Treatment Of Malignant Solid Tumors Research Articles

Expert consensus on BRAF inhibitors in the treatment of malignant solid tumors (2024 edition)

The global aging population is leading to an increasing incidence of cancer, exacerbating the global burden of cancer. By 2040, the total number of cancer patients worldwide is projected to reach 28 million. With advancements in tumor molecular biology research and the widespread application of next-generation sequencing technology, precision treatment for cancer has made significant progress in clinical settings. Selective targeting of the Braf gene has emerged as one of the early successful cases of precision medicine for tumors. Braf gene mutations can result in unrestricted activation of downstream kinases in the mitogen-activated protein kinase (MAPK) cell signaling pathway, promoting rapid proliferation of tumor cells. BRAF inhibitors, either as monotherapy or in combination with MEK inhibitor, have been approved for various cancers, including melanoma, non-small cell lung cancer, thyroid cancer, colorectal cancer and glioma, among others. Clinical studies related to BRAF inhibitors are continuously exploring new applications. However, there is currently no consensus on the use of BRAF inhibitors in the diagnosis and treatment of multiple solid cancers in China. This article integrates clinical evidence of Braf mutations in multiple solid cancers to establish an expert consensus on the diagnosis and treatment of malignant solid cancers with Braf gene mutations. The goal is to promote and guide the standardized application of BRAF inhibitors.

Immune checkpoint inhibitor-related pneumonitis: research advances in prediction and management.

The advent of immune-checkpoint inhibitors (ICIs) has revolutionized the treatment of malignant solid tumors in the last decade, producing lasting benefits in a subset of patients. However, unattended excessive immune responses may lead to immune-related adverse events (irAEs). IrAEs can manifest in different organs within the body, with pulmonary toxicity commonly referred to as immune checkpoint inhibitor-related pneumonitis (CIP). The CIP incidence remains high and is anticipated to rise further as the therapeutic indications for ICIs expand to encompass a wider range of malignancies. The diagnosis and treatment of CIP is difficult due to the large individual differences in its pathogenesis and severity, and severe CIP often leads to a poor prognosis for patients. This review summarizes the current state of clinical research on the incidence, risk factors, predictive biomarkers, diagnosis, and treatment for CIP, and we address future directions for the prevention and accurate prediction of CIP.

Does Use of Intratumoral Injections in Solid Tumor Malignancies Improve Outcomes and Reduce Adverse Events? An Integrative Review.

The purpose of this review is to assess the efficacy and adverse events associated with intratumoral injection in the treatment of solid tumor malignancies. A literature review was conducted using PubMed, the Cochrane Database of Systematic Reviews, CINAHL, and Scopus databases from 2009 to 2022. A total of 588 articles were retrieved, with five selected based on inclusion and exclusion criteria. Inclusion criteria specified English language publications, in human trials, and use of intratumoral anticancer agents. The findings from this integrative review demonstrate treatment efficacy as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria with increased stable disease and partial response in patients as well as a prolonged survival period. Additionally, findings show that this therapy is associated with predominantly mild adverse events.

Activatable biomimetic raspberry-like nanoplatform enabled robust cascade therapy via spatiotemporal regulation of tumor immunogenicity and immunosuppression

Smart nanomedicine capable of stimulating the immunity cycle and synchronously modulating the tumor immunosuppressive microenvironment is highly desirable for treatment of malignant solid tumor. Herein, an activable biomimetic raspberry like nanoplatform (abbreviated as RCuS@tMCP) was created for photothermal cascade immunotherapy by the spatiotemporal control of immunogenic tumor cell death (ICD) and tumor associated macrophages (TAMs) reprogramming. RCuS@tMCP was developed by conjugating the second near-infrared (NIR-II) photothermal agent copper sulfide nanoparticles (CuS NPs) as the “raspberry seeds” on the surface of biomimic CpG/protamine immunocore (denoted as tMCP) through matrix metalloproteinase-2 cleavable peptide. In the tumor microenvironment, RCuS@tMCP enzymatically unlocked the small sized RGDK peptide modified CuS NPs (ca.12 nm), which penetrated deeply and specifically to αvβ3 overexpressed tumor cells and elicited in situ ICD under NIR-II laser irradiation, thus triggering an effective antitumor immune response. Meanwhile, the remaining tMCP precisely recognized TAMs under the guidance of M2 peptide and reeducated them to tumoricidal ones, thereby boosted the power of cytotoxic T lymphocytes. By the spatiotemporal cooperation, RCuS@tMCP significantly inhibited the tumor growth of both primary and distant 4T1 tumors and prevented malignant metastasis as demonstrated both in vitro and in vivo data. This study provides an appealing and intelligent therapeutic toolbox for efficient immunological cascade therapy.

Cancer nanomedicine in preoperative therapeutics: Nanotechnology-enabled neoadjuvant chemotherapy, radiotherapy, immunotherapy, and phototherapy.

Surgical resection remains a mainstay in the treatment of malignant solid tumors. However, the use of neoadjuvant treatments, including chemotherapy, radiotherapy, phototherapy, and immunotherapy, either alone or in combination, as a preoperative intervention regimen, have attracted increasing attention in the last decade. Early randomized, controlled trials in some tumor settings have not shown a significant difference between the survival rates in long-term neoadjuvant therapy and adjuvant therapy. However, this has not hampered the increasing use of neoadjuvant treatments in clinical practice, due to its evident downstaging of primary tumors to delineate the surgical margin, tailoring systemic therapy response as a clinical tool to optimize subsequent therapeutic regimens, and decreasing the need for surgery, with its potential for increased morbidity. The recent expansion of nanotechnology-based nanomedicine and related medical technologies provides a new approach to address the current challenges of neoadjuvant therapy for preoperative therapeutics. This review not only summarizes how nanomedicine plays an important role in a range of neoadjuvant therapeutic modalities, but also highlights the potential use of nanomedicine as neoadjuvant therapy in preclinical and clinic settings for tumor management.

Abstract 1864: An improved trispecific antibody (TsAb) platform for optimally engaging T cells for the treatment of solid tumor malignancies

Abstract T-cell recruiting bispecific antibodies have been shown to be clinically effective in treating hematological malignancies. However, their application against solid tumors is limited by several challenges, including a narrow therapeutic window due to cytokine release syndrome (CRS) induced toxicity, limited number of functional T cells, and an immunosuppressive tumor microenvironment (TME). Engagement of CD28 co-stimulatory domain can promote T cell fitness and sustained activation to overcome T -cell anergy. Here, we describe the development of a novel tri-specific antibody (TsAb) platform which is designed to optimally engage T cells via co-stimulation of both CD3 and of CD28 to achieve more effective tumor cell killing without increased CRS induction. To that end, we identified three selected formats (TsAb-1, TsAb-2 and TsAb-3) based on improved properties of the antibody formats, such as safety, efficacy, stability and developability. These formats have been developed to target three different well-established solid tumor-associated antigens (TAAs) as proof of concept. The binding activity of TsAbs to TAA, CD3 and CD28 was evaluated by ELISA and flow cytometry. Tumor cell cytotoxicity was assessed and secretion of cytokines by immune cells using a tumor cell-PBMC co-culture assay. Effective engagement of CD3 and CD28 was evaluated by flow analysis of CD25 Bcl-xL expression, respectively. Additionally, flow immunophenotyping was performed to characterize the differentiation of memory T cell subsets. Our results show that while all three TsAb formats displayed comparable cytotoxicity, TsAb-3 triggered immune cell activation only upon TAA engagement and T cell synapse formation. TsAb-3 showed > 90% purity, no CRS induction in PBMCs alone or in coculture with low TAA-expressing tumor cells. Additionally, tethered TsAb-3 format was unable to stimulate PBMCs in the absence of TAA. Upon further analysis of T cell phenotype differentiation, TsAb-3 showed enhanced CD25+ T cell activation, Bcl-xL induction and increased T-effector and memory cell phenotypes on day 3 and day 7. In conclusion, our data support further development of TsAb as a versatile and improved T cell engager therapeutics for the treatment of solid malignancies. These versatile formats can be utilized not only in T cell engager therapeutics, but also in rationale combinations with immune check point inhibitors. Citation Format: Reshmi Nair, Veena Somasundaram, Arvind Goswami, Jaya Bhatnagar, Sourav Paul, Chaitali Dey, Kalyanaraman Vaidyanathan, Rajkumar Paul, Sankar Periasamy, Mary Helen KG, Mahalakshmi NV, Abhishek Sinha, Rachel Salazar, Avanish K. Varshney. An improved trispecific antibody (TsAb) platform for optimally engaging T cells for the treatment of solid tumor malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1864.

Study of the suppression of a tumor growth expressing a carcinoembryonic antigen with a new high-tech drug carplasmin (CAR-T therapy) in Balb/c nude mice

Introduction. Adoptive immunotherapy based on chimeric antigen receptors (CAR) is considered as a promising direction in the treatment of solid malignant tumors. To produce genetically modified human T-lymphocytes, lenti/retroviral transduction is currently most often used. However, safety concerns associated with the viral vector production and possible unwanted genome modification limit the clinical utility of CAR-T cells. Therefore, non-viral transfection methods, in particular electroporation, using of DNA or RNA vectors, are being actively studied as a method for producing CAR-T lymphocytes.Aim. To evaluate in vivo antitumor activity of the new high-tech drug carplasmin, intended for CAR-T therapy of tumors expressing carcinoembryonic antigen (CEA). Materials and methods. Carplasmin was obtained by electroporation of activated human lymphocytes with plasmid DNA carrying the third generation CAR gene specific to CEA. The study was performed on a human colorectal cancer xenograft model obtained by intraperitoneal injection of CEA-positive HCT116 cell line to athymic Balb/c nude mice. Carplasmin treatment was carried out once a week, starting from the third day after HCT116 cell inoculation. Mice in the two control groups were treated with either electroporated lymphocytes without plasmid addition (pulse-lymphocytes) or RPMI-1640 culture medium (group without treatment).Results. In vivo, carplasmin demonstrated a pronounced antitumor effect. Seven weekly injections of the drug to inoculated mice led to a prominent effect of antitumor therapy: 80 % of the animals in the experimental group survived (with 40 % of the mice had a complete remission without signs of a detectable tumor), compared to 100 % death in the control group (without treatment).Conclusion. The results of preclinical efficacy studies demonstrate that carplasmin is a promising drug for the treatment of CEA-positive intraperitoneal tumors.

Role of Immunotherapy in Breast Cancer.

The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of solid tumor malignancies. In breast cancer, the most robust data to date for ICI exist for triple-negative breast cancer (TNBC). Preclinical studies suggested increased antitumoral immune response in patients with TNBC undergoing ICI treatment. Early clinical trials investigated the use of ICI monotherapy in patients with metastatic TNBC with promising results, particularly in the first-line setting and for those patients whose tumors had high programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) expression. Subsequent trials evaluated the use of ICI in combination with conventional chemotherapy to enhance the host immune response. Pembrolizumab combined with chemotherapy in the KEYNOTE-355 study resulted in improved progression-free survival and overall survival benefits for patients with PD-L1 combined positive score > 10 metastatic TNBC. In early-stage disease, two phase III trials demonstrated increased rates of pathologic complete response at the time of surgery with the addition of neoadjuvant ICI to standard chemotherapy. The large KEYNOTE-522 trial showed improved event-free survival with neoadjuvant and adjuvant ICI. Several biomarkers have been identified, which may be predictive of response to ICI therapy including PD-1/PD-L1 expression, tumor mutational burden, tumor-infiltrating lymphocytes, and multigene assays capturing favorable immune cell signatures. For hormone receptor-positive and human epidermal growth factor receptor-positive breast cancer, there are ongoing studies evaluating ICI therapy in combination with chemotherapy and targeted agents. Finally, across all subtypes, several novel immunotherapeutic agents are under investigation including novel ICIs, cancer vaccines, adoptive cellular therapy, and oncolytic viruses.

Split genome-based retroviral replicating vectors achieve efficient gene delivery and therapeutic effect in a human glioblastoma xenograft model

The murine leukemia virus-based semi-retroviral replicating vectors (MuLV-based sRRV) had been developed to improve safety and transgene capacity for cancer gene therapy. However, despite the apparent advantages of the sRRV, improvements in the in vivo transduction efficiency are still required to deliver therapeutic genes efficiently for clinical use. In this study, we established a gibbon ape leukemia virus (GaLV) envelopepseudotyped semi-replication-competent retrovirus vector system (spRRV) which is composed of two transcomplementing replication-defective retroviral vectors termed MuLV-Gag-Pol and GaLV-Env. We found that the spRRV shows considerable improvement in efficiencies of gene transfer and spreading in both human glioblastoma cells and pre-established human glioblastoma mouse model compared with an sRRV system. When treated with ganciclovir after intratumoral injection of each vector system into pre-established U-87 MG glioblastomas, the group of mice injected with spRRV expressing the herpes simplex virus type 1-thymidine kinase (HSV1-tk) gene showed a survival rate of 100% for more than 150 days, but all control groups of mice (HSV1-tk/PBS-treated and GFP/GCV-treated groups) died within 45 days after tumor injection. In conclusion, these findings sug-gest that intratumoral delivery of the HSV1-tk gene by the spRRV system is worthy of development in clinical trials for the treatment of malignant solid tumors. [BMB Reports 2022; 55(12): 615-620].

GSOR22 Presentation Time: 12:15 PM: A Novel Radiosensitizer Kortuc Enhanced Brachytherapy for Unresectable Recurrent Uterine Cervical Cancer

<h3>Purpose</h3> To evaluate the tolerability, safety and efficacy of KORTUC Intratumoral injection with brachytherapy in unresectable recurrent cervical cancer. <h3>Materials and Methods</h3> A novel radiosensitizer KORTUC (Kochi Oxydol Radiation Therapy for Unresectable Carcinoma) was invested by Dr. Yasuhiro Ogawa at Kochi University (Japan) in 2006 and was developed for the treatment of malignant solid tumours that contain numerous hypoxic cancer cells and/or large quantities of antioxidative enzymes. Hydrogen peroxide is the only agent known to be capable of inactivating antioxidative enzymes and producing oxygen simultaneously when applied to tumour tissues. KORTUC is a solution that contains 3% hydrogen peroxide with 1% sodium hyaluronate. Hydrogen peroxide is the active ingredient for this radiosensitizer. Sodium hyaluronate viscosity sustains the hydrogen peroxide in the tumour as well as delays decomposition of hydrogen peroxide and maintains a high concentration of oxygen in the tumour. Injecting the two components together at a particular ratio is the key feature of this product. Currently Phase 2 clinical trial for locally advanced and recurrent breast cancer has been conducted in the United Kingdom and India. Our institution, (Osaka Medical and Pharmaceutical University, Japan) has conducted single-arm clinical research of KORTUC since May 2010, we dosed KORTUC more than 250 patients of various solid cancers including more than 40 patients of the gynecological tumors treated with brachytherapy as of today. In this study we report our experiences of KORTUC with brachytherapy in recurrent local advanced cervical cancer patients who are likely the high risk of poor prognosis.From April 2012 to January 2020, 15 female patients with recurrent cervical cancer received KORTUC with brachytherapy. Previous treatments of 15 recurrent patients were surgery (n=4), radiation therapy (n=8), surgery + radiation therapy (n=3). The primary lesion of these 15 patients were vaginal stump (n=5), pelvic wall (n=3), cervix (n=3), vaginal wall (n=2), and lymph node (n=2). KORTUC was injected intratumorally under direct vision of colposcopy prior to radiation therapy. The dose of KORTUC ranged from 4 to 12 mL adjusted by tumor size. For patients who had the Interstitial brachytherapy, KORTUC was administered before and after the applicator insertion prior to irradiation. <h3>Results</h3> Intratumoral injection of KORTUC was completed without any technical and safety issues in all 15 patients. KORTUC was well tolerated and no adverse events judged to be related to KORTUC injection were observed, except the transient local pain at the injection site in some patients. KORTUC also showed efficacy in local control in recurrent patients. <h3>Conclusion</h3> Based on this result, we would like to confirm in a future study, KORTUC's efficacy with external irradiation as well as brachytherapy for the newly diagnosed unresectable locally advanced cervical cancer with high risk factors of poor prognosis. KORTUC may have potential as an effective radiation response enhancer in multiple cancer types in which locoregional control after RT alone remains poor.

MoS2 nanoflower-mediated enhanced intratumoral penetration and piezoelectric catalytic therapy

The absence of lymphatic vessels in tumors leads to the retention of interstitial fluid, and the formation of an inverse pressure difference between the tumor and blood vessels hinders drug delivery deep into the tumor, which leads to tumor recurrence and metastasis. Therefore, we designed a novel strategy to downregulate tumor interstitial fluid pressure (TIFP) by water splitting in the tumor interstitium based on piezoelectric catalysis nanomedicine. First, the chemotherapeutic drug doxorubicin (DOX) was loaded on the piezoelectric catalytic material MoS2 and then encapsulated with tumor cell membrane (CM) to obtain MD@C. MD@C could not only target the tumor through homologous targeting but, more importantly, also triggered piezoelectric catalytic water splitting under ultrasound (US) stimulation; as a result, the TIFPs of U14 and PAN02 tumor-bearing mice were reduced to 57.14% and 45.5%, respectively, and the tumor inhibition rates of MD@C were 96.75% and 99.21%, which increased the perfusion of blood-derived drugs in the tumors. Moreover, the hydroxyl radicals generated by piezoelectric catalysis could effectively inhibit the growth of tumors in combination with DOX. Consequently, the piezoelectric catalytic water splitting strategy of MD@C can enhance drug delivery, providing a new universal platform for the treatment of solid malignant tumors.

Combined treatment of marizomib and cisplatin modulates cervical cancer growth and invasion and enhances antitumor potential in vitro and in vivo.

Proteasome inhibition is an attractive approach for anticancer therapy. Cisplatin (cis-diamminedichloroplatinum, CDDP) is widely used as a standard chemotherapy drug in the treatment of solid malignant tumors, such as cervical cancer, ovarian cancer, colorectal cancer, and lung cancer. However, the development of CDDP resistance largely limits its clinical application. Proteasome inhibitors may enhance traditional chemotherapy agent-induced cytotoxicity and apoptosis. Marizomib (NPI-0052, salinosporamide A, Mzb), a second-generation proteasome inhibitor, shows synergistic anticancer activity with some drugs. Currently, the effect of Mzb on cervical cancer cell proliferation remains unclear. In this study, we explored the role of Mzb in three cervical cancer cell lines, HeLa, CaSki, and C33A, representing major molecular subtypes of cervical cancer and xenografts. We found that Mzb alone showed noteworthy cytotoxic effects, and its combination with CDDP resulted in more obvious cytotoxicity and apoptosis in cervical cancer cell lines and xenografts. In order to investigate the mechanism of this effect, we probed whether Mzb alone or in combination with CDDP had a better antitumor response by enhancing CDDP-induced angiopoietin 1 (Ang-1) expression and inhibiting the expression of TEK receptor tyrosine kinase (Tie-2) in the Ang-1/Tie-2 pathway, FMS-like tyrosine kinase 3 ligand (Flt-3L) and stem cell factor (SCF) as identified by a cytokine antibody chip test. The results suggest that Mzb has better antitumor effects on cervical cancer cells and can sensitize cervical cancer cells to CDDP treatment both in vitro and in vivo. Accordingly, we conclude that the combination of CDDP with Mzb produces synergistic anticancer activity and that Mzb may be a potential effective drug in combination therapy for cervical cancer patients.

Phase-Changeable Nanoparticle-Mediated Energy Conversion Promotes Highly Efficient High-Intensity Focused Ultrasound Ablation.

This review describes how phase-changeable nanoparticles enable highly-efficient high-intensity focused ultrasound ablation (HIFU). HIFU is effective in the clinical treatment of solid malignant tumors; however, it has intrinsic disadvantages for treating some deep lesions, such as damage to surrounding normal tissues. When phase-changeable nanoparticles are used in HIFU treatment, they could serve as good synergistic agents because they are transported in the blood and permeated and accumulated effectively in tissues. HIFU's thermal effects can trigger nanoparticles to undergo a special phase transition, thus enhancing HIFU ablation efficiency. Nanoparticles can also carry anticancer agents and release them in the targeted area to achieve chemo-synergistic therapy response. Although the formation of nanoparticles is complicated and HIFU applications are still in an early stage, the potential for their use in synergy with HIFU treatment shows promising results.

Sequential Administrations of a Vascular-Disrupting Agent, High-Intensity Focused Ultrasound, and a Radioactively labeled Necrosis Avid Compound for Eradicating Solid Malignancies.

Radical treatment of malignant solid tumors should aim to be less traumatic, precise, and effective. OncoCiDia, as a noninvasive, sequential dual-targeting, small-molecule, broad spectrum anticancer theranostic approach, may fulfill these requirements of solid cancer (Onco) treatment with both tumoricidal (Ci) and diagnostic (Dia) effects. However, it is unlikely to cure patients with cancer, especially those with large and irregular tumors and with tumors residing in certain organs, such as the brain and pancreas, because of insufficient necrosis generation. To amplify ablative efficacy, this shortcoming could be overcome by combining high-intensity focused ultrasound (HIFU) with the use of a vascular-disrupting agent (VDA) and a radioactively labeled necrosis avid compound (NAC), such as 131I-Hypericin (131I-Hyp), which are the first and second targeting drugs used in OncoCiDia. This study proposes the combined use of OncoCiDia and HIFU (Onco-HIFU-CiDia) as a synergistic treatment for malignant tumors to achieve a curative multimodality and multidrug regimen for patients with solid cancers, in accordance with the current trend of cancer patient care.

The latest trends in improving CAR-T cell therapy: from leukemia to solid malignant tumors

CAR-Т cell therapy with the use of cytotoxic lymphocytes with chimeric antigen receptors occupies an important place among modern approaches to the cancer treatment. This therapy has established itself as an effective method of the treatment of CD19+ acute lymphoblastic leukemia. Nevertheless, the recurrences of the illness are not uncommon; the treatment of solid tumors with genetically engineered lymphocytes shows modest results and it is accompanied by the high toxicity. One thing, however, is certain: CAR-Т cell therapy has great potential in the treatment of cancer and further improving of the structure and functions of genetically engineered lymphocytes with chimeric Т cell receptors help greatly increase the efficiency of antitumor treatment.The review includes the current data on the structure of chimeric lymphocytes of different generations and the trends in improving CAR-Т cell therapy. It includes also the fundamental platform for formation of ideology of use CAR-Т cells for the treatment of solid malignant tumors.

Magnetic lipid nanovehicles synergize the controlled thermal release of chemotherapeutics with magnetic ablation while enabling non-invasive monitoring by MRI for melanoma theranostics

Nowadays, a number of promising strategies are being developed that aim at combining diagnostic and therapeutic capabilities into clinically effective formulations. Thus, the combination of a modified release provided by an organic encapsulation and the intrinsic physico-chemical properties from an inorganic counterpart opens new perspectives in biomedical applications. Herein, a biocompatible magnetic lipid nanocomposite vehicle was developed through an efficient, green and simple method to simultaneously incorporate magnetic nanoparticles and an anticancer drug (doxorubicin) into a natural nano-matrix. The theranostic performance of the final magnetic formulation was validated in vitro and in vivo, in melanoma tumors. The systemic administration of the proposed magnetic hybrid nanocomposite carrier enhanced anti-tumoral activity through a synergistic combination of magnetic hyperthermia effects and antimitotic therapy, together with MRI reporting capability. The application of an alternating magnetic field was found to play a dual role, (i) acting as an extra layer of control (remote, on-demand) over the chemotherapy release and (ii) inducing a local thermal ablation of tumor cells. This combination of chemotherapy with thermotherapy establishes a synergistic platform for the treatment of solid malignant tumors under lower drug dosing schemes, which may realize the dual goal of reduced systemic toxicity and enhanced anti-tumoral efficacy.

Pioneering Iodine-125-Labeled Nanoscale Covalent Organic Frameworks for Brachytherapy.

Brachytherapy has been clinically used for the treatment of malignant solid tumors. However, the classic therapeutic radioactive 125I seed must be surgically implanted directly into tumors. To avoid the surgery and prevent irrational radioactive distribution, radioiodine-loaded nanomaterials are ever-developing for brachytherapy. Hence, it is still a notable challenge to obtain an advanced material that simultaneously incorporates features of high radiolabeling rate, short labeling time, good radiolabeling stability, and long tumor retention time. Covalent organic frameworks (COFs), which are crystalline polymers with ordered pores, are widely applied in guest delivery of drugs based on their high porosity and modifiable skeleton. Herein, we developed a functionalized nanoscale PEG-COF-Ag material, which could rapidly capture radioiodine reaching a 94% radiolabeling yield in 30 s. In addition, more than 95% 125I was maintained after 24 h in PBS (phosphate-buffered saline) as well as in serum and over 90% for nearly 1 week. PEG-COF-Ag-125I (125I-COF) demonstrated excellent cancer cell killing performance in vitro, and further experiments in vivo revealed a long tumor retention time and effective tumor treatment during the radiotherapy. The results indicate that radioiodine-labeled PEG-COF-Ag could be potentially applied in brachytherapy with a promising therapeutic effect.

Cisplatin-induced ototoxicity: Updates on molecular mechanisms and otoprotective strategies

Cisplatin is a highly effective antitumor drug generally used in the treatment of solid malignant tumors. However, cisplatin causes severe side effects such as bone marrow depression, nephrotoxicity, and ototoxicity, thus limiting its clinical application. The incidence of ototoxicity induced by cisplatin ranges from 20% to 70%, and it usually manifests as a progressive, bilateral and irreversible hearing loss. Although the etiology of cisplatin-induced ototoxicity remains unclear, an increasing body of evidence suggests that the ototoxicity of cisplatin is mainly related to the production of reactive oxygen species and activation of apoptotic pathway in cochlear tissues. Many drugs have been well proved to protect cisplatin-induced hearing loss in vitro and in vivo. However, the anti-tumor effect of cisplatin is also weakened by systemic administration of those drugs for hearing protection, especially antioxidants. Therefore, establishing a local administration strategy contributes to the otoprotection without affecting the effect of cisplatin. This review introduces the pathology of ototoxicity caused by cisplatin, and focuses on recent developments in the mechanisms and protective strategies of cisplatin-induced ototoxicity.

P25.11 Evaluation of the Safety of Tumor Treating Fields (TTFields) Application to the Torso – in Vivo Studies

Tumor Treating Fields (TTFields) are a noninvasive, antineoplastic treatment delivered locoregionally to tumor bed via low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. This treatment modality has been shown to be cytotoxic to rapidly dividing cells, with highest efficacy demonstrated at different optimal frequencies depending on tumor cell-type. TTFields therapy has extended survival of patients with newly diagnosed glioblastoma (GBM) and is FDA approved for the treatment of newly diagnosed and recurrent GBM. The overall tolerable safety profile of TTFields in patients (EF-11 and EF-14 clinical trials) is attributed to the low rate of mitotic events in normal, quiescent brain cells. Further evaluation of the safety profile is needed to treat various solid tumor cancer types at the torso region in which there are high rates of cellular proliferation. Hence, we investigated the safety of TTFields delivery to the torso of rats at conditions deemed effective for treating the aforementioned cancer cell types. TTFields were applied to torsos of Sprague Dawley (SD) female rats for 2 weeks using the Novo-TTF100L system at frequencies of 150 or 200 kHz and intensities of 1-2 V/cm RMS. Throughout the treatment period, animals underwent daily clinical examinations. At treatment cessation, blood samples were analyzed and comparative histological evaluation of major internal organs was performed. Animals from the TTFields treatment groups showed no significant differences in comparison to control groups for the following parameters: activity level, food and water intake, stools, motor neurological status, respiration, weight, complete blood count, blood biochemistry, and pathological findings. Safety of TTFields at frequencies of 150 and 200 kHz was demonstrated in healthy rats when delivered to the torso, where there are normal tissues that exhibit high rates of cellular proliferation. Results further suggest that TTFields is a feasibly safe and tolerable treatment modality for treating thoracic as well as other abdominal and pelvic cancers within the torso. Clinical studies investigating TTFields for the treatment of solid malignant tumors located in the torso are currently underway, including locally advanced pancreatic cancer (PANOVA-3 Study, NCT03377491), ovarian cancer (INNOVATE-3 Study, NCT03940196), lung cancer (LUNAR Study, NCT02973789), hepatocellular carcinoma (HEPANOVA Study, NCT03606590), and gastric cancer.

Attenuation of nociceptive and paclitaxel-induced neuropathic pain by targeting inflammatory, CGRP and substance P signaling using 3-Hydroxyflavone

Paclitaxel is an anti-microtubule agent, most widely used chemotherapeutic agent for the treatment of malignant solid tumors. However, it is associated with some severe side effects including painful neurotoxicity with reporting of neuropathic pain and sensory abnormalities by patients during and after paclitaxel therapy. Peripheral neuropathy was induced by the administration of paclitaxel (4 mg/kg on days 1, 3, 5, and 7). In this study, the anti-nociceptive and anti-inflammatory propensity of 3-Hydroxyflavone (3HF) in mice and the preventive effect of 3HF against paclitaxel-induced peripheral neuropathy in Sprague Dawley (SD) rats were investigated. Moreover, tactile and cold allodynia, thermal and tail immersion hyperalgesia, and effects on motor-coordination were also evaluated. Furthermore, the expression of proinflammatory cytokines i.e. Calcitonin gene-related peptide (CGRP), and Substance P from the spinal cord was examined through RT-PCR. Additionally, a computational structural biology approach was applied to search the potential therapeutic targets and to predict the binding mechanism of 3HF.Treatment of 3HF alleviated the nociceptive pain, paw edema, development of tactile and cold allodynia, and hyperalgesia. Similarly, treatment with 3HF suppressed the paclitaxel-induced increase in mRNA expression of several inflammatory cytokines including tumor necrosis factor -α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), CGRP, and Substance P. However, the daily treatment of 3HF did not affect the motor behaviors of rats. The inhibitory mechanism of 3HF in neuropathic pain is predicted with extensive computational bioinformatics approach which indicates that the 3HF effectively interacts with the binding domains of Nuclear factor-kappa B (NF-κB), CGRP receptor and the receptor of Substance P to exert its inhibitory activities. However, the computationally predicted binding affinities revealed that the potential of binding of the compound with Substance P receptor (Neurokinin 1 receptor) is higher than the other receptors; there NK1R could be the most possible binding target of 3HF. These findings indicate that 3HF has anti-nociceptive, anti-inflammatory, and anti-neuropathic pain effects against paclitaxel-induced neuropathic pain.