Novel immunotherapies for breast cancer: Focus on 2023 findings.

Immunotherapy has emerged as a revolutionary approach in cancer therapy, and recent advancements hold significant promise for breast cancer (BCa) management. Employing the patient's immune system to combat BCa has become a focal point in immunotherapeutic investigations. Strategies such as immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), and targeting the tumor microenvironment (TME) have disclosed encouraging clinical outcomes. ICIs, particularly programmed cell death protein 1 (PD-1)/PD-L1 inhibitors, exhibit efficacy in specific BCa subtypes, including triple-negative BCa (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive cancers. ACT approaches, including tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapy, showed promising clinical outcomes in enhancing tumor recognition and elimination. Targeting the TME through immune agonists and oncolytic viruses signifies a burgeoning field of research. While challenges persist in patient selection, resistance mechanisms, and combination therapy optimization, these novel immunotherapies hold transformative potential for BCa treatment. Continued research and clinical trials are imperative to refine and implement these innovative approaches, paving the way for improved outcomes and revolutionizing the management of BCa. This review provides a concise overview of the latest immunotherapies (2023 studies) in BCa, highlighting their potential and current status.

Bispecific antibodies revolutionizing breast cancer treatment: a comprehensive overview.

Breast cancer (BCa) is known as a complex and prevalent disease requiring the development of novel anticancer therapeutic approaches. Bispecific antibodies (BsAbs) have emerged as a favorable strategy for BCa treatment due to their unique ability to target two different antigens simultaneously. By targeting tumor-associated antigens (TAAs) on cancer cells, engaging immune effector cells, or blocking critical signaling pathways, BsAbs offer enhanced tumor specificity and immune system involvement, improving anti-cancer activity. Preclinical and clinical studies have demonstrated the potential of BsAbs in BCa. For example, BsAbs targeting human epidermal growth factor receptor 2 (HER2) have shown the ability to redirect immune cells to HER2-positive BCa cells, resulting in effective tumor cell killing. Moreover, targeting the PD-1/PD-L1 pathway by BsAbs has demonstrated promising outcomes in overcoming immunosuppression and enhancing immune-mediated tumor clearance. Combining BsAbs with existing therapeutic approaches, such as chemotherapy, targeted therapies, or immune checkpoint inhibitors (ICIs), has also revealed synergistic effects in preclinical models and early clinical trials, emphasizing the usefulness and potential of BsAbs in BCa treatment. This review summarizes the latest evidence about BsAbs in treating BCa and the challenges and opportunities of their use in BCa.

Could immunoscore improve the prognostic and therapeutic management in patients with solid tumors?

The Immunoscore (ISc) is an emerging immune-based scoring system that has shown potential in improving the prognostic and therapeutic management of patients with solid tumors. The ISc evaluates the immune infiltrate within the tumor microenvironment (TME) and has demonstrated superior predictive ability compared to traditional histopathological parameters. It has been particularly promising in colorectal, lung, breast, and melanoma cancers. This review summarizes the clinical evidence supporting the prognostic value of the ISc and explores its potential in guiding therapeutic decisions, such as the selection of adjuvant therapies and recognizing patients likely to profit from immune checkpoint inhibitors (ICIs). The challenges and future directions of ISc implementation are also discussed, including standardization and integration into routine clinical practice.

Multifunctional nanocarriers for targeted drug delivery and diagnostic applications of lymph nodes metastasis: a review of recent trends and future perspectives.

Lymph node metastasis is a frequent occurrence in a variety of tumour forms and poses an enormous challenge to cancer treatment. This process is critical to the development of the disease and is frequently linked to a poor prognosis. Over 90% of cancerous cells move through lymph nodes, making them important entry routes for the spread of cancer cells. The prognosis of cancer patients is significantly impacted by lymph node metastases, which also affects treatment choices. Targeting lymph node metastases presents numerous difficulties for conventional medication delivery techniques. It is still very difficult to selectively target cancer cells in lymph nodes without risking injury to healthy organs and unforeseen consequences. Additionally, systemic delivery of drugs is hampered by the slow flow rate of lymphatic vessels. Chemotherapeutic medicines' poor solubility and stability further reduce their effectiveness when taken orally. Additionally, the extracellular matrix that surrounds lymph node tumours is extensive, which makes it difficult for conventional pharmaceutical delivery systems to reach cancer cells. The development of nanocarriers for precise drug delivery to LNs has attracted a lot of interest to overcome these obstacles. Most solid tumours first spread through the lymphatic system, hence effective drug administration to these tissues is essential for better therapeutic results. Nanocarriers have several benefits, including the capacity to pass through barriers like blood-brain barriers and membranes to reach the lymphatic system. High medication dosages can be enclosed thanks to the physicochemical characteristics of nanocarriers, such as their higher surface-to-volume ratio. Additionally, ligands, antibodies, polymers, or biological molecules can be attached to nanocarrier surfaces to change their properties, allowing for the targeted delivery of lymph node epithelial cells. This use of nanocarriers for drug delivery maximizes on-target effects and related adverse effects while improving the effectiveness of medication delivery to target locations. More research and development in this field is needed to optimize nanocarrier design, increase targeting capabilities, and expand clinical applications for better cancer care.

Organoid Models for Precision Cancer Immunotherapy.

Cancer immunotherapy is exploited for the treatment of disease by modulating the immune system. Since the conventional in vivo animal and 2D in vitro models insufficiently recapitulate the complex tumor immune microenvironment (TIME) of the original tumor. In addition, due to the involvement of the immune system in cancer immunotherapy, more physiomimetic cancer models, such as patient-derived organoids (PDOs), are required to evaluate the efficacy of immunotherapy agents. On the other hand, the dynamic interactions between the neoplastic cells and non-neoplastic host components in the TIME can promote carcinogenesis, tumor metastasis, cancer progression, and drug resistance of cancer cells. Indeed, tumor organoid models can properly recapitulate the TIME by preserving endogenous stromal components including various immune cells, or by adding exogenous immune cells, cancer-associated fibroblasts (CAFs), vasculature, and other components. Therefore, organoid culture platforms could model immunotherapy responses and facilitate the immunotherapy preclinical testing. Here, we discuss the various organoid culture approaches for the modeling of TIME and the applications of complex tumor organoids in testing cancer immunotherapeutics and personalized cancer immunotherapy.

Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand?

Colorectal cancer (CRC) is the second leading cause of cancer death in the world. Immunotherapy using monoclonal antibodies, immune-checkpoint inhibitors, adoptive cell therapy, and cancer vaccines has raised great hopes for treating poor prognosis metastatic CRCs that are resistant to the conventional therapies. However, high inter-tumor and intra-tumor heterogeneity hinder the success of immunotherapy in CRC. Patients with a similar tumor phenotype respond differently to the same immunotherapy regimen. Mutation-based classification, molecular subtyping, and immunoscoring of CRCs facilitated the multi-aspect grouping of CRC patients and improved immunotherapy. Personalized immunotherapy using tumor-specific neoantigens provides the opportunity to consider each patient as an independent group deserving of individualized immunotherapy. In the recent decade, the development of sequencing and multi-omics techniques has helped us classify patients more precisely. The expansion of such advanced techniques along with the neoantigen-based immunotherapy could herald a new era in treating heterogeneous tumors such as CRC. In this review article, we provided the latest findings in immunotherapy of CRC. We elaborated on the heterogeneity of CRC patients as a bottleneck of CRC immunotherapy and reviewed the latest advances in personalized immunotherapy to overcome CRC heterogeneity.

Preclinical tumor organoid models in personalized cancer therapy: Not everyone fits the mold.

In contrast to conventional cancer treatment, in personalized cancer medicine each patient receives a specific treatment. The response to therapy, clinical outcomes, and tumor behavior such as metastases, tumor progression, carcinogenesis can be significantly affected by the heterogeneous tumor microenvironment (TME) and interpersonal differences. Therefore, using native tumor microenvironment mimicking models is necessary to improving personalized cancer therapy. Both in vitro 2D cell culture and in vivo animal models poorly recapitulate the heterogeneous tumor (immune) microenvironments of native tumors. The development of 3D culture models, native tumor microenvironment mimicking models, made it possible to evaluate the chemoresistance of tumor tissue and the functionality of drugs in the presence of cell-extracellular matrix and cell-cell interactions in a 3D construction. Various personalized tumor models have been designed to preserving the native tumor microenvironment, including patient-derived tumor xenografts and organoid culture strategies. In this review, we will discuss the patient-derived organoids as a native tumor microenvironment mimicking model in personalized cancer therapy. In addition, we will also review the potential and the limitations of organoid culture systems for predicting patient outcomes and preclinical drug screening. Finally, we will discuss immunotherapy drug screening in tumor organoids by using microfluidic technology.

A Systematic Review of the Potential Chemoprotective Effects of Resveratrol on Doxorubicin-Induced Cardiotoxicity: Focus on the Antioxidant, Antiapoptotic, and Anti-Inflammatory Activities.

PURPOSE: Although doxorubicin chemotherapeutic drug is commonly used to treat various solid and hematological tumors, its clinical use is restricted because of its adverse effects on the normal cells/tissues, especially cardiotoxicity. The use of resveratrol may mitigate the doxorubicin-induced cardiotoxic effects. For this aim, we systematically reviewed the potential chemoprotective effects of resveratrol against the doxorubicin-induced cardiotoxicity. METHODS: In the current study, a systematic search was performed based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline for the identification of all relevant studies on "the role of resveratrol on doxorubicin-induced cardiotoxicity" in the electronic databases of Web of Science, PubMed, and Scopus up to March 2021 using search terms in their titles and abstracts. Two hundred and eighteen articles were screened in accordance with a predefined set of inclusion and exclusion criteria. Finally, 33 eligible articles were included in this systematic review. RESULTS: The in vitro and in vivo findings demonstrated a decreased cell survival, increased mortality, decreased heart weight, and increased ascites in the doxorubicin-treated groups compared to the control groups. The combined treatment of resveratrol and doxorubicin showed an opposite pattern than the doxorubicin-treated groups alone. Furthermore, this chemotherapeutic agent induced the biochemical and histopathological changes on the cardiac cells/tissue; however, the results (for most of the cases) revealed that these alterations induced by doxorubicin were reversed near to normal levels (control groups) by resveratrol coadministration. CONCLUSION: The results of this systematic review stated that coadministration of resveratrol alleviates the doxorubicin-induced cardiotoxicity. Resveratrol exerts these chemoprotective effects through several main mechanisms of antioxidant, antiapoptosis, and anti-inflammatory.

Development of humanized mouse with patient-derived xenografts for cancer immunotherapy studies: A comprehensive review.

Immunotherapy has revolutionized cancer treatment, however, not all tumor types and patients are completely responsive to this approach. Establishing predictive pre-clinical models would allow for more accurate and practical immunotherapeutic drug development. Mouse models are extensively used as in vivo system for biomedical research. However, due to the significant differences between rodents and human, it is impossible to translate most of the findings from mouse models to human. Pharmacological development and advancing personalized medicine using patient-derived xenografts relies on producing mouse models in which murine cells and genes are substituted with their human equivalent. Humanized mice (HM) provide a suitable platform to evaluate xenograft growth in the context of a human immune system. In this review, we discussed recent advances in the generation and application of HM models. We also reviewed new insights into the basic mechanisms, pre-clinical evaluation of onco-immunotherapies, current limitations in the application of these models as well as available improvement strategies. Finally, we pointed out some issues for future studies.

Role of immune regulatory cells in breast cancer: Foe or friend?

Breast cancer (BC) is the most common cancer among women between the ages of 20 and 50, affecting more than 2.1 million people and causing the annual death of more than 627,000 women worldwide. Based on the available knowledge, the immune system and its components are involved in the pathogenesis of several malignancies, including BC. Cancer immunobiology suggests that immune cells can play a dual role and induce anti-tumor or immunosuppressive responses, depending on the tumor microenvironment (TME) signals. The most important effector immune cells with anti-tumor properties are natural killer (NK) cells, B, and T lymphocytes. On the other hand, immune and non-immune cells with regulatory/inhibitory phenotype, including regulatory T cells (Tregs), regulatory B cells (Bregs), tolerogenic dendritic cells (tDCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), mesenchymal stem cells (MSCs), and regulatory natural killer cells (NKregs), can promote the growth and development of tumor cells by inhibiting anti-tumor responses, inducing angiogenesis and metastasis, as well as the expression of inhibitory molecules and suppressor mediators of the immune system. However, due to the complexity of the interaction and the modification in the immune cells' phenotype and the networking of the immune responses, the exact mechanism of action of the immunosuppressive and regulatory cells is not yet fully understood. This review article reviews the immune responses involved in BC as well as the role of regulatory and inhibitory cells in the pathogenesis of the disease. Finally, therapeutic approaches based on inhibition of immunosuppressive responses derived from regulatory cells are discussed.

Oncolytic Virotherapy in Solid Tumors: The Challenges and Achievements.

Oncolytic virotherapy (OVT) is a promising approach in cancer immunotherapy. Oncolytic viruses (OVs) could be applied in cancer immunotherapy without in-depth knowledge of tumor antigens. The capability of genetic modification makes OVs exciting therapeutic tools with a high potential for manipulation. Improving efficacy, employing immunostimulatory elements, changing the immunosuppressive tumor microenvironment (TME) to inflammatory TME, optimizing their delivery system, and increasing the safety are the main areas of OVs manipulations. Recently, the reciprocal interaction of OVs and TME has become a hot topic for investigators to enhance the efficacy of OVT with less off-target adverse events. Current investigations suggest that the main application of OVT is to provoke the antitumor immune response in the TME, which synergize the effects of other immunotherapies such as immune-checkpoint blockers and adoptive cell therapy. In this review, we focused on the effects of OVs on the TME and antitumor immune responses. Furthermore, OVT challenges, including its moderate efficiency, safety concerns, and delivery strategies, along with recent achievements to overcome challenges, are thoroughly discussed.

Nanotechnology Assisted Chemotherapy for Targeted Cancer Treatment: Recent Advances and Clinical Perspectives.

Nanotechnology has recently provided exciting platforms in the field of anticancer research with promising potentials for improving drug delivery efficacy and treatment outcomes. Nanoparticles (NPs) possess different advantages over the micro and bulk therapeutic agents, including their capability to carry high payloads of drugs, with prolonged half-life, reduced toxicity of the drugs, and increased targeting efficiency. The wide variety of nanovectors, coupled with different conjugation and encapsulation methods available for different theranostic agents provide promising opportunities to fine-tune the pharmacological properties of these agents for more effective cancer treatment methods. This review discusses applications of NPs-assisted chemotherapy in preclinical and clinical settings and recent advances in design and synthesis of different nanocarriers for chemotherapeutic agents. Moreover, physicochemical properties of different nanocarriers, their impacts on different tumor targeting strategies and effective parameters for efficient targeted drug delivery are discussed. Finally, the current approved NPs-assisted chemotherapeutic agents for clinical applications and under different phases of clinical trials are discussed.

Immune-mediated adverse effects of immune-checkpoint inhibitors and their management in cancer.

Within the past decade, immune-checkpoint inhibitors (ICPIs), including anti-programmed cell death 1 (PD-1), anti-programmed cell death 1 ligand 1 (PD-L1), and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, are undoubtfully the most remarkable advances in cancer therapy. The immune responses are modulated by these ICPIs via blocking the inhibitory PD-1/PD-L1 path and result in immune activation in the suppressive microenvironment of the tumor. While ICPIs result in benefits for numerous patients with malignancy and lead to disease control and survival, toxicity and safety problems have emerged as well. Although immune mediated adverse effects due to ICPIs could involve any organ system, skin, endocrine glands, and gastrointestinal tract, are one of the most commonly affected. Fortunately, in most of the cases, these immune­mediated adverse effects (imAEs) are manageable, while in some cases these toxicities are fulminant and fatal and lead to the withdrawal of treatment. Numerous attempts have been started and are continuing to reduce the incidence rate of imAEs. Further studies are required for a better understanding of these imAEs, decrease the occurrence, and lighten the severity. In this work, we overview the imAEs and also, highlight the most important aspects of the imAEs management.

Current progress in the clinical use of circulating tumor cells as prognostic biomarkers.

The process of metastasis is characterized by the shedding of tumor cells into the bloodstream, where they are transported to other parts of the body to seed new tumors. These cells, known as circulating tumor cells (CTCs), have the potential to reveal much about an individual cancer case, and theoretically can aid in the prediction of outcomes and design of precision treatments. Recent advances in technology now allow for the robust and reproducible characterization of CTCs from a simple blood draw. Both the number of circulating cells and important molecular characteristics correlated with clinical phenotypes such as drug resistance can be obtained and used for real-time prognostic analysis. Molecular characterization can provide a snapshot of the activity of the main tumor (serving as a "liquid biopsy") and early warnings concerning changes such as the development of resistance, and aid in predicting the efficacy of different therapeutic approaches for treatment optimization. Herein, the authors review the current clinical use of CTCs as prognostic biomarkers for several different cancers. The quantification of CTCs can lead to more accurate staging and decision making regarding options such as adjuvant chemotherapy.

Recent advances in carbohydrate-based cancer vaccines.

Cancer is a complex multifactorial disease for which many promising therapeutic strategies such as immunotherapy are emerging. Malignant cells frequently express aberrant cell surface carbohydrates, which differentiate them from normal "healthy" cells. This characteristic presents a window for the development of synthetic carbohydrate antigen-based cancer vaccines which can be recognized by the immune system and can bring about T cell-dependent immune responses. Antibodies generated against the carbohydrate antigens partake in the inactivation of carbohydrate-decorated cancer cells, by slowing down tumor cell growth and inducing cancer cell apoptosis. Novel synthetic strategies for carbohydrate antigens have led to several synthetic cancer vaccine candidates. In the present review, we describe the latest progress in carbohydrate-based cancer vaccines and their clinical evaluation in various cancers.