Abstract Purpose Mounting evidence demonstrates that combining radiotherapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study is to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity. Methods We utilized a nanofluidic drug-eluting seed (NDES) for the sustained intratumoral delivery of combinational antibodies, CD40 and PDL1. To enhance immune and tumor response, we combined the NDES intratumoral platform with RT to treat the 4T1 murine model of advanced triple negative breast cancer (TNBC). We compared the efficacy of NDES against intraperitoneal (IP) administration, which mimics conventional systemic treatment. Tumor growth was recorded, and local and systemic immune responses were assessed via imaging mass cytometry and flow cytometry. Livers and lungs were histologically analyzed for evaluation of toxicity and metastasis, respectively. Results The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via the NDES (NDES CD40/PDL1) showed an increase in both local and systemic immune response. In combination with RT, NDES CD40/PDL1 achieved significant tumor burden reduction and liver inflammation mitigation when compared to systemic treatment. Importantly, our treatment strategy boosted the abscopal effect towards attenuating lung metastatic burden. Conclusions Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via the NDES, offering promise for improving therapeutic index and clinical response.
Patient-centered therapeutic management for chronic medical conditions is a desired but unmet need, largely attributable to the lack of adequate technologies for tailored drug administration. While triggered devices that control the delivery of therapeutics exist, they often rely on impractical continuous external activation. As such, next generation continuously tunable drug delivery systems independent of sustained external activation remain an elusive goal. Here we present the development and...
Molecular transport through nanofluidic structures exhibits properties that are unique at the nanoscale. The high surface-to-volume ratio of nanometer-sized confined spaces renders particle interactions with the surface of central importance. The electrical double layer (EDL) at the solid-liquid interface of charged surfaces, generates an enrichment of counterions and the exclusion of co-ions that lead to a change in their diffusivity. In addition, the diffusive transport is altered by steric an...
: Agonistic CD40 antibodies activate dendritic cells and can expand and activate tumor-specific T cells. Our purpose was to assess the CD40 agonistic antibody ADC-1013 in the clinical setting including intratumoral administration since preclinical studies have indicated that intratumoral is better than intravenous administration. A Phase I, open label, multicenter study was conducted in patients with advanced solid tumors who had received established treatments. A modified 3 + 3 dose-escalation ...
Background Immunotherapy is currently being examined as a treatment modality for glioblastoma. Maintaining an optimal total lymphocyte count (TLC) after radiotherapy (RT) and using temozolomide may be beneficial in optimizing immunotherapy. However, conventional temozolomide-based chemoradiation is known to induce immunosuppressive effects, including lymphopenia. Therefore, this study aimed to identify potential clinical predictors of acute severe lymphopenia (ASL) in patients receiving chemorad...
Last. Jillian L. Scavone(National Comprehensive Cancer Network)H-Index: 9
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: The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenter...
: Mounting evidence suggests that radiation stimulates the immune system and this contributes to the abscopal effect, which is defined as "response at a distance from the irradiated volume." Though identified more than 50 years ago, the abscopal effect is revisited today. One rationale is that the abscopal effect is often observed with efficient immunotherapy. Here, we give an overview of the clinical data on the abscopal effect, generated by a combination of immunotherapy and radiotherapy (RT)....
Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma1–3, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor4–6. The latter is essential for achieving abscopal responses in murine cancers6. The...
Immune stimulation has emerged as a promising approach to the treatment of neoplastic diseases. Currently approved therapeutics, such as anti-CTLA4 and anti-PD1, are primarily aimed at blocking inhibitory signaling by immune cells. An alternative and potentially synergistic approach would involve activation of immune pathways by agonism of stimulatory receptors, such as CD40. Agonistic antibodies, while promising in principle, have encountered significant barriers in clinical trials limited by t...
Last. Sherene Loi(University of Melbourne)H-Index: 85
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Abstract Background Unresectable locally advanced or metastatic triple-negative (hormone-receptor–negative and human epidermal growth factor receptor 2 [HER2]–negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)–paclitaxel may enhance the anticancer activity of atezolizumab. Methods In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitax...
Abstract Conventional systemic immunotherapy administration often results in insufficient anti-tumor immune response and adverse side effects. Delivering immunotherapeutics intratumorally could maximize tumor exposure, elicit efficient anti-tumor immune response, and minimize toxicity. To fulfill the unmet clinical need for sustained local drug delivery and to avoid repeated intratumoral injections, we developed a nanofluidic-based device for intratumoral drug delivery called the nanofluidic dru...
Breast cancer treatment remains challenging due to high levels of cell metastasis. Chemotherapy drug combinations can inhibit both tumor growth in situ and metastasis to distant organs. Therefore, here, we developed chondroitin sulfate liposomes (CSLs) as a carrier for the co-delivery of retinoic acid (RA) and doxorubicin (DOX) and examined their efficiency in suppressing lung metastasis of breast cancer. CSLs were prepared using CS–deoxycholic acid conjugates and found to encapsulate both RA an...
#2Mitra Dolatkhah(Tabriz University of Medical Sciences)H-Index: 2
Last. Jaleh Barar(Tabriz University of Medical Sciences)H-Index: 38
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Abstract Breast cancer (BC) is one of the prevalent cancers among women. Generally, the treatment of BC is mostly based on several prominent strategies, including chemotherapy, surgery, endocrine therapy, molecular targeted therapy, and radiation. Owing to the growing knowledge about the complexity of BC pathobiology, immunotherapy as a promising treatment modality has substantially improved the patients' care in the clinic. Immunotherapy is used to harness the patient's immune system to recogni...
It has been suggested that particle size plays an important role in determining the genotoxicity of gold nanoparticles (GNPs). The purpose of this study was to compare the potential radio-sensitization effects of two different sized GNPs (3.9 and 37.4 nm) fabricated and examined in vitro in Lewis lung carcinoma (LLC) as a model of non-small cell lung cancer through use of comet and clonogenic assays. After treatment with 2Gy X-ray irradiation, both particle sizes demonstrated increased DNA damag...