Search Results (3,331)

Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody–drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape. Full article

Pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer mortality in the United States, presents significant treatment challenges due to its late diagnosis and poor prognosis. Despite advances, the five-year survival rates remain dismally low, with only a fraction of patients eligible for potentially curative surgical interventions. This review aims to comprehensively examine the current landscape of targeted therapies in PDAC, focusing on recent developments in precision medicine approaches. We explore various molecular targets, including KRAS mutations, DNA damage repair deficiencies, mismatch repair pathway alterations, and rare genetic fusions. The review discusses emerging therapies, such as PARP inhibitors, immune checkpoint inhibitors, and novel targeted agents, like RET and NTRK inhibitors. We analyze the results of key clinical trials and highlight the potential of these targeted approaches in specific patient subgroups. Recent developments in PDAC research have emphasized precision oncology, facilitated by next-generation sequencing and the identification of genetic and epigenetic alterations. This approach tailors treatments to individual genetic profiles, improving outcomes and reducing side effects. Significant strides have been made in classifying PDAC into various subtypes, enhancing therapeutic precision. The identification of specific mutations in genes like KRAS, along with advancements in targeted therapies, including small molecule inhibitors, offers new hope. Furthermore, emerging therapies targeting DNA repair pathways and immunotherapeutic strategies also show promising results. As research evolves, integrating these targeted therapies with conventional treatments might improve survival rates and quality of life for PDAC patients, underscoring the shift towards a more personalized treatment paradigm. Full article

Penile squamous cell carcinoma (pSCC) is a rare malignancy with a global incidence ranging from 0.1 to 0.7 per 100,000 males. Prognosis is generally favorable for localized tumors, but metastatic pSCC remains challenging, with low survival rates. The role of novel biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI), in predicting the response to immune checkpoint inhibitors (ICIs) has been investigated in various cancers. However, MSI has not been observed in pSCC, limiting immunotherapy options for this patient subgroup. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) are a distinct form of genomic instability associated with deficient MSH3 expression, which has been proposed as a potential biomarker in several cancers. This study investigates EMAST and MSH3 expression in a cohort of 78 pSCC cases using PCR, fragment analysis and immunohistochemistry. For the detection of EMAST, the stability of five microsatellite markers (D9S242, D20S82, MYCL1, D8S321 and D20S85) was analyzed. None of the cases showed an instability. As for MSH3 immunohistochemistry, all analyzable cases showed retained MSH3 expression. These results strongly suggest that neither EMAST nor MSH3 deficiency is involved in the carcinogenesis of pSCC and do not represent reliable predictive biomarkers in this entity. Furthermore, these findings are in full agreement with our previous study showing a very low frequency of MSI and further support the thesis that EMAST and MSI are strongly interconnected forms of genomic instability. Further research is needed to explore novel therapeutic targets and predictive biomarkers for immunotherapy in this patient population. Full article

Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptors (ERs), human epidermal growth factor receptor 2 (HER2), and progesterone receptors (PRs). TNBC has the poorest prognosis among breast cancer subtypes and is more likely to respond to immunotherapy due to its higher expression of PD-L1 and a greater percentage of tumor-infiltrating lymphocytes. Immunotherapy has revolutionized TNBC treatment, especially with the FDA’s approval of pembrolizumab (Keytruda) combined with chemotherapy for advanced cases, opening new avenues for treating this deadly disease. Although immunotherapy can significantly improve patient outcomes in a subset of patients, achieving the desired response rate for all remains an unmet clinical goal. Strategies that enhance responses to immune checkpoint blockade, including combining immunotherapy with chemotherapy, molecularly targeted therapy, or radiotherapy, may improve response rates and clinical outcomes. In this review, we provide a short background on TNBC and immunotherapy and explore the different types of immunotherapy strategies that are currently being evaluated in TNBC. Additionally, we review why combination strategies may be beneficial, provide an overview of the combination strategies, and discuss the novel immunotherapeutic opportunities that may be approved in the near future for TNBC. Full article

This review article explores the fundamental role of receptor targeting in overcoming drug resistance in cancer therapy, an area of critical concern given the persistently high rates of cancer morbidity and mortality globally. We highlight how receptor biology intersects with the development of therapeutic resistance with a specific focus on anti-angiogenic agents, immune checkpoint inhibitors, and monoclonal antibodies, which directly or indirectly influence receptor pathways. We also explore how other receptor tyrosine kinases can initially suppress tumor growth, yet often lead to resistance, underscoring the need for novel combinatorial approaches that incorporate advanced receptor modulation techniques. Further, the review delves into the mechanisms by which modulation of the tumor microenvironment and immune system via receptor pathways can overcome resistance to traditional immunotherapies. Additionally, emerging technologies in receptor-targeted nanomedicine are also highlighted, showcasing their potential to revolutionize drug delivery and improve therapeutic outcomes by targeting specific receptor interactions. Ultimately, this review calls for a deeper understanding of receptor dynamics to develop more precise interventions, including insights from various healthcare settings that can prevent or circumvent drug resistance, thus enhancing patient outcomes in oncology. Full article

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment paradigm of lung cancer, resulting in notable enhancements in patient survival. Nevertheless, evaluating treatment response in patients undergoing immunotherapy poses distinct challenges due to unconventional response patterns like pseudoprogressive disease (PPD), dissociated response (DR), and hyperprogressive disease (HPD). Conventional response criteria such as the RECIST 1.1 may not adequately address these complexities. To tackle this issue, novel response criteria such as the iRECIST and imRECIST have been proposed, enabling a more comprehensive assessment of treatment response by incorporating additional scans and considering the best overall response even after radiologic progressive disease evaluation. Additionally, [18F]FDG PET/CT imaging has emerged as a valuable modality for evaluating treatment response, with various metabolic response criteria such as the PERCIMT, imPERCIST, and iPERCIST developed to overcome the limitations of traditional criteria, particularly in detecting pseudoprogression. A multidisciplinary approach involving oncologists, radiologists, and nuclear medicine specialists is crucial for effectively navigating these complexities and enhancing patient outcomes in the era of immunotherapy for lung cancer. In this review, we delineate the key components of these guidelines, summarizing essential aspects for radiologists and nuclear medicine physicians. Furthermore, we provide insights into how imaging can guide the management of individual lung cancer patients in real-world multidisciplinary settings. Full article

Cancer immunotherapy has emerged as a transformative approach in oncology, utilizing the body’s immune system to specifically target and destroy malignant cells. This review explores the scope and impact of various immunotherapeutic strategies, including monoclonal antibodies, chimeric antigen receptor (CAR)-T cell therapy, checkpoint inhibitors, cytokine therapy, and therapeutic vaccines. Monoclonal antibodies, such as Rituximab and Trastuzumab, have revolutionized treatment paradigms for lymphoma and breast cancer by offering targeted interventions that reduce off-target effects. CAR-T cell therapy presents a potentially curative option for refractory hematologic malignancies, although challenges remain in effectively treating solid tumors. Checkpoint inhibitors have redefined the management of cancers like melanoma and lung cancer; however, managing immune-related adverse events and ensuring durable responses are critical areas of focus. Cytokine therapy continues to play a vital role in modulating the immune response, with advancements in cytokine engineering improving specificity and reducing systemic toxicity. Therapeutic vaccines, particularly mRNA-based vaccines, represent a frontier in personalized cancer treatment, aiming to generate robust, long-lasting immune responses against tumor-specific antigens. Despite these advancements, the field faces significant challenges, including immune resistance, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Future research should address these obstacles through emerging technologies, such as next-generation antibodies, Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-based gene editing, and AI-driven drug discovery. By integrating these novel approaches, cancer immunotherapy holds the promise of offering more durable, less toxic, and highly personalized treatment options, ultimately improving patient outcomes and survival rates. Full article

Intensity-modulated radiation therapy (IMRT) improves disease control and reduces treatment-related toxicity in patients with localized nasopharyngeal carcinoma (NPC). However, due to the proximity of the auditory apparatus to the treatment volume and the frequent incorporation of cisplatin-based chemotherapy, treatment-related sensorineural hearing loss (SNHL) remains a common debilitating complication among NPC survivors. The reported crude incidence of SNHL following IMRT for NPC varies widely at 1–46% due to differences in auditory assessment methods and thresholds, follow-up durations, chemotherapy usage, and patient compositions. International guidelines and radiation dosimetric studies have recommended constraining the cochlear mean dose to less than 44–50 Gy, but the risk of SNHL remains high despite adherence to these constraints. Potential strategies to improve hearing outcomes in NPC survivors include cautious de-escalation of radiotherapy dose and volume, individualization of cochlear constraints, optimization of radiotherapy planning techniques, and the use of substitutes or alternative schedules for cisplatin-based chemotherapy. The addition of immune checkpoint inhibitors to chemoradiotherapy did not impact ototoxicity. Prospective studies that employ both objective and patient-reported auditory outcomes are warranted to test the long-term benefits of various approaches. This article aims to provide a comprehensive review of the incidence and radiation dose–toxicity relationship of SNHL in NPC survivors and to summarize potential strategies to optimize hearing outcomes in relation to nuances in radiotherapy planning and the selection of systemic therapy. Full article

The use of neoadjuvant systemic therapy (NST) has become increasingly important in the treatment of breast cancer because of its various advantages. These include the ability to downstage tumors without compromising locoregional control and the potential to obtain valuable information about clinical and biological response to therapy with implications for individual prognoses. Surgical response assessment paves the way for response-adapted therapy, and pathological complete response (pCR; defined as ypT0/is ypN0) serves as an additional endpoint for drug development trials. Recommended NST regimens commonly consist of anthracyclines and taxane, with dose-dense anthracyclines and weekly paclitaxel often preferred, whenever feasible. For patients with human epidermal growth factor receptor-2 (HER2)-positive tumors, dual anti-HER2 therapy (trastuzumab and pertuzumab) is indicated together with NST in case of elevated risk of recurrence. For patients with triple-negative breast cancer (TNBC), adding carboplatin to NST correlates with improved pCR and survival rates, as does the addition of immune checkpoint inhibitors. For hormone receptor (HR)-positive/HER2-negative cancers, emerging data on NST including immune checkpoint inhibitors may elevate the significance of NST in high-risk luminal breast cancer. Here, we present a synthesis of the results from neoadjuvant clinical trials that aim at optimizing treatment options for patients with high-risk breast cancer. Full article

Certain anticancer therapies inevitably increase the risk of cardiovascular events, now the second leading cause of death among cancer patients. This underscores the critical need for developing effective drugs or regimens for cardiovascular protection. Statins possess properties such as antioxidative stress, anti-inflammatory effects, antifibrotic activity, endothelial protection, and immune modulation. These pathological processes are central to the cardiotoxicity associated with anticancer treatment. There is prospective clinical evidence confirming the protective role of statins in chemotherapy-induced cardiotoxicity. Numerous preclinical studies have demonstrated that statins can ameliorate heart and endothelial damage caused by radiotherapy, although clinical studies are scarce. In the animal models of trastuzumab-induced cardiomyopathy, statins provide protection through anti-inflammatory, antioxidant, and antifibrotic mechanisms. In animal and cell models, statins can mitigate inflammation, endothelial damage, and cardiac injury induced by immune checkpoint inhibitors. Chimeric antigen receptor (CAR)-T cell therapy-induced cardiotoxicity and immune effector cell-associated neurotoxicity syndrome are associated with uncontrolled inflammation and immune activation. Due to their anti-inflammatory and immunomodulatory effects, statins have been used to manage CAR-T cell therapy-induced immune effector cell-associated neurotoxicity syndrome in a clinical trial. However, direct evidence proving that statins can mitigate CAR-T cell therapy-induced cardiotoxicity is still lacking. This review summarizes the possible mechanisms of anticancer therapy-induced cardiotoxicity and the potential mechanisms by which statins may reduce related cardiac damage. We also discuss the current status of research on the protective effect of statins in anticancer treatment-related cardiovascular disease and provide directions for future research. Additionally, we propose further studies on using statins for the prevention of cardiovascular disease in anticancer treatment. Full article

Background/Objectives: Immunotherapy has changed the therapeutic approach for various solid tumors, especially lung tumors, malignant melanoma, renal and urogenital carcinomas, demonstrating significant antitumor activity, with tolerable safety profiles and durable responses. However, not all patients benefit from immunotherapy, underscoring the need for predictive biomarkers that can identify those most likely to respond to treatment. Methods: The integration of predictive biomarkers into clinical practice for immune checkpoint inhibitors (ICI) holds great promise for personalized cancer treatment. Programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), microsatellite instability (MSI), gene expression profiles and circulating tumor DNA (ctDNA) have shown potential in predicting ICI responses across various cancers. Results: Challenges such as standardization, validation, regulatory approval, and cost-effectiveness must be addressed to realize their full potential. Predictive biomarkers are crucial for optimizing the clinical use of ICIs in cancer therapy. Conclusions: While significant progress has been made, further research and collaboration among clinicians, researchers, and regulatory institutes are essential to overcome the challenges of clinical implementation. However, little is known about the relationship between local and systemic immune responses and the correlation with response to oncological therapies and patient survival. Full article

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma. However, over 50% of patients experience limited or no response to ICI therapy. Resistance to ICIs is influenced by a complex interplay of tumour intrinsic and extrinsic factors. This review summarizes current ICIs for melanoma and the factors involved in resistance to the treatment. We also discuss emerging evidence that the microbiota can impact ICI treatment outcomes by modulating tumour biology and anti-tumour immune function. Furthermore, microbiota profiles may offer a non-invasive method for predicting ICI response. Therefore, future research into microbiota manipulation could provide cost-effective strategies to enhance ICI efficacy and improve outcomes for melanoma patients. Full article

Background: Nivolumab plus ipilimumab (nivo/ipi) combination therapy is highly effective in treating advanced melanoma, but serious immune-related adverse events (irAEs) are prevalent. The overall response rate (ORR) of the BRAF inhibitor plus MEK inhibitor (BRAFi/MEKi) combination therapy for BRAF^V600-mutant advanced melanoma surpasses that of immune checkpoint inhibitors (ICIs). However, the OS and PFS of BRAFi/MEKi combination therapy are inferior to those of ICIs. Methods: We retrospectively evaluated 22 melanoma patients treated with nivo/ipi therapy and 13 patients treated with encorafenib plus binimetinib (enco/bini) between November 2018 and July 2023. Results: The ORR of nivo/ipi for metastatic melanoma patients was significantly higher in the first-line cohort [60.0% (95% CI: 31.2–83.3%)] than in the second-line or beyond cohort [8.3% (95% CI: 0–37.5%)], whereas the ORR of enco/bini was comparable between the first-line cohort [75.0% (95% CI: 28.9–96.6%)] and the second-line or beyond cohort [77.8% (95% CI: 44.3–94.7%)]. The median PFS of nivo/ipi significantly improved in the first-line cohort [7.7 months (95% CI: 2.0–11.9)] compared to the second-line or beyond cohort [2.3 months (95% CI: 0.5–6.0)] (p = 0.0109). In addition to efficacy, the incidence of grade 3 or greater AEs was comparable in the first-line and second-line or beyond cohorts. Conclusions: Although our present data are based on a small number of cases, they suggest that nivo/ipi should be administered as the first-line therapy for the treatment of BRAF^V600-mutant metastatic melanoma, rather than enco/bini, aligning with findings from previous clinical trials. Full article

Glioblastoma (GBM) is the most common and most malignant primary brain tumor, presenting significant treatment challenges due to its heterogeneity, invasiveness, and resistance to conventional therapies. Despite aggressive treatment protocols, the prognosis remains poor, with a median survival time of approximately 15 months. Recent advancements in mRNA vaccine technology, particularly the development of lipid nanoparticles (LNPs), have revitalized interest in mRNA-based therapies. These vaccines offer unique advantages, including rapid production, personalization based on tumor-specific mutations, and a strong induction of both humoral and cellular immune responses. mRNA vaccines have demonstrated potential in preclinical models, showing significant tumor regression and improved survival rates. Early-phase clinical trials have indicated that mRNA vaccines are safe and can induce robust immune responses in GBM patients. Combining mRNA vaccines with other immunotherapeutic approaches, such as checkpoint inhibitors, has shown synergistic effects, further enhancing their efficacy. However, challenges such as optimizing delivery systems and overcoming the immunosuppressive tumor microenvironment remain. Future research should focus on addressing these challenges and exploring combination therapies to maximize therapeutic benefits. Large-scale, randomized clinical trials are essential to validate the efficacy and safety of mRNA vaccines in GBM therapy. The potential to reshape the tumor microenvironment and establish long-term immunological memory underscores the transformative potential of mRNA vaccines in cancer immunotherapy. Full article

Penile cancer (PC) is a rare malignancy predominantly of squamous cell origin. Approximately 40% of penile tumors are associated with human papillomavirus (HPV) infection. Diagnosing PC remains challenging due to its rarity and variety of clinical presentations. Furthermore, the impact of HPV on the tumor immune microenvironment complicates clinical management, although recent advancements in immune checkpoint inhibitors (ICIs) have shown some efficacy in treating HPV-associated PC. Ongoing research efforts aim to develop oncologic treatments that target HPV-induced cellular modifications. Additionally, novel therapeutic vaccines and adoptive T-cell therapies targeting HPV oncoproteins represent emerging treatment modalities. Our review highlights the complex interplay between HPV and penile carcinogenesis, emphasizing its epidemiology, etiology, clinicopathological characteristics, and potential therapeutic implications. Full article