Photodynamic priming with triple-receptor targeted nanoconjugates that trigger T cell-mediated immune responses in a 3D in vitro heterocellular model of pancreatic cancer

Photodynamic priming (PDP), a collateral effect of photodynamic therapy, can transiently alter the tumor microenvironment (TME) beyond the cytotoxic zone. Studies have demonstrated that PDP increases tumor permeability and modulates immune-stimulatory effects by inducing immunogenic cell death, via the release of damage-associated molecular patterns and tumor-associated antigens. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of cancers with a stubborn immunosuppressive TME and a dense stroma, representing a challenge for current molecular targeted therapies often involving macromolecules. We, therefore, tested the hypothesis that PDP\u27s TME modulation will enable targeted therapy and result in immune stimulation. Using triple-receptor-targeted photoimmuno-nanoconjugate (TR-PINs)-mediated PDP, targeting epidermal growth factor receptor, transferrin receptor, and human epidermal growth factor receptor 2 we show light dose-dependent TR-PINs mediated cytotoxicity in human PDAC cells (MIA PaCa-2), co-cultured with human pancreatic cancer-associated fibroblasts (PCAFs) in spheroids. Furthermore, TR-PINs induced the expression of heat shock proteins (Hsp60, Hsp70), Calreticulin, and high mobility group box 1 in a light dose and time-dependent manner. TR-PINs-mediated T cell activation was observed in co-cultures of immune cells with the MIA PaCa-2-PCAF spheroids. Both CD4+ T and CD8+ T cells showed light dose and time-dependant antitumor reactivity by upregulating degranulation marker CD107a and interferon-gamma post-PDP. Substantial tumor cell death in immune cell-spheroid co-cultures by day 3 shows the augmentation by antitumor T cell activation and their ability to recognize tumors for a light dose-dependent kill. These data confirm enhanced destruction of heterogeneous pancreatic spheroids mediated by PDP-induced phototoxicity, TME modulation and increased immunogenicity with targeted nanoconstructs

Adjuvant chemotherapy for resected triple negative breast cancer patients: A network meta-analysis

The current standard of care for resected early-stage triple negative breast cancer (TNBC) patients who did not receive systemic preoperative therapy is adjuvant anthracycline- and taxane-based chemotherapy (CT). A network meta-analysis (NMA) of randomized controlled trials (phase III) enrolling patients with resected stage I-III TNBC comparing adjuvant regimens was performed. Overall survival (OS) and disease-free survival (DFS) data were extracted. A total of 27 phase III clinical trials were selected including 15,242 TNBC patients. This NMA showed an OS benefit from the incorporation of capecitabine into classic anthracycline/taxane-based combinations compared to anthracyclines with or without taxanes alone

LAG3: The biological processes that motivate targeting this immune checkpoint molecule in human cancer

The programmed cell death 1 (PD-1) pathway is an important regulator of immune responses in peripheral tissues, including abnormal situations such as the tumor microenvironment. This pathway is currently the principal target for immunotherapeutic compounds designed to block immune checkpoint pathways, with these drugs improving clinical outcomes in a number of solid and hematological tumors. Medical oncology is experiencing an immune revolution that has scientists and clinicians looking at alternative, non-redundant inhibitory pathways also involved in regulating immune responses in cancer. A variety of targets have emerged for combinatorial approaches in immune checkpoint blockade. The main purpose of this narrative review is to summarize the biological role of lymphocyte activation gene 3 (LAG3), an emerging targetable inhibitory immune checkpoint molecule. We briefly discuss its role in infection, autoimmune disease and cancer, with a more detailed analysis of current data on LAG3 expression in breast cancer. Current clinical trials testing soluble LAG3 immunoglobulin and LAG3 antagonists are also presented in this work.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Tumor-infiltrating lymphocytes in breast cancer according to tumor subtype: Current state of the art

The recent success of the immune checkpoint blockade in cancer immunotherapy has modified the treatment algorithms in a variety of aggressive neoplastic diseases. Nevertheless, optimal selection of ideal candidates to these drugs remains a challenge. The presence, location and composition of a pre-existing tumor immune infiltrate seem to impact on the benefit from these treatments. The association between the presence of baseline tumor-infiltrating lymphocytes (TIL) and patients' outcomes has been widely investigated in breast cancer, although immunotherapeutic strategies have historically been less successful with respect to other neoplastic diseases such as melanoma and kidney cancer. TIL extent varies and has different associations with outcomes in the various breast cancer subtypes. Furthermore, the presence of baseline high TIL has been associated with an increased benefit from some chemotherapeutic and targeted agents even though some conflicting results have been observed on this regard. This review aims to summarize the state of the art of TIL in breast cancer with a focus on their assessment, prevalence and clinical implications in the different subtypes

Significance of TIM3 expression in cancer: From biology to the clinic

Targeting inhibitory immune checkpoint molecules has dramatically changed treatment paradigms in medical oncology. Understanding the best strategies to unleash a pre-existing immune response or to induce an efficient immune response against tumors has emerged as a research priority. In this work, we focus on a novel target for cancer immunotherapy, the inhibitory receptor T-cell immunoglobulin and mucin domain 3 (TIM3). This narrative review describes TIM3 biology in different (tumor-infiltrating) immune cells, particularly in the immunosuppressive regulatory T cells and dysfunctional/exhausted cytotoxic T lymphocytes, but also in cells that confer innate immunity – natural killer and dendritic cells. We discuss the functional role of TIM3, its expression and its clinical significance in a variety of tumors, and confront the heterogeneous results emerging from different studies, including clinical trials of immunotherapy. Finally, this work summarizes the principal early-phase clinical trials exploring TIM3 blockade and discusses some future perspectives.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Breast MRI: Clinical Indications, Recommendations, and Future Applications in Breast Cancer Diagnosis

Purpose of review: This article aims to provide an updated overview of the indications for diagnostic breast magnetic resonance imaging (MRI), discusses the available and novel imaging exams proposed for breast cancer detection, and discusses considerations when performing breast MRI in the clinical setting. Recent findings: Breast MRI is superior in identifying lesions in women with a very high risk of breast cancer or average risk with dense breasts. Moreover, the application of breast MRI has benefits in numerous other clinical cases as well; e.g., the assessment of the extent of disease, evaluation of response to neoadjuvant therapy (NAT), evaluation of lymph nodes and primary occult tumor, evaluation of lesions suspicious of Paget's disease, and suspicious discharge and breast implants. Breast cancer is the most frequently detected tumor among women around the globe and is often diagnosed as a result of abnormal findings on mammography. Although effective multimodal therapies significantly decline mortality rates, breast cancer remains one of the leading causes of cancer death. A proactive approach to identifying suspicious breast lesions at early stages can enhance the efficacy of anti-cancer treatments, improve patient recovery, and significantly improve long-term survival. However, the currently applied mammography to detect breast cancer has its limitations. High false-positive and false-negative rates are observed in women with dense breasts. Since approximately half of the screening population comprises women with dense breasts, mammography is often incorrectly used. The application of breast MRI should significantly impact the correct cases of breast abnormality detection in women. Radiomics provides valuable data obtained from breast MRI, further improving breast cancer diagnosis. Introducing these constantly evolving algorithms in clinical practice will lead to the right breast detection tool, optimized surveillance program, and individualized breast cancer treatment

Targeting CTLA-4 in cancer: Is it the ideal companion for PD-1 blockade immunotherapy combinations?

Immunotherapy approaches boosting spontaneous and durable antitumor immune responses through immune checkpoint blockade are revolutionizing treatment and patient outcomes in solid tumors and hematological malignancies. Among the various inhibitory molecules employed by the immune system to regulate the adaptive immune responses, cytotoxic T lymphocyte antigen-4 (CTLA-4) is the first successfully targeted immune checkpoint molecule in the clinic, giving rise to significant but selective benefit either when targeted alone or in combination with anti-programmed cell death protein-1 (PD-1) antibodies (Abs). However, the use of anti-CTLA-4 Abs was associated with the incidence of autoimmune-like adverse events (AEs), which were particularly frequent and severe with the use of combinational strategies. Nevertheless, the higher incidence of AEs is associated with an improved clinical benefit indicating treatment response. A prompt recognition of AEs followed by early and adequate treatment with immunosuppressive agents allows the management of these potentially serious AEs. This narrative review aims to summarize CTLA-4 biology, the rationale for the use as a companion for anti-PD-1 Abs in humans with results from the most relevant Phase III clinical trials including anti-CTLA-4 Abs in combination with anti-PD-1 Abs in solid tumors.SCOPUS: re.jinfo:eu-repo/semantics/publishe

The Abscopal Effect in the Era of Cancer Immunotherapy: a Spontaneous Synergism Boosting Anti-tumor Immunity?

Radiotherapy is one of the main treatment strategies used in cancer. Aside from the local control of the disease, which is mediated by a direct cytotoxic effect on tumor cells, radiotherapy has also been shown to exert immune-mediated local and systemic effects. Radiotherapy can elicit anti-tumor responses in distant sites from the radiation field; this phenomenon is known as the abscopal effect and has been described in patients previously treated with immune checkpoint blockade (ICB). Considering that the efficacy of immunotherapy has been demonstrated only in a subset of patients—who often benefit with lasting responses—efforts are ongoing to potentiate its activity with the development of new combination strategies. Radiotherapy might represent a potential candidate for a synergistic combination with immunotherapy, by improving the immunogenicity of tumors and by enhancing local and systemic immune effects. This review aims to summarize the current pre-clinical and clinical data on the immune effects of radiotherapy and their potential implications for cancer immunotherapy.[Figure not available: see fulltext.].SCOPUS: re.jinfo:eu-repo/semantics/publishe

Targeting PD-1 in cancer: Biological insights with a focus on breast cancer

Programmed cell death-1 (PD-1) receptor and its ligands physiologically regulate the activity of the adaptive immune system to limit excessive inflammatory processes, thus preventing normal tissue damage. Tumor cells escape from the host immune surveillance using this pathway, rendering it relevant therapeutic target. Despite the relevant clinical efficacy observed in patients with solid and hematological malignancies, the clinical benefit of these novel treatments is limited to a relatively restricted number of patients. A wide amount of genomic and immune related features is currently under investigation as potential predictive biomarkers for treatment selection. The results obtained so far are encouraging but still imperfect. Combination strategies using different immunotherapeutic agents or with other treatments (such as chemotherapy) are being investigated, showing promising but still not completely satisfactory results. This review aims to shed light on the main principles of targeting PD-1 in breast cancer, from biology through its functional and clinical implications.SCOPUS: re.jinfo:eu-repo/semantics/publishe