinoma Diagnosed on EGD

Introduction: Neoplasms of the duodenum account for a fraction of overall gastrointestinal tumors. Even when a lesion is found in the duodenum, it is more likely to be of secondary neoplastic origin than primary. Here we present a unique case of primary renal cell carcinoma (RCC) diagnosed on EGD. Case Description/Methods: A 55-year-old male with a history of alcohol use disorder presented to the emergency department for lightheadedness, fatigue, and 100-pound unintentional weight loss over 3 months. On exam, the patient was found to be hypotensive, tachycardic, and jaundiced. Laboratory values were pertinent for a Hemoglobin of 4.4 g/dl. After adequate resuscitation, esophagogastroduodenoscopy (EGD) was performed that showed a large partially obstructive, infiltrative, and ulcerated mass with no bleeding in the second part of the duodenum. Histology from the duodenal mass biopsy revealed clear cell carcinoma of renal origin with mucosal ulceration. An abdominal computerized tomography (CT) scan showed a heterogeneous, centrally necrotic right renal mass causing mass effect on the second and third portions of the duodenum, right hemicolon, and hepatic flexure. The scan was also suggestive of duodenal invasion by the mass. Solid pulmonary nodule biopsy was unequivocal for metastasis. The patient was discussed in tumor board and deemed to be a candidate for cytoreductive surgery with partial duodenal resection and systemic immunotherapy if metastasis was confirmed on future biopsies (Figure). Discussion: Duodenal metastasis from RCC is very rare and poses a diagnostic challenge. The most common presentation is with upper gastrointestinal hemorrhage or obstruction, though sometimes it can present with perforation, intussusception, or obstructive jaundice. Duodenal involvement is often from direct infiltration or metastatic spread. Delay in care and large tumor size are the likely reasons for the rare presentation seen in this patient. This case highlights the importance of considering all neoplasms of extraintestinal origin when duodenal lesions are identified endoscopically.Figure 1.: Left: 2nd portion of duodenum. Right: CT Abdomen/Pelvis.

Drug-related immune-mediated myelopathies.

Iatrogenic immune-mediated inflammatory disorders of the spinal cord are an uncommon but potentially severe complication of drug therapy for several human diseases. Particularly the introduction of novel biological agents in the treatment of systemic inflammatory disorders and cancer immunotherapy have led to a significant increase in immune-related adverse events of the central nervous system (CNS). The use of Tumor necrosis factor alpha (TNF-alpha) inhibitors in rheumatic and inflammatory bowel diseases has been associated with demyelinating and other inflammatory CNS conditions, including myelitis. The introduction of immune checkpoint inhibitors in the treatment of several human malignancies has led to an increase in drug-induced immune-related adverse events including in the CNS. Other drugs that have been associated with immune-mediated myelitis include tyrosine-kinase inhibitors and chimeric antigen receptor (CAR) T Cell therapy. A high degree of suspicion is necessary when diagnosing these conditions, as early diagnosis and treatment is crucial in preventing further neurological damage and disability. The treatment of drug-induced inflammatory myelitis typically involves administration of high-dose intravenous corticosteroids, however additional immunosuppressive agents may be required in severe or refractory cases. While most cases are monophasic and remit following discontinuation of the offending agent, chronic immunosuppressive therapy may be indicated in cases with a progressive or relapsing disease course or when a diagnosis of a specific underlying neuro-inflammatory disorder is made. Outcomes are generally favorable, however depend on the specific therapeutic agent used, the clinical presentation and patient factors. In this review we aim to describe the clinical characteristics, imaging findings and management for the most common forms of iatrogenic immune-mediated myelopathies.

Intratumoral delivery of TransCon™ TLR7/8 Agonist promotes sustained anti-tumor activity and local immune cell activation while minimizing systemic cytokine induction

BackgroundIntratumoral (IT) delivery of toll-like receptor (TLR) agonists has shown encouraging anti-tumor benefit in preclinical and early clinical studies. However, IT delivery of TLR agonists may lead to rapid effusion from the tumor microenvironment (TME), potentially limiting the duration of local inflammation and increasing the risk of systemic adverse events.MethodsTo address these limitations, TransCon™ TLR7/8 Agonist—an investigational sustained-release prodrug of resiquimod that uses a TransCon linker and hydrogel technology to achieve sustained and predictable IT release of resiquimod—was developed. TransCon TLR7/8 Agonist was characterized for resiquimod release in vitro and in vivo, in mice and rats, and was assessed for anti-tumor efficacy and pharmacodynamic activity in mice.ResultsFollowing a single IT dose, TransCon TLR7/8 Agonist mediated potent tumor growth inhibition which was associated with sustained resiquimod release over several weeks with minimal induction of systemic cytokines. TransCon TLR7/8 Agonist monotherapy promoted activation of antigen-presenting cells in the TME and tumor-draining lymph nodes, with evidence of activation and expansion of CD8+ T cells in the tumor-draining lymph node and TME. Combination of TransCon TLR7/8 Agonist with systemic immunotherapy further promoted anti-tumor activity in TransCon TLR7/8 Agonist-treated tumors. In a bilateral tumor setting, combination of TransCon TLR7/8 Agonist with systemic IL-2 potentiated tumor growth inhibition in both injected and non-injected tumors and conferred protection against tumor rechallenge following complete regressions.ConclusionsOur findings show that a single dose of TransCon TLR7/8 Agonist can mediate sustained local release of resiquimod in the TME and promote potent anti-tumor effects as monotherapy and in combination with systemic immunotherapy, supporting TransCon TLR7/8 Agonist as a novel intratumoral TLR agonist for cancer therapy. A clinical trial to evaluate the safety and efficacy of TransCon TLR7/8 Agonist, as monotherapy and in combination with pembrolizumab, in cancer patients is currently ongoing (transcendIT-101; NCT04799054).

Integrated TCR repertoire analysis and single-cell transcriptomic profiling of tumor-infiltrating T cells in renal cell carcinoma identifies shared and tumor-restricted expanded clones with unique phenotypes.

Objective responses of metastatic renal cell carcinoma (RCC) associated with systemic immunotherapies suggest the potential for T-cell-mediated tumor clearance. Recent analyses associate clonally expanded T cells present in the tumor at diagnosis with responses to immune checkpoint inhibitors (ICIs). To identify and further characterize tumor-associated, clonally expanded T cells, we characterized the density, spatial distribution, T-cell receptor (TCR) repertoire, and transcriptome of tumor-infiltrating T cells from 14 renal tumors at the time of resection and compared them with T cells in peripheral blood and normal adjacent kidney. Multiplex immunohistochemistry revealed that T-cell density was higher in clear cell RCC (ccRCC) than in other renal tumor histologies with spatially nonuniform T-cell hotspots and exclusion zones. TCR repertoire analysis also revealed increased clonal expansion in ccRCC tumors compared with non-clear cell histologies or normal tissues. Expanded T-cell clones were most frequently CD8+ with some detectable in peripheral blood or normal kidney and others found exclusively within the tumor. Divergent expression profiles for chemokine receptors and ligands and the Ki67 proliferation marker distinguished tumor-restricted T-cell clones from those also present in blood suggesting a distinct phenotype for subsets of clonally expanded T cells that also differed for upregulated markers of T-cell activation and exhaustion. Thus, our single-cell level stratification of clonally expanded tumor infiltrating T-cell subpopulations provides a framework for further analysis. Future studies will address the spatial orientation of these clonal subsets within tumors and their association with treatment outcomes for ICIs or other therapeutic modalities.

Treatment of metastatic uveal melanoma in 2022: improved treatment regimens and improved prognosis.

Until recently, metastatic uveal melanoma was associated with essentially uniform fatality within months. However, recent developments in screening, improved understanding of the genetic underpinnings of metastatic disease, and pivotal medication approvals have improved the disease's rate of fatality. Routine implementation of genetic testing at the time of primary tumor treatment via gene expression profiling or chromosomal analysis has identified patients who are at high risk for metastatic disease. Enhanced screening with imaging directed at the liver and lungs has allowed for identification of early disease and lower tumor burden. Significant work on improved liver directed therapy along with systemic chemotherapy and immunotherapy has improved life expectancy. The first systemic immunotherapy specifically for metastatic uveal melanoma was approved this year. This medication, tebentafusp, is likely to improve life expectancy for all patients with metastatic melanoma assuming they have appropriate human leukocyte antigen (HLA) markers. Multiple clinical trials with novel immunotherapeutic agents are promising as well. The prognosis for patients with uveal melanoma is far better than ever before because of recent developments in the understanding and treatment of metastatic disease.

A trial of intra-pleural bacterial immunotherapy in malignant pleural mesothelioma (TILT) — a randomised feasibility study using the trial within a cohort (TwiC) methodology

BackgroundMalignant pleural mesothelioma (MPM) is an aggressive thoracic malignancy with a poor prognosis. Systemic immunotherapy is an effective frontline treatment for MPM, and there is a scientific rationale supporting the possible efficacy of local, i.e. intra-pleural immune modulators. Trial of intra-pleural bacterial immunotherapy (TILT) investigated the feasibility of performing a randomised trial of intra-pleural bacterial immunotherapy in people with MPM, using the trials within cohorts (TwiC) methodology.MethodsTILT was a multicentre, three-armed, randomised, feasibility TwiC of intra-pleural OK432, BCG, or usual care in people with MPM. Eligible participants were identified from within the ASSESS-meso study, a prospective, longitudinal, observational cohort study, and were randomly selected to be offered a single dose of OK432 or BCG, via an indwelling pleural catheter. The primary outcome was feasibility, evaluated against prespecified recruitment, attrition and data completeness targets. The acceptability of trial processes and interventions was assessed during qualitative interviews with participants and family members at the end of the trial. TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016–004,727-23) and the ISRCTN Register on 04 December 2017.ResultsSeven participants were randomised from a planned sample size of 12; thus, the 66% recruitment rate target was not met. Two participants withdrew after randomisation, breaching the pre-stated attrition threshold of 10%. It was not possible to maintain blinding of control participants, which negated a fundamental tenet of the TwiC design. The trial processes and methodology were generally acceptable to participants and relatives, despite several recipients of intra-pleural bacterial agents experiencing significant local and systemic inflammatory responses.ConclusionIt was possible to design a clinical trial of an investigational medicinal product based on the TwiC design and to obtain the necessary regulatory approvals. However, whilst acceptable to participants and relatives, the TwiC design was not a feasible method of investigating intra-pleural bacterial immunotherapy in people with MPM. Future trials investigating this topic should consider the eligibility constraints and recruitment difficulties encountered.Trial registrationTILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004727-23) and the ISRCTN Register (10432197) on 04 December 2017.

Abstract IA18: Immune checkpoint inhibitors and nonalcoholic steatohepatitis (NASH)

Abstract Hepatocellular carcinoma (HCC) usually arises in the setting of liver cirrhosis from viral or non-viral causes. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is a rising cause of HCC in the United States and many other parts of the world. Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD1) or its ligand have improved outcomes for patients with advanced HCC. In general, clinical biomarkers are not currently used to identify patients most likely to benefit from systemic immunotherapy in HCC, and whether etiology has any effect on immunotherapy responses in HCC has been unclear. In this session, we will review recent preclinical data suggesting that NASH may impair immune responses in HCC. We will also review data from The Cancer Genome Atlas (TCGA) comparing the tumor immune microenvironment of viral-associated and non-viral HCC, and review the preponderance of clinical evidence indicating that HBV, HCV, and non-viral HCC all derive clinical benefit from immune checkpoint inhibitor therapy. Citation Format: Mark Yarchoan. Immune checkpoint inhibitors and nonalcoholic steatohepatitis (NASH) [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA18.

Systemic immunotherapy for the treatment of warts: Aliterature review.

Immunotherapy has emerged as a critical therapeutic tool for the treatment of warts. Immunotherapy for warts is currently restricted to recalcitrant lesions. A small number of regimens appear to be extremely effective. Furthermore, there is a scarcity of evidence-based research. Furthermore, in the majority of cases, their safety and effectiveness have not been evaluated in double-blind, controlled clinical trials, making the reproducibility of many of the listed treatments difficult to analyze and a possible placebo effect difficult to rule out. Analyzing and discussing different types of systemic immunotherapy. The different types of immunotherapy for warts are mentioned in this report. Systemic immunotherapeutic modalities commonly used in the treatment Echinacea, propolis, oral retinoids, glycyrrhizinic acid, levamisole, cimetidine, and zinc sulfate have all been reported as effective treatment modalities for different types of warts. Immunotherapy has emerged as one of the most important therapeutic modalities for warts. Such treatment is required not only for recalcitrant or multiple lesions, but also in the majority of treated cases.

Ferroptosis: From Basic Research to Clinical Therapeutics in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and highly heterogeneous malignancies worldwide. Despite the rapid development of multidisciplinary treatment and personalized precision medicine strategies, the overall survival of HCC patients remains poor. The limited survival benefit may be attributed to difficulty in early diagnosis, the high recurrence rate and high tumor heterogeneity. Ferroptosis, a novel mode of cell death driven by iron-dependent lipid peroxidation, has been implicated in the development and therapeutic response of various tumors, including HCC. In this review, we discuss the regulatory network of ferroptosis, describe the crosstalk between ferroptosis and HCC-related signaling pathways, and elucidate the potential role of ferroptosis in various treatment modalities for HCC, such as systemic therapy, radiotherapy, immunotherapy, interventional therapy and nanotherapy, and applications in the diagnosis and prognosis of HCC, to provide a theoretical basis for the diagnosis and treatment of HCC to effectively improve the survival of HCC patients.

Hepatocellular-Cholangiocarcinoma Collision Tumors: An Update of Current Management Practices.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare form of primary hepatic collision tumor, with an incidence ranging from 0.4 to 14.2%. Given the diagnostic challenges and lack of randomized trials, standardized treatment has yet to be established. We aim to review the literature to summarize the diagnosis, molecular characteristics, current treatment modalities, and challenges for cHCC-CC. A literature review was performed using PubMed. We included studies investigating and describing cHCC-CC, focusing on surgical, medical, and radiologic treatments. Overall prognosis is poor, with a 5-year survival rate under 30%. Minor or major hepatectomy with R0 resection is the only curative treatment; however, recurrence is likely (as high as 50% within 5years). The role of liver transplantation is also highly debated given the biliary nature of these tumors, with cHCC-CC as a relative contraindication for liver transplantation. Although gemcitabine-based treatments had higher progression-free survival over sorafenib, there is no standard chemotherapy regimen. Treatment with gemcitabine and platinum demonstrates improved disease control rates compared to gemcitabine in conjunction with 5-fluorouracil (78.4% verse 38.5% respectively). Additionally, platinum-containing chemotherapy regimens exhibit a higher overall response rate than non-platinum regimens (21.4% verse 7.0% respectively). These molecular-directed therapies have prolonged survival for HCC, but further investigation needs to be done to assess their utility in patients with cHCC-CC. cHCC-CC is a rare and complex subset of primary hepatic neoplasms with a dismal prognosis and unstandardized treatment options. Further trials need to be performed to investigate systemic chemotherapy and immunotherapy options for patients with unresectable disease.

Update on Immune Checkpoint Inhibitors for Conjunctival Melanoma.

The management of conjunctival melanoma is challenging due to the more frequent local recurrence and metastasis compared to other conjunctival neoplasms. Locally advanced conjunctival melanoma may require an orbital exenteration, and treatment options for metastatic conjunctival melanoma have been limited until recently. This review aims to provide comprehensive updates on immunotherapy for conjunctival melanoma, focusing on immune checkpoint inhibitors. We reviewed the available literature on the use of immunotherapy for the treatment of conjunctival melanoma. Systemic immunotherapy, particularly with checkpoint inhibitors, has recently been reported to have improved outcomes for patients with conjunctival melanoma. Immune checkpoint inhibitors that are currently approved by the US Food and Drug Administration for melanoma include anti-PD-1 (nivolumab and pembrolizumab), anti-PDL-1 (avelumab and atezolizumab), and anti-CTLA-4 inhibitors (ipilimumab). Most recent reports described using immune checkpoint inhibitors in patients with locally advanced conjunctival melanoma in an attempt to avoid orbital exenteration or in patients with metastatic conjunctival melanoma.Although the current data are limited to case reports and small case series, eye care providers should be aware of the potential role of immunotherapy for patients with locally advanced, recurrent, or metastatic conjunctival melanoma.

Hypofractionated or Conventionally Fractionated Adjuvant Radiotherapy After Regional Lymph Node Dissection for High-Risk Stage III Melanoma

AimsAdjuvant radiotherapy can be beneficial after regional lymph node dissection for high-risk stage III melanoma, as it has been shown to reduce the risk of recurrence in the node field. However, the optimal fractionation schedule is unknown and both hypofractionated and conventionally fractionated adjuvant radiotherapy are used. The present study examined the oncological outcomes of these two approaches in patients treated in an era before effective systemic immunotherapy became available. Materials and methodsThis retrospective cohort study involved 335 patients with stage III melanoma who received adjuvant radiotherapy after therapeutic regional lymph node dissection for metastatic melanoma between 1990 and 2011. Information on tumour characteristics, radiotherapy doses and fractionation schedules and patient outcomes was retrieved from the institution's database and patients' medical records. ResultsHypofractionated radiotherapy (median dose 33 Gy in six fractions over 3 weeks) was given to 95 patients (28%) and conventionally fractionated radiotherapy (median dose 48 Gy in 20 fractions over 4 weeks) to 240 patients (72%). Five-year lymph node field control rates were 86.0% (95% confidence interval 78.4–94.4%) for the hypofractionated group and 85.5% (95% confidence interval 80.5–90.7%) for the conventional fractionation group (P = 0.87). There were no significant differences in recurrence-free survival (RFS) (41.7%, 95% confidence interval 32.5–53.5 versus 31.9%, 95% confidence interval 26.1–38.9; P = 0.18) or overall survival (41.2%, 95% confidence interval 32.1–52.8 versus 45.0%, 95% confidence interval 38.7–52.4; P = 0.77). On multivariate analysis, extranodal spread was associated with decreased RFS (P = 0.04) and the number of resected lymph nodes containing metastatic melanoma was associated with decreased RFS (P = 0.0006) and overall survival (P = 0.01). ConclusionLymph node field control rates, RFS and overall survival were similar after hypofractionated and conventionally fractionated adjuvant radiotherapy. The presence of extranodal spread and an increasing number of positive lymph nodes were predictive of an unfavourable outcome.

Clinical and biological markers for risk-stratification of T1 high-grade non-muscle invasive bladder cancer.

To summarize the prognostic and predictive role of current clinical and biological markers in patients with T1 high-grade (T1HG) nonmuscle invasive bladder cancer (NMIBC). Classical clinico-pathologic markers such as age, tumor size, focality, and location as well as the presence of concomitant carcinoma in situ, lymphovascular invasion, and histological variants at the time of transurethral resection (TUR) should be used in the risk-stratification of T1HG to improve patients' selection for early aggressive treatment. pathological T1 substaging has shown to predict disease progression and response to intravesical therapy, and should therefore be reported in the pathological assessment to improve clinical decision-making. Urinary inducible cytokines measured at different time points during Bacillus Calmette-Guerin therapy may be used to predict response to treatment, while urinary mRNA-based biomarkers may be of value to select patients for repeated TUR (reTUR). The advent of genomic classification in NMIBC and that of immune markers may improve current risk-stratification tools and pave the way toward personalized treatment. The role of clinico-pathologic variables in the risk-stratification of T1HG NMIBC remains unaltered, despite insufficient. Urinary biomarkers and tissue-based immune markers hold the promise to revolutionize the paradigm of risk-stratification due to their potential role in predicting response to intravesical and systemic immunotherapy. However, to date, none of the investigated biomarkers is used in clinical practice to risk-stratify T1HG patients due to the lack of external and/or prospective validations.