Over the last two decades, the diagnosis and treatment of breast cancer patients have improved considerably. However, brain metastases remain a major clinical challenge and a leading cause of mortality. Thus, a better understanding of the pathways involved in the metastatic cascade is essential. To this end, we have investigated the reciprocal effects of astrocytes and breast cancer cells, employing traditional 2D cell culture and our unique 3D multicellular tumouroid models. Our findings revealed that astrocytes enhance the proliferation, migration and invasion of breast cancer cells, suggesting a supportive role for astrocytes in breast cancer outgrowth to the brain. Elucidating the key players in astrocyte-breast cancer cells crosstalk, we found that CCL2 is highly expressed in breast cancer brain metastases tissue sections from both patients and mice. Our in vitro and in vivo models further confirmed that CCL2 has a functional role in brain metastasis. Given their aggressive nature, we sought additional immune checkpoints for rationale combination therapy. Among the promising candidates were the adhesion molecule P-selectin, which we have recently shown to play a key role in the crosstalk with microglia cells and the co-inhibitory receptor PD-1, the main target of currently approved immunotherapies. Finally, combining CCL2 inhibition with immunomodulators targeting either PD-1/PD-L1 or P-selectin/P-Selectin Ligand-1 axes in our human 3D tumouroid models and in vivo presented more favourable outcomes than each monotherapy. Taken together, we propose that CCL2-CCR2/CCR4 is a key pathway promoting breast cancer brain metastases and a promising target for an immunotherapeutic combination approach.

Neurodegenerative diseases (NDD) are characterized by the progressive loss of neurons and the impairment of cellular functions. Messenger RNA (mRNA) has emerged as a promising therapy for treating NDD, as it can encode missing or dysfunctional proteins and anti-inflammatory cytokines or neuroprotective proteins to halt the progression of these diseases. However, effective mRNA delivery to the central nervous system (CNS) remains a significant challenge due to the limited penetration of the blood-brain barrier (BBB). Lipid nanoparticles (LNPs) offer an efficient solution by encapsulating and protecting mRNA, facilitating transfection and intracellular delivery. This review discusses the pathophysiological mechanisms of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), Huntington's disease (HD), ischemic stroke, spinal cord injury, and Friedreich's ataxia. Additionally, it explores the potential of LNP-mediated mRNA delivery as a therapeutic strategy for these diseases. Various approaches to overcoming BBB-related challenges and enhancing the delivery and efficacy of mRNA-LNPs are discussed, including non-invasive methods with strong potential for clinical translation. With advancements in artificial intelligence (AI)-guided mRNA and LNP design, targeted delivery, gene editing, and CAR-T cell therapy, mRNA-LNPs could significantly transform the treatment landscape for NDD, paving the way for future clinical applications.

Neoadjuvant immunotherapy has rapidly evolved as a novel approach in oncology, reshaping the standard treatment for several malignancies, including melanoma, lung, bladder, colorectal, and breast cancer. While it has an acceptable safety profile, challenges persist due to the complexity of the tumor microenvironment (TME), immune evasion, T-cell exhaustion, and identification of biomarkers. Addressing these issues is critical for optimizing treatment regimens, minimizing immune-related adverse events, and ensuring successful clinical integration.

This review explores current research on neoadjuvant immunotherapy, emphasizing its impact on standard of care treatment, efficacy, safety, and clinical challenges. A literature search was conducted using PubMed and ClinicalTrials.gov for studies published in the last 5 years. Ongoing research aims to enhance the efficacy of neoadjuvant immunotherapy, identify resistance mechanisms, and broaden indications. Current clinical trials focus on biomarker-driven patient selection, refining immune response modulation through combination strategies, and developing evidence-based protocols for implementation into routine oncology practice.

Neoadjuvant immunotherapeutic options have rapidly changed the oncological treatment landscape in only a few years, and this treatment paradigm has quickly become a new standard of care in multiple solid tumors. With continued clinical investigation, neoadjuvant immunotherapy has the dramatic potential to further advance cancer care.

Pathological complete response (pCR) after neoadjuvant chemoimmunotherapy (NACi) is associated with improved patient outcomes in early triple-negative breast cancer (TNBC). This study aimed to identify factors associated with pCR after NACi. This cohort included all patients with stage II-III TNBC treated with NACi who underwent surgery at Institut Curie hospitals between 08/2021-06/2023. Among 208 patients, the overall pCR rate was 70% and was similar in ER < 1% (69%) and ER-low TNBC (73%, p = 0.6). In a multivariate model, Ki-67 ≥ 30% (OR 5.19 [1.73-17.3]), centralized TILs ≥ 30% (OR = 3.08 [1.42-7.04]), absence of DCIS at initial biopsy (OR = 2.56 [1.08-6.25]) and germline mutations in homologous recombination genes (OR = 9.50 [2.37-67.7]) remained strong independent predictors of pCR. These findings may guide treatment decisions in patients with TNBC undergoing NACi. Almost all patients with germline mutations in HR genes achieved pCR, supporting de-escalation trials. We suggest that ER-low tumors should be managed as TNBC tumors.

Immune checkpoint inhibitors (ICIs) are emerging treatment options for children with brain tumors, who are already at risk for developing endocrinopathies due to tumor location and treatment. Endocrine ICI-related adverse effects (irAEs) are common in adults but poorly characterized in the pediatric population. The aims of this study were to determine in pediatric brain tumor patients in a single institution (1) if endocrine surveillance took place before and after ICIs were initiated, and (2) the occurrence of endocrine irAEs.

This is a retrospective chart review of 22 pediatric brain tumor patients treated with ICIs at Children's Hospital Los Angeles between 2010 and 2022. We analyzed endocrine laboratory results, patient demographics, and treatment course.

Most patients (82 %) received surveillance in at least one endocrine system before ICI treatment - all had thyroid function tested (100 %) whereas non-thyroid endocrine functions were seldomly assessed (6-22 %). Only those patients with surveillance prior to treatment had ongoing surveillance after ICI initiation - 100 % for thyroid function and 17-39 % for other endocrine systems. Hypothyroidism was the only endocrine problem diagnosed after ICI initiation, in two patients (9 %). Of note, most patients (68 %) expired during or shortly after ICI treatment.

This is one of the first institutional surveys of pediatric ICIs in a high-volume pediatric brain tumor center. Thyroid surveillance commonly occurred in pediatric patients, revealing diagnoses of hypothyroidism, which is consistent with adult data. However, little information is available for non-thyroid endocrine conditions, reflecting the need for comprehensive and systematic endocrine surveillance.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer known for its high aggressiveness and poor prognosis. Conventional treatment of TNBC is challenging due to its heterogeneity and lack of clear targets. Recent advancements in immunotherapy have shown promise in treating TNBC, with immune checkpoint therapy playing a significant role in comprehensive treatment plans. The tumor microenvironment (TME), comprising immune cells, stromal cells, and various cytokines, plays a crucial role in TNBC progression and response to immunotherapy. The high presence of tumor-infiltrating lymphocytes and immune checkpoint proteins in TNBC indicates the potential of immunotherapeutic strategies. However, the complexity of the TME, while offering therapeutic targets, requires further exploration of its multiple roles in immunotherapy. In this review, we discuss the interaction mechanism between TME and TNBC immunotherapy based on the characteristics and composition of TME, and elaborate on and analyze the effect of TME on immunotherapy, the potential of TME as an immune target, and the ability of TME as a biomarker. Understanding these dynamics will offer new insights for enhancing therapeutic approaches and investigating stratification and prognostic markers for TNBC patients.

Since the introduction of immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors, survival has improved significantly for patients with irresectable and metastatic skin cancer, including cutaneous squamous cell cancer and melanoma. However, systemic administration of these drugs is associated with immune related adverse events (irAEs), which can be severe, irreversible and even fatal. To reduce the risk of irAEs associated with systemic exposure to immunotherapeutic drugs, local administration of low doses could be considered. This systematic review provides an overview of early phase clinical trials with drugs that are currently under investigation for intratumoral administration in patients with melanoma and non-melanoma skin cancer.

The increase in the availability of real-world data (RWD), in combination with advances in machine learning (ML) methods, provides a unique opportunity for the integration of the two to explore complex clinical pharmacology questions. Here we present a recently developed RWD/ML framework that utilizes ML algorithms to understand the influence and importance of various covariates on the use of a given dose and schedule for drugs that have multiple approved dosing regimens. To demonstrate the application of this framework, we present atezolizumab as a use case on account of its three approved alternative intravenous (IV) dosing regimens. As expected, the real-world use of atezolizumab has generally been increasing since 2016 for the 1200 mg every 3 weeks regimen and since 2019 for the 1680 mg every 4 weeks regimen. Out of the ML algorithms evaluated, XGBoost performed the best, as measured by the area under the precision-recall curve, with an emphasis on the under-sampled class given the imbalance in the data. The importance of features was measured by Shapley Additive exPlanations (SHAP) values and showed metastatic breast cancer and use of protein-bound paclitaxel as the most correlated with the use of 840 mg every 2 weeks. Although patient usage data for alternative IV dosing regimens are still maturing, these analyses provide initial insights on the use of atezolizumab and set up a framework for the re-analysis of atezolizumab (at a future data cut) as well as application to other molecules with approved alternative dosing regimens.

This study explores the critical role of inhibitors targeting the mammalian target of rapamycin (mTOR) signaling pathway in breast cancer research and treatment. The mTOR pathway, a central regulator of cellular processes, has been identified as a crucial factor in the development and progression of breast cancer. The essay explains the complex molecular mechanisms through which mTOR inhibitors, such as rapamycin and its analogs, exert their anticancer effects. These inhibitors can stop cell growth, proliferation, and survival in breast cancer cells by blocking critical signaling pathways within the mTOR pathway. Furthermore, the essay discusses the implications of using mTOR inhibitors as a comprehensive therapeutic strategy. It emphasizes the potential benefits of combining mTOR inhibitors with other treatment approaches to enhance the effectiveness of breast cancer treatment. The evolving landscape of breast cancer research underscores the significance of mTOR as a therapeutic target and highlights ongoing efforts to improve and optimize mTOR inhibitors for clinical use. In conclusion, the essay asserts that inhibitors of the mTOR signaling pathway offer a promising approach in the fight against breast cancer. These inhibitors provide a focused and effective intervention targeting specific dysregulations within the mTOR pathway. As research advances, the integration of mTOR inhibitors into customized combination therapies holds excellent potential for shaping a more effective and personalized approach to breast cancer treatment, ultimately leading to improved outcomes for individuals affected by this complex and diverse disease.

Atezolizumab (TECENTRIQ®) and nivolumab (OPDIVO®) are both immunotherapeutic indications targeting programmed cell death 1 ligand 1 (PD-L1) and programmed cell death 1 (PD-1), respectively. These inhibitors hold promise as therapies for triple-negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) and have demonstrated encouraging results in reducing the progression and spread of tumors. However, due to their adverse effects and low response rates, the US Food and Drug Administration (FDA) has withdrawn the approval of atezolizumab in TNBC and nivolumab in HCC treatment. The withdrawals of atezolizumab and nivolumab have raised concerns regarding their effectiveness and the ability to predict treatment responses. Therefore, the current study aims to investigate the immunotherapy withdrawal of PD-1/PD-L1 inhibitors, specifically atezolizumab for TNBC and nivolumab for HCC. This study will examine both the structural and clinical aspects. This review provides detailed insights into the structure of the PD-1 receptor and its ligands, the interactions between PD-1 and PD-L1, and their interactions with the withdrawn antibodies (atezolizumab and nivolumab) as well as PD-1 and PD-L1 modifications. In addition, this review further assesses these antibodies in the context of TNBC and HCC. It seeks to elucidate the factors that contribute to diverse responses to PD-1/PD-L1 therapy in different types of cancer and propose approaches for predicting responses, mitigating the potential risks linked to therapy withdrawals, and optimizing patient outcomes. By better understanding the mechanisms underlying responses to PD-1/PD-L1 therapy and developing strategies to predict these responses, it is possible to create more efficient treatments for TNBC and HCC.

Recent advances in cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), have revolutionized the clinical outcome of many cancer patients. Despite the fact that impressive progress has been made in recent decades, the response rate remains unsatisfactory, and many patients do not benefit from ICIs. Herein, we summarized advanced studies and the latest insights on immune inhibitory factors in the tumor microenvironment. Our in-depth discussion and updated landscape of tumor immunosuppressive microenvironment may provide new strategies for reversing tumor immune evasion, enhancing the efficacy of ICIs therapy, and ultimately achieving a better clinical outcome.

We examined the association between immunotherapy-containing and standard chemotherapy regimens with treatment delays and postoperative complications in stage II-III triple-negative breast cancer. The effect of immune-related adverse events (irAEs) was compared.

We compared 139 women treated with neoadjuvant pembrolizumab plus chemotherapy (KEYNOTE-522 regimen) from August 2021 to September 2022 with 287 consecutive patients who received neoadjuvant chemotherapy alone prior to July 2021 and underwent surgery. Baseline characteristics, time to treatments, and surgical complications were compared using two-sample non-parametric tests. Linear regression evaluated association of irAEs with time to surgery and radiation. Logistic regression identified factors associated with surgical complications.

Age, body mass index, race, American Society of Anesthesiologists (ASA) class, and mastectomy rates were similar among cohorts. No clinically relevant difference in time from end of neoadjuvant treatment to surgery was observed [KEYNOTE-522: median 32 (IQR 27, 43) days; non-KEYNOTE-522: median 31 (IQR 26, 37) days; P = 0.048]. Time to radiation did not differ (P = 0.7). A total of 26 patients (9%; non-KEYNOTE-522) versus 11 (8%; KEYNOTE-522) experienced postoperative complications (P = 0.6). In the KEYNOTE-522 cohort, 59 (43%) of 137 patients experienced 82 irAEs; 40 (68%) required treatment. Older age (P = 0.018) and ASA class 4 (P = 0.007) were associated with delays to surgery after adjusting for clinical factors. Experiencing ≥ 1 irAE was associated with delay to radiation (P = 0.029). IrAEs were not associated with surgical complications (P = 0.4).

We observed no clinically meaningful difference between times to surgery/adjuvant radiation or postoperative complications and type of preoperative chemotherapy. IrAEs were associated with delay to adjuvant radiation but not with postoperative complications or delay to surgery.

Immunotherapy has revolutionized cancer therapy and now represents a standard of care for many tumor types, including triple-negative breast cancer. Despite the positive results that have led to the approval of immunotherapy in both early- and advanced-stage triple-negative breast cancer, pivotal clinical trials cannot address the myriad questions arising in everyday clinical practice, often falling short in delivering all the information that clinicians require. In this manuscript, we aim to address some of these practical questions, with the purpose of providing clinicians with a guide for optimizing the use of immune checkpoint inhibitors in the management of breast cancer patients and identifying opportunities for future research to clarify unresolved questions.

As one of the most prevalent forms of cancer worldwide, breast cancer has garnered significant attention within the clinical research setting. While traditional treatment employs a multidisciplinary approach including a variety of therapies such as chemotherapy, hormone therapy, and even surgery, researchers have since directed their attention to the budding role of neoantigens. Neoantigens are defined as tumor-specific antigens that result from a multitude of genetic alterations, the most prevalent of which is the single nucleotide variant. As a result of their foreign nature, neoantigens elicit immune responses upon presentation by Major Histocompatibility Complexes I and II followed by recognition by T cell receptors. Previously, researchers have been able to utilize these immunogenic properties and manufacture neoantigen-specific T-cells and neoantigen vaccines. Within the context of breast cancer, biomarkers such as tumor protein 53 (TP53), Survivin, Partner and Localizer of BRCA2 (PALB2), and protein tyrosine phosphatase receptor T (PTPRT) display exceeding potential to serve as neoantigens. However, despite their seemingly limitless potential, neoantigens must overcome various obstacles if they are to be fairly distributed to patients. For instance, a prolonged period between the identification of a neoantigen and the dispersal of treatment poses a serious risk within the context of breast cancer. Regardless of these current obstacles, it appears highly promising that future research into neoantigens will make an everlasting impact on the health outcomes within the realm of breast cancer. The purpose of this literature review is to comprehensively discuss the etiology of various forms of breast cancer and current treatment modalities followed by the significance of neoantigens in cancer therapeutics and their application to breast cancer. Further, we have discussed the limitations, future directions, and the role of transcriptomics in neoantigen identification and personalized medicine. The concepts discussed in the original and review articles were included in this review article.

We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, treated with entinostat + nivolumab + ipilimumab from the dose escalation (N = 6) and expansion cohort (N = 18) of ETCTN-9844 ( NCT02453620 ). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and change in tumor CD8:FoxP3 ratio. There were no dose-limiting toxicities. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), with 40% (N = 4) in triple-negative breast cancer and 10% (N = 1) in hormone receptor-positive breast cancer. The clinical benefit rate was 40% (N = 8), and progression-free survival at 6 months was 50%. Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however, no correlation was noted between changes in CD8:FoxP3 ratio, PD-L1 status and tumor mutational burden and response. These findings support further investigation of this treatment in a phase II trial.

Neoadjuvant systemic therapy (NST) was initially reserved for unresectable patients however it has been increasingly used to facilitate breast conservation, downstage the axilla, and inform adjuvant therapy decisions based on response. For patients with HER2+ and triple-negative breast cancer (TNBC), clinical trials have resulted in the ability to individualize treatment regimens. For HER2+ breast cancer, de-escalation of neoadjuvant regimens to minimize cytotoxic chemotherapy and de-escalation or escalation of adjuvant regimens based on response have been effective. For TNBC, the approval of the combination of chemotherapy plus immunotherapy in the neoadjuvant setting has resulted in a major practice shift and opened the door to many additional treatment questions including de-escalation of the chemotherapy backbone or the adjuvant regimen. For both HER2+ and TNBC, most patients are treated with NST except those with very small tumors. Efforts are also being made to optimally identify patients with T1c tumors who may benefit from more aggressive NST. For patients treated according to or enrolled in NST de-escalation trials, breast conservation (even those who become eligible based on response to NST) and sentinel lymph node biopsy when cN0 at the completion of NST are safe and feasible. Continued involvement of surgeons and multidisciplinary teams in the design and reporting of trials will streamline their adoption into clinical practice. Surgeons need to remain aware of ongoing systemic therapy trials to appropriately select patients for NST and plan for appropriate post-neoadjuvant surgical care.

Malignancies represent a persisting worldwide health burden. Tumor treatment is commonly based on surgical and/or non-surgical therapies. In the recent decade, novel non-surgical treatment strategies involving monoclonal antibodies (mAB) and immune checkpoint inhibitors (ICI) have been successfully incorporated into standard treatment algorithms. Such emerging therapy concepts have demonstrated improved complete remission rates and prolonged progression-free survival compared to conventional chemotherapies. However, the in-toto surgical tumor resection followed by reconstructive surgery oftentimes remains the only curative therapy. Breast cancer (BC), skin cancer (SC), head and neck cancer (HNC), and sarcoma amongst other cancer entities commonly require reconstructive surgery to restore form, aesthetics, and functionality. Understanding the basic principles, strengths, and limitations of mAB and ICI as (neo-) adjuvant therapies and treatment alternatives for resectable or unresectable tumors is paramount for optimized surgical therapy planning. Yet, there is a scarcity of studies that condense the current body of literature on mAB and ICI for BC, SC, HNC, and sarcoma. This knowledge gap may result in suboptimal treatment planning, ultimately impairing patient outcomes. Herein, we aim to summarize the current translational endeavors focusing on mAB and ICI. This line of research may serve as an evidence-based fundament to guide targeted therapy and optimize interdisciplinary anti-cancer strategies.

This study aims to explore whether neoadjuvant chemotherapy with immunotherapy (NACI) leads to different tumor shrinkage patterns, based on magnetic resonance imaging (MRI), compared to neoadjuvant chemotherapy (NAC) alone in patients with triple-negative breast cancer (TNBC). Additionally, the study investigates the relationship between tumor shrinkage patterns and treatment efficacy was investigated.

This retrospective study included patients with TNBC patients receiving NAC or NACI from January 2019 until July 2021 at our center. Pre- and post-treatment MRI results were obtained for each patient, and tumor shrinkage patterns were classified into three categories as follows: 1) concentric shrinkage (CS); 2) diffuse decrease; and 3) no change. Tumor shrinkage patterns were compared between the NAC and NACI groups, and the relevance of the patterns to treatment efficacy was assessed.

Of the 99 patients, 65 received NAC and 34 received NACI. The CS pattern was observed in 53% and 20% of patients in the NAC and NACI groups, respectively. Diffuse decrease pattern was observed in 36% and 68% of patients in the NAC and NACI groups. The association between the treatment regimens (NAC and NACI) and tumor shrinkage patterns was statistically significant (p = 0.004). The postoperative pathological complete response (pCR) rate was 45% and 82% in the NAC and NACI groups (p < 0.001), respectively. In the NACI group, 17% of patients with the CS pattern and 56% of those with the diffuse decrease pattern achieved pCR (p = 0.903). All tumor shrinkage patterns were associated with achieved a high pCR rate in the NACI group.

Our study demonstrates that the diffuse decrease pattern of tumor shrinkage is more common following NACI than that following NAC. Furthermore, our findings suggest that all tumor shrinkage patterns are associated with a high pCR rate in patients with TNBC treated with NACI.

ClinicalTrials.gov Identifier: NCT04909554.

Following major developments in cancer immunotherapy, treatments targeting immune checkpoint proteins (ICP) gained interest in breast cancer, though studies mostly focus on patients with metastatic disease as well as patients nonresponsive to the conventional treatments. Herein, we aimed to investigate the levels of ICP in tumor stroma and tumor infiltrating lymphocytes, and tumor tissue prior to neoadjuvant chemotherapy administration to evaluate the relationship between ICP levels, clinicopathological parameters, and NAC response.

This study was conducted with 51 patients where PD-1, PD-L1, CTLA-4, TIM-3, CD24 and CD44 levels were investigated in CD45+ cells while CD326, CD24, CD44 and PD-L1 protein expression levels were investigated in CD45- population. In addition, CD44 and CD24 levels were evaluated in the tumor stroma. TIL levels were investigated according to the TILS Working Group. Treatment responses after NAC were evaluated according to the MD Anderson RCB score.

Our results revealed positive correlation between CTLA-4 and CD44 expression in cases with high TIL levels as well as TIL levels and CTLA-4 expression in cases with partial response. Similarly, positive correlation was detected between TIM3 and PD-L1 levels in cases with good response. In addition, a negative correlation between TILs after NAC and PD-1/PD-L1 expression in lymphocytes in cases with partial complete response.

Our study provides preliminary data about the correlation between ICP and clinicopathological status and NAC response in breast cancer, in addition to underlining the requirement for further research to determine their potential as therapeutic targets.

The triple-negative breast cancer (TNBC) subtype is characterized by the lack of expression of ERα (estrogen receptor α), PR (progesterone receptor) and no overexpression of HER-2. However, TNBC can express the androgen receptor (AR) or estrogen receptor β (ERβ). Also, TNBC secretes steroid hormones and is influenced by hormonal fluctuations, so the steroid inhibition could exert a beneficial effect in TNBC treatment. The aim of this study was to evaluate the effect of dutasteride, anastrozole and ASP9521 in in vitro processes using human TNBC cell lines. For this, immunofluorescence, sensitivity, proliferation and wound healing assays were performed, and hormone concentrations were studied. Results revealed that all TNBC cell lines expressed AR and ERβ; the ones that expressed them most intensely were more sensitive to antihormonal treatments. All treatments reduced cell viability, highlighting MDA-MB-453 and SUM-159. Indeed, a decrease in androgen levels was observed in these cell lines, which could relate to a reduction in cell viability. In addition, MCF-7 and SUM-159 increased cell migration under treatments, increasing estrogen levels, which could favor cell migration. Thus, antihormonal treatments could be beneficial for TNBC therapies. This study clarifies the importance of steroid hormones in AR and ERβ-positive cell lines of TNBC.

Immune checkpoint inhibitors have shown minimal clinical activity in hormone receptor-positive metastatic breast cancer (HR+mBC). Doxorubicin and low-dose cyclophosphamide are reported to induce immune responses and counter regulatory T cells (Tregs). Here, we report the efficacy and safety of combined programmed cell death protein-1/cytotoxic T-lymphocyte-associated protein 4 blockade concomitant with or after immunomodulatory chemotherapy for HR+mBC.

Patients with HR+mBC starting first-/second- line chemotherapy (chemo) were randomized 2:3 to chemotherapy (pegylated liposomal doxorubicin 20 mg/m2 every second week plus cyclophosphamide 50 mg by mouth/day in every other 2-week cycle) with or without concomitant ipilimumab (ipi; 1 mg/kg every sixth week) and nivolumab (nivo; 240 mg every second week). Patients in the chemo-only arm were offered cross-over to ipi/nivo without chemotherapy. Co-primary endpoints were safety in all patients starting therapy and progression-free survival (PFS) in the per-protocol (PP) population, defined as all patients evaluated for response and receiving at least two treatment cycles. Secondary endpoints included objective response rate, clinical benefit rate, Treg changes during therapy and assessment of programmed death-ligand 1 (PD-L1), mutational burden and immune gene signatures as biomarkers.

Eighty-two patients were randomized and received immune-chemo (N=49) or chemo-only (N=33), 16 patients continued to the ipi/nivo-only cross-over arm. Median follow-up was 41.4 months. Serious adverse events occurred in 63% in the immune-chemo arm, 39% in the chemo-only arm and 31% in the cross-over-arm. In the PP population (N=78) median PFS in the immune-chemo arm was 5.1 months, compared with 3.6 months in the chemo-only arm, with HR 0.94 (95% CI 0.59 to 1.51). Clinical benefit rates were 55% (26/47) and 48% (15/31) in the immune-chemo and chemo-only arms, respectively. In the cross-over-arm (ipi/nivo-only), objective responses were observed in 19% of patients (3/16) and clinical benefit in 25% (4/16). Treg levels in blood decreased after study chemotherapy. High-grade immune-related adverse events were associated with prolonged PFS. PD-L1 status and mutational burden were not associated with ipi/nivo benefit, whereas a numerical PFS advantage was observed for patients with a high Treg gene signature in tumor.

The addition of ipi/nivo to chemotherapy increased toxicity without improving efficacy. Ipi/nivo administered sequentially to chemotherapy was tolerable and induced clinical responses.

ClinicalTrials.gov Identifier: NCT03409198.

Objectives: Heparanase (HPSE), an endoglycosidase that cleaves heparan sulfate, regulates various biological processes related to tumor progression. We explore the prognostic value of HPSE and its relationship with immunotherapy response in patients with breast cancer, to improve the effectiveness of immunotherapy and increase the survival outcomes. Methods: In the study, we explored the prognostic value of HPSE through the The Cancer Genome Atlas (TCGA) database. By using the single-sample gene set enrichment analysis (ssGSEA) method, we measured the infiltration levels of 24 immune cell types in the tumor microenvironment. Cancer Therapeutics Response Portal (CTRP) and PRISM datasets provide the area under the dose-response curve (AUC) to measure drug sensitivity. Using nomograms, we predicted overall survival ability. In vivo studies, we investigated the relationship between HPSE and immune checkpoint proteins and pro-inflammatory cytokines by immunohistochemistry of Triple-Negative Breast Cancer tumors in mice. Results: Our model demonstrated that the integrating of HPSE with the clinical stage effectively predicts patients' survival time, highlighting high HPSE expression as a prognostic risk factor for breast cancer. Then the Receiver Operating Characteristic (ROC) curve [AUC of 1 year = 0.747, AUC of 3 years = 0.731] and Decision Curve Analysis (DCA) curve illustrated the satisfactory discriminative capacity of our model, emphasizing its valuable clinical applicability. Immune-related results showed that HPSE correlates strongly with immune infiltrating cells, immune-related genes, and the anti-cancer immunity cycle. In vivo studies have demonstrated that HPSE in breast cancer is associated with increased expression of immune checkpoint proteins CD274 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and is positively correlated with the pro-inflammatory cytokine TNF-α. Meanwhile, we analyzed the 11 types of drugs that are sensitive to the HPSE gene. Conclusion: Our results show that HPSE can serve as an effective biomarker to predict the prognosis of breast cancer patients and reflect the impact of immunotherapy.

Triple-negative breast cancer (TNBC) has poorer outcomes than other breast cancers (BC), including HER2+ BC. Cathepsin D (CathD) is a poor prognosis marker overproduced by BC cells, hypersecreted in the tumour microenvironment with tumour-promoting activity. Here, we characterized the immunomodulatory activity of the anti-CathD antibody F1 and its improved Fab-aglycosylated version (F1M1) in immunocompetent mouse models of TNBC (C57BL/6 mice harbouring E0771 cell grafts) and HER2-amplified BC (BALB/c mice harbouring TUBO cell grafts).

CathD expression was evaluated by western blotting and immunofluorescence, and antibody binding to CathD by ELISA. Antibody anti-tumour efficacy was investigated in mouse models. Immune cell recruitment and activation were assessed by immunohistochemistry, immunophenotyping, and RT-qPCR.

F1 and F1M1 antibodies remodelled the tumour immune landscape. Both antibodies promoted innate antitumour immunity by preventing the recruitment of immunosuppressive M2-polarized tumour-associated macrophages (TAMs) and by activating natural killer cells in the tumour microenvironment of both models. This translated into a reduction of T-cell exhaustion markers in the tumour microenvironment that could be locally supported by enhanced activation of anti-tumour antigen-presenting cell (M1-polarized TAMs and cDC1 cells) functions. Both antibodies inhibited tumour growth in the highly-immunogenic E0771 model, but only marginally in the immune-excluded TUBO model, indicating that anti-CathD immunotherapy is more relevant for BC with a high immune cell infiltrate, as often observed in TNBC.

Anti-CathD antibody-based therapy triggers the anti-tumour innate and adaptive immunity in preclinical models of BC and is a promising immunotherapy for immunogenic TNBC.

GM-CSF has been employed as an adjuvant to cancer immunotherapy with mixed results based on dosage. We previously showed that GM-CSF regulated tumor angiogenesis by stimulating soluble vascular endothelial growth factor (VEGF) receptor-1 from monocytes/macrophages in a dose-dependent manner that neutralized free VEGF, and intratumoral injections of high-dose GM-CSF ablated blood vessels and worsened hypoxia in orthotopic polyoma middle T Ag (PyMT) triple-negative breast cancer (TNBC). In this study, we assessed both immunoregulatory and oxygen-regulatory components of low-dose versus high-dose GM-CSF to compare effects on tumor oxygen, vasculature, and antitumor immunity. We performed intratumoral injections of low-dose GM-CSF or saline controls for 3 wk in FVB/N PyMT TNBC. Low-dose GM-CSF uniquely reduced tumor hypoxia and normalized tumor vasculature by increasing NG2+ pericyte coverage on CD31+ endothelial cells. Priming of "cold," anti-PD1-resistant PyMT tumors with low-dose GM-CSF (hypoxia reduced) sensitized tumors to anti-PD1, whereas high-dose GM-CSF (hypoxia exacerbated) did not. Low-dose GM-CSF reduced hypoxic and inflammatory tumor-associated macrophage (TAM) transcriptional profiles; however, no phenotypic modulation of TAMs or tumor-infiltrating lymphocytes were observed by flow cytometry. In contrast, high-dose GM-CSF priming increased infiltration of TAMs lacking the MHC class IIhi phenotype or immunostimulatory marker expression, indicating an immunosuppressive phenotype under hypoxia. However, in anti-PD1 (programmed cell death 1)-susceptible BALB/c 4T1 tumors (considered hot versus PyMT), high-dose GM-CSF increased MHC class IIhi TAMs and immunostimulatory molecules, suggesting disparate effects of high-dose GM-CSF across PyMT versus 4T1 TNBC models. Our data demonstrate a (to our knowledge) novel role for low-dose GM-CSF in reducing tumor hypoxia for synergy with anti-PD1 and highlight why dosage and setting of GM-CSF in cancer immunotherapy regimens require careful consideration.

Chemo-immunotherapy is the first-line standard of care for patients with PD-L1 positive metastatic triple-negative breast cancer (mTNBC). SYNERGY (NCT03616886) is a dose-finding phase I and a randomized phase II, open-label trial evaluating if targeting the immunosuppressive adenosine pathway can enhance the antitumor activity of chemo-immunotherapy. The phase I part included 6 patients with untreated locally-advanced or mTNBC to determine the safety and recommended phase II dose of the anti-CD73 antibody oleclumab in combination with the anti-PD-L1 durvalumab and 12 cycles of weekly carboplatin and paclitaxel. In the phase II part, 127 women were randomized 1:1 to receive chemo-immunotherapy, with (arm A) or without (arm B) oleclumab. The primary endpoint was the clinical benefit rate at week 24, defined as stable disease, partial or complete response per RECIST v1.1. Secondary endpoints included objective response rate, duration of response, survival outcomes (progression-free survival and overall survival), and safety. The trial did not meet its primary endpoint, as the 24-week clinical benefit rate was not significantly improved by adding oleclumab (43% vs. 44%, p = 0.61). Exploratory median progression-free survival was 5.9 months in arm A as compared to 7.0 months in arm B (p = 0.90). The safety profile was manageable in both arms.

Immunotherapy has revolutionized cancer treatment, including TNBC, which has limited options of treatment and poor prognosis. ICIs studied in TNBC include pembrolizumab, nivolumab, atezolizumab, and durvalumab. Initial studies exploring ICI monotherapy demonstrated promising yet limited responses. Subsequent studies, KEYNOTE 522 and KEYNOTE 355, which combined ICI with chemotherapy, have resulted in the FDA approval of pembrolizumab in the early-stage and metastatic setting, respectively.

This article provides a comprehensive review of the role of ICI in the treatment of TNBC. We reviewed the trials that have evaluated ICI monotherapy, dual therapy, ICI in combination with chemotherapy, targeted therapy, vaccines and radiation. Additionally, we reviewed potential biomarkers of response and immune-related adverse events (irAEs). A literature search was conducted via PubMed and ClinicalTrials.gov as of 5 June 2023.

Various approaches combining immunotherapy with chemotherapy, targeted therapy, vaccines and radiation have been assessed. Pembrolizumab remains the only ICI approved in both the early stage and mTNBC. The role of adjuvant pembrolizumab in those who achieved pCR after neoadjuvant therapy is being investigated. Combining ICI with PARP inhibitors and radiation shows promise. More research is needed in identifying predictors of response. Monitoring of irAEs remains crucial.

RECISTv1.1 (Response Evaluation Criteria In Solid Tumors) is the most commonly used response grading criteria in early oncology trials. In this perspective, we argue that RECISTv1.1 is ambiguous regarding lesion-to-lesion variation that can introduce bias in decision making. We show theoretical examples of how lesion-to-lesion variability causes bias in RECISTv1.1, leading to misclassification of patient response. Next, we review immune checkpoint inhibitor (ICI) clinical trial data and find that lesion-to-lesion heterogeneity is widespread in ICI-treated patients. We illustrate the implications of ignoring lesion-to-lesion heterogeneity in interpreting biomarker data, selecting treatments for patients with progressive disease, and go/no-go decisions in drug development. Further, we propose that Quantitative Systems Pharmacology (QSP) models can aid in developing better metrics of patient response and treatment efficacy by capturing patient responses robustly by considering lesion-to-lesion heterogeneity. Overall, we believe patient response evaluation with an appreciation of lesion-to-lesion heterogeneity can potentially improve decision-making at the early stage of oncology drug development and benefit patient care.

Emerging evidence suggests that breast microbiota dysbiosis contributes to cancer initiation, progression, prognosis and treatment efficacy. Anyway, available data are referred only to female patients, and studies on males are completely missing. Male breast cancer (MBC) is 70-100 times less frequent, but the mortality rate adjusted to incidence is higher in men than in females. Currently, MBC diagnostic approaches and treatments have generally been extrapolated from the clinical experience gained in women, while few studies focus on characterizing male cancer biology. Taking into account the rising importance of the oncobiome field and the need of MBC targeted studies, we explored the breast cancer oncobiome of male and female patients.

16S rRNA gene sequencing was performed in 20 tumor and 20 non-pathological adjacent FFPE breast tissues from male and female patients.

We documented, for the first time, the presence of a sexually dimorphic breast-associated microbiota, here defined as "breast microgenderome". Moreover, the paired analysis of tumor and non-pathological adjacent tissues suggests the presence of a cancer-associated dysbiosis in male patients, with surrounding tissue conserving a healthier microbiome, whereas in female patients, the entire breast tissue is predisposed to cancer development. Finally, the phylum Tenericutes, especially the genera Mesoplasma and Mycobacterium, could to be involved in breast carcinogenesis, in both sexes, deserving further investigation, not only for its role in cancer development but even as potential prognostic biomarker.

Breast microbiota characterization can enhance the understanding of male breast cancer pathogenesis, being useful for detection of new prognostic biomarkers and development of innovative personalized therapies, remarking the relevant gender differences.

Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, and patient quality of life considerations, among other topics. To address this need for guidance, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline. The Expert Panel drew on the published literature as well as their own clinical experience to develop evidence- and consensus-based recommendations to provide guidance to cancer care professionals treating patients with gynecologic cancer.

Immunotherapy, particularly agents targeting the immunoregulatory PD-1/PD-L1 axis, harnesses the power of the immune system to treat cancer, with unique potential for a durable treatment effect due to immunologic memory. The PD-1 inhibitor pembrolizumab combined with neoadjuvant chemotherapy followed by adjuvant pembrolizumab improves event-free survival and is a new standard of care for high-risk, early-stage triple-negative breast cancer (TNBC), regardless of tumor PD-L1 expression. For metastatic TNBC, pembrolizumab combined with chemotherapy is a new standard of care for the first-line therapy of PD-L1+ metastatic TNBC, with improvement in overall survival. The PD-L1 inhibitor atezolizumab combined with nab-paclitaxel is also approved outside the United States for the first-line treatment of metastatic PD-L1+ TNBC. Current research focuses on refining the use of immunotherapy in TNBC by defining informative predictive biomarkers, developing immunotherapy in early and advanced HER2-driven and luminal breast cancers, and overcoming primary and secondary resistance to immunotherapy through unique immune-based strategies.

Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors have transformed the treatment landscape of advanced hepatocellular carcinoma (HCC), but consistent responses are not observed in all patients, and prognostic biomarkers to guide treatment decisions are lacking. We aimed to evaluate the predictive value of PD-L1 expression in advanced HCC patients treated with PD-1/PD-L1 inhibitors.

A comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted. Studies comparing the objective response rate (ORR) and/or disease control rate (DCR) based on the tumor PD-L1 status of HCC were included.

Eleven studies with 1,330 HCC patients treated with PD-1/PD-L1 inhibitors were included. Pooled odds ratio (OR) analysis demonstrated a significantly improved ORR in PD-L1-positive patients compared with PD-L1-negative patients (OR, 1.86, 95% CI, 1.35-2.55). Similar results were observed in the anti-PD-1 treatment (p < 0.001) and anti-PD-1/PD-L1 monotherapy (p < 0.001) subgroups. The pooled ORRs in the PD-L1-positive and PD-L1-negative groups were 26% (95% CI, 20%-32%) and 18% (95% CI, 13%-22%), respectively. For DCR, the pooled OR analysis showed no significant difference between PD-L1-positive patients and PD-L1-negative patients (66% [95% CI, 55%-76%] vs. 69% [95% CI, 62%-76%]; OR, 0.92, 95% CI, 0.59-1.44). The results were consistent across the drug target and combination treatment subgroups.

Positive PD-L1 expression is associated with a better ORR in advanced HCC patients treated with anti-PD-1/PD-L1-based therapies. This feature can help to identify HCC patients who will benefit most from PD-1/PD-L1 inhibitors.

The second leading cause of cancer death in women worldwide is breast cancer (BC), and despite significant advances in BC therapies, a significant proportion of patients develop metastasis and disease recurrence. Currently used treatments, like radiotherapy, chemotherapy, and hormone replacement therapy, result in poor responses and high recurrence rates. Alternative therapies are therefore needed for this type of cancer. Cancer patients may benefit from immunotherapy, a novel treatment strategy in cancer treatment. Even though immunotherapy has been successful in many cases, some patients do not respond to the treatment or those who do respond relapse or progress. The purpose of this review is to discuss several different immunotherapy approaches approved for the treatment of BC, as well as different strategies for immunotherapy for the treatment of BC.

Recent progress in immunobiology has led the way to successful host immunity enhancement against breast cancer. In triple-negative breast cancer, the combination of cancer immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors with chemotherapy was effective both in advanced and early setting phase 3 clinical trials. These encouraging results lead to the first approvals of immune checkpoint inhibitors in triple-negative breast cancer and thus offer new therapeutic possibilities in aggressive tumors and hard-to-treat populations. Furthermore, several ongoing trials are investigating combining immunotherapies involving immune checkpoint inhibitors with conventional therapies and as well as with other immunotherapeutic strategies such as cancer vaccines, CAR-T cells, bispecific antibodies, and oncolytic viruses in all breast cancer subtypes. This review provides an overview of immunotherapies currently under clinical development and updated key results from clinical trials. Finally, we discuss the challenges to the successful implementation of immune treatment in managing breast cancer and their implications for the design of future clinical trials.

Breast cancer (BC) is a representative malignant tumor that affects women across the world, and it is the main cause of cancer-related deaths in women. Although a large number of treatment methods have been developed for BC in recent years, the results are sometimes unsatisfying. In recent years, treatments of BC have been expanded with immunotherapy. In our article, we list some tumor markers related to immunotherapy for BC. Moreover, we introduce the existing relatively mature immunotherapy and the markers' pathogenesis are involved. The combination of immunotherapy and other therapies for BC are introduced in detail, including the combination of immunotherapy and chemotherapy, the combined use of immunosuppressants and chemotherapy drugs, immunotherapy and molecular targeted therapy. We summarize the clinical effects of these methods. In addition, this paper also makes a preliminary exploration of the combination of immunotherapy, radiotherapy, and nanotechnology for BC.