Combination Therapy Strategies Research Articles

Combination of Ablation and Immunotherapy for Hepatocellular Carcinoma: Where We Are and Where to Go.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and is increasing in incidence. Local ablative therapy plays a leading role in HCC treatment. Radiofrequency (RFA) is one of the first-line therapies for early local ablation. Other local ablation techniques (e.g., microwave ablation, cryoablation, irreversible electroporation, phototherapy.) have been extensively explored in clinical trials or cell/animal studies but have not yet been established as a standard treatment or applied clinically. On the one hand, single treatment may not meet the needs. On the other hand, ablative therapy can stimulate local and systemic immune effects. The combination strategy of immunotherapy and ablation is reasonable. In this review, we briefly summarized the current status and progress of ablation and immunotherapy for HCC. The immune effects of local ablation and the strategies of combination therapy, especially synergistic strategies based on biomedical materials, were discussed. This review is hoped to provide references for future researches on ablative immunotherapy to arrive to a promising new era of HCC treatment.

Nanoparticles with rough surface improve the therapeutic effect of photothermal immunotherapy against melanoma

Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core‒shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.

Glioblastoma Cell-Derived lncRNA-Containing Exosomes Induce Microglia to Produce Complement C5, Promoting Chemotherapy Resistance.

Glioblastoma (GBM), the most common malignant primary brain cancer in adults, nearly always becomes resistant to current treatments, including the chemotherapeutic temozolomide (TMZ). The long noncoding RNA (lncRNA) TMZ-associated lncRNA in GBM recurrence (lnc-TALC) promotes GBM resistance to TMZ. Exosomes can release biochemical cargo into the tumor microenvironment (TME) or transfer their contents, including lncRNAs, to other cells as a form of intercellular communication. In this study, we found that lnc-TALC could be incorporated into exosomes and transmitted to tumor-associated macrophages (TAM) and could promote M2 polarization of the microglia. This M2 polarization correlated with secretion of the complement components C5/C5a, which occurred downstream of lnc-TALC binding to ENO1 to promote the phosphorylation of p38 MAPK. In addition, C5 promoted the repair of TMZ-induced DNA damage, leading to chemotherapy resistance, and C5a-targeted immunotherapy showed improved efficacy that limited lnc-TALC-mediated TMZ resistance. Our results reveal that exosome-transmitted lnc-TALC could remodel the GBM microenvironment and reduce tumor sensitivity to TMZ chemotherapy, indicating that the lnc-TALC-mediated cross-talk between GBM cells and microglia could attenuate chemotherapy efficacy and pointing to potential combination therapy strategies to overcome TMZ resistance in GBM.See related Spotlight by Zhao and Xie, p. 1372.

Progress in the Application of Immune Checkpoint Inhibitor-Based Immunotherapy for Targeting Different Types of Colorectal Cancer.

Colorectal cancer (CRC), a common malignant disease, has the second highest mortality rate among all cancer types. Due to the diversity and heterogeneity of CRC, few effective treatment strategies have been developed in recent years, except for surgical resection. As immunotherapy has become a revolutionary treatment after surgery, along with chemoradiotherapy and targeted therapy, numerous basic research studies and clinical trials have been conducted on CRC. Therefore, immune checkpoint inhibitor (ICI) therapy has become the main anti-CRC immunotherapy method used at present. With the rapid development of biotechnology and cell research, an increasing number of monotherapy or combination therapy strategies using ICIs for CRC have been designed in recent years. Methods to classify and review ICI strategies for different types of CRC to better guide treatment are continuously investigated. However, the identification of why the ICIs would be more effective in targeting particular subtypes of CRC such as high microsatellite instability (MSI-H) is more important because of the different immune backgrounds in patients. This review intends to classify different subtypes of CRC and summarizes the basic and clinical studies on ICIs for each subtype of CRC currently available. In addition, we also attempt to briefly discuss the progress in immunotherapy methods other than ICI therapy, such as chemoimmunotherapy strategy, chimeric antigen receptor-modified T (CAR-T) cells, or immunotherapy based on oncolytic viruses. Finally, we provide a perspective on the development of immunotherapy in the treatment of CRC and attempt to propose a new systematic classification of CRC based on immunological strategies, which may improve guidance for the selection of immunotherapy strategies for different subtypes of CRC in the future.

Co-delivery of Dexamethasone and a MicroRNA-155 Inhibitor Using Dendrimer-Entrapped Gold Nanoparticles for Acute Lung Injury Therapy.

Development of nanomedicines for effective therapy of acute lung injury (ALI), a common critical respiratory failure syndrome, remains to be challenging. We report here a unique design of a functional nanoplatform based on generation 5 (G5) poly(amidoamine) dendrimer-entrapped gold nanoparticles (Au DENPs) to co-deliver dexamethasone (Dex) and a microRNA-155 inhibitor (miR-155i) for combination chemotherapy and gene therapy of ALI. In this study, we synthesized Au DENPs with 10 Dex moieties attached per G5 dendrimer and an Au core diameter of 2.1 nm and used them to compress miR-155i. The generated polyplexes own a positive zeta potential (16-26 mV) and a small hydrodynamic diameter (175-230 nm) and display desired cytocompatibility and efficient miR-155i delivery to lipopolysaccharide (LPS)-activated alveolar macrophages, thus upregulating the suppressor of cytokine signaling 1 and IL-10 expression and downregulating the pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Likewise, as a synthetic glucocorticoid with a potent anti-inflammatory property, the attached Dex on the surface of Au DENPs could inhibit pro-inflammatory cytokine secretion by down-regulating cyclooxygenase-2 expression in the LPS-activated alveolar macrophages. The integration of Dex and miR-155i within one nanoformulation enables superior downregulation of pro-inflammatory cytokines for successful repair of damaged lung tissues in an ALI model, as demonstrated by histological examinations and pro-inflammatory cytokine downregulation in ALI lesion at the gene and protein levels. Such a combined chemotherapy and gene therapy strategy enabled by dendrimer nanotechnology may hold great promise to treat other types of inflammatory diseases.

Terraflow, a New High Parameter Data Analysis Tool, Reveals Systemic T-Cell Exhaustion and Dysfunctional Cytokine Production in Classical Hodgkin Lymphoma

BackgroundClassical Hodgkin lymphoma (cHL) is characterized by rare, malignant Hodgkin/Reed Sternberg (HRS) cells that shape their microenvironment (TME) to inhibit anti-tumor immune response. Systemic immune dysregulation may influence treatment response and toxicity, but the systemic influence of the TME is less well described. The wide variety of proteins measured in high-parmater flow cytometry make it a powerful tool for immune monitoring, but presents challenges in immuno-monitoring. Combinatorial expression of these proteins defines cell types that may influence disease. TerraFlow is a fully automated data analysis platform that evaluates millions of phenotypes and selects the populations that best predict clinical variables. The analysis can be performed using classical Boolean gates or a non-gating approach that approximates gates without using manual thresholds, allowing immunophenotypes to be comprehensively surveyed for disease associations. The platform was used to find phenotypes that discriminate healthy versus cHL patients (AUC = 1) and pre versus post treatment patient phenotypes(AUC = 0.79).MethodsHuman Subjects: Informed consent was obtained from cHL patients (N=44) treated at the Perlmutter Cancer Center (PCC) at NYU Langone Health and New York Presbyterian Weil Cornell (NYP) between 2011 and 2016. Blood samples were drawn at multiple time-points, for this study pre-treatment and 3 month post-treatment samples were used. Age-matched, cryopreserved healthy donor PBMC (n=25) were obtained from STEMCELL Technologies (Cambridge, MA).Patient-derived blood was processed for isolation of PBMC, stained analyzed on a Symphony Flow Cytometer (BD Biosciences, San Jose, CA).Analysis: Data was analyzed using an original platform called terraFlow. Many immune cell subsets are defined by the combinations of proteins they express. TerraFlow systematically evaluates millions of cell types by generating every possible combination of 1 to 5 markers. A network-based algorithm then selects the “best” phenotype from each set of inter-related combinations based on statistical power and ease of interpretation. Each phenotype is defined using a minimal gating strategy that can be replicated in a diagnostic panel or cell sorter. Together, phenotypes describe all the major differences between patient groups. A new platform developed by Epistemic AI was used to mine scientific literature and interpret selected phenotypes.ResultsWe observed clear perturbations in the cHL systemic T-cell compartment pre-treatment as shown in Figure 1. These include higher levels of activated (CD278+), exhausted (CD366+, PD1+, CD152+), and suppressive (GITR+) T-cells compared to healthy donors, and diminished levels of T-cells producing effector cytokines (like IFNγ and IL4). Subsets of cytokine-producing cells that co-express markers of exhaustion (i.e., TNF+ CD366+ cells) are also elevated in cHL patients. Finally, T-cells expressing CD127 a receptor for IL7 involved in homeostatic renewal of cells and observed on naive and central memory T-cells are reduced. Taken together, these findings suggest that in cHL the systemic T-cell compartment is shifted toward a more exhausted profile, and away from less differentiated cells, with the potential for self-renewal. Our data also demonstrates a shift from T-helper 1 and T-helper 2 type toward T-helper 17 cells suggesting that T-cell effector function may be reduced.ConclusionUsing a novel data analysis platform, TerraFlow we demonstrate dysregulation in systemic T cell function in cHL patients pre-treatment that persists within 3 months of completing therapy. Associations of phenotypes with clinical variables, and post-treatment phenotypes will be described in detail at the meeting. Our results detail new immunotherapy and biomarker research targets, and suggest novel strategies for combination therapies. [Display omitted] DisclosuresLi: BD Bioscience: Current Employment. Ruan: Kite Pharma: Consultancy; AstraZeneca: Research Funding; BMS: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seagen: Consultancy. Diefenbach: Incyte: Research Funding; Trillium: Research Funding; Celgene: Research Funding; IGM Biosciences: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Gilead: Current equity holder in publicly-traded company; AbbVie: Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; MEI: Consultancy, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; IMab: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding.

Establishing a Novel Pipeline That Combines in-Silico Prediction with in-Vitro and Ex-Vivo Validation to Discover Secondary Drug Combinations Against Relapsed and/or Refractory Multiple Myeloma

Multiple myeloma (MM) is the second-most common hematological malignancy in the US. MM is an incurable, age-dependent plasma cell neoplasm with a 5-year survival rate of less than 50%. Extensive inter-individual variation in response to standard-of-care drugs like proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), drug resistance, and dose-limiting toxicities are critical problems for the treatment of MM. Clinical success in anti-myeloma treatment, therefore, warrants continuous development of novel combination therapy strategies with the explicit goal to improve the therapeutic efficacy by concomitantly targeting multiple signaling pathways.Previously, we have reported the development of an in-house computational pipeline called secDrug that applies greedy algorithm-based set-covering computational optimization method followed by a regularization technique to predict secondary drugs that can be repurposed as novel synergistic partners of standard-of-care drugs for the management of refractory/ resistant MM. Top among these secondary drugs (secDrugs) were the HSP90 inhibitor 17-AAG.In this study, we used 17-AAG as a proof of principle to establish a pipeline that integrates our in silico predictions with in vitro and ex vivo validation as well as multi-omics technologies to identify, validate, and characterize therapeutic agents that could be used either alone or in combination with standard-of-care drugs for the treatment of R/R MM patients (Figure 1).To screen and validate our in silico prediction results, we performed in vitro cytotoxicity assays using 17-AAG on a panel of human myeloma cell lines (HMCLs; in vitro model systems) that captures a wide range of biological and genetic heterogeneity representing the complexities encountered in clinical settings. These cell lines include HMCLs representing innate sensitive/resistance, >10 pairs of parental and clonally-derived PI- and IMiD-resistant pairs (P vs VR or LenR; representing acquired/emerging resistance/relapse), NRAS mutants which leads to the constitutive activation of oncogenic Ras signaling, and CRISPR-edited HSP90 knockdown cell line. Our results showed that 17-AAG has high synergistic activity in combination with PI in inducing apoptosis even in innate and acquired PI-resistant HMCLs and significantly reduces the effective dose of PI required to achieve IC 50 (Chou-Talalay's Dose Reduction Index or DRI 7±1.4). Moreover, 17-AAG+IMiD showed synergistic cell killing activity in clonally-derived IMiD resistant HMCL. Further, 17-AAG induced cell death was comparable with Hsp90 knockdown as evident from the cytotoxicity assay using PI and 17-AAG in combination in RPMI8226-wild type and RPMI-HSP90AA1 knocked down cell line. Notably, 17-AAG was strikingly effective against the NRAS-mutant cell line indicating an additional niche (NRas mutant myeloma) where 17-AAG could be most effective.Next, we performed RNA sequencing to elucidate the molecular mechanisms behind 17-AAG drug action, drug synergy, 17-AAG-induced cell death. Our gene expression profiling (GEP) followed by Ingenuity Pathway Analysis (IPA) analysis revealed protein ubiquitination, aryl hydrocarbon receptor signalling pathway as the top canonical pathways. 17-AAG induced apoptosis via mitochondrial mediated pathway in myeloma. 17-AAG exerts its cytotoxic effect by activating intrinsic pathway of apoptosis which we further confirmed through the increase in reactive oxygen species generation and decrease in mitochondrial membrane potential. 17-AAG was also effective in reducing the expression of hallmarks of MM such as p65/NF-kB, IRF4, c-Myc. Finally, we performed mass cytometry (CyTOF; Cytometry by time of flight) on primary bone-marrow cells (PMCs) from myeloma patients for further validation of proteomic signatures at the single-cell level. CyTOF analysis confirmed 17-AAG-induced cell death and key changes in MM-specific proteomic markers. 17-AAG treated PMCs showed elevated cleaved caspase levels and down-regulation of IRF4 and phospho-STAT3. GEP and CyTOF results were confirmed using immunoblotting assays.Together, our study demonstrates a unique pipeline for drug repositioning that has the potential to revolutionize clinical decision-making by minimizing the number of drugs required for discovering successful combination chemotherapy regimens against drug-resistant myeloma. [Display omitted] DisclosuresKumar: BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Combination Therapy Strategy for Lymphoma Based on Cancer Energy Metabolism of OPB-111077, a Novel Antitumor Agent Inhibiting Mitochondrial Oxidative Phosphorylation

Development of antitumor agents targeting energy metabolism pathways of cancer cells has attracted much attention in recent days. In general, most cancer cells are known to display Warburg effect. Recently, it has been reported that cancer cells exist as heterogeneous groups in the microenvironment surrounding cancer cells and that not only glycolysis but also mitochondrial oxidative phosphorylation (OXPHOS) is important for cancer growth. In addition, many research groups have reported that the acquisition of anticancer drug resistance is caused by metabolic reprogramming from glycolysis to OXPHOS. Therefore, OXPHOS inhibitors could be useful antitumor agents. OPB-111077 is an orally active novel antitumor agent and has the inhibitory effect on mitochondrial OXPHOS. OPB-111077 had the inhibitory effect on mitochondrial respiratory chain complex I which led to the inhibition of energy production and activation of AMPK-mTOR energy stress sensor pathway. In in vitro growth inhibition studies, OPB-111077 showed potent inhibitory effects on the growth of various human blood tumor cell lines derived from leukemia, multiple myeloma and lymphoma with IC 50 values between 18.6 and 525.3 nM, and on the growth of human solid tumor cell lines derived from liver cancer, lung cancer, gastric cancer and breast cancer with IC 50 values ranging from 92.6 to 1727.7 nM. In in vivo studies using SCID mice bearing tumors from human tumor cell lines, daily oral administration of OPB-111077 demonstrated significant antitumor effects against leukemia, lymphoma, liver, gastric and breast cancer cell line-derived tumor, dose-dependently.Here, we report the combination therapy strategy based on the cancer energy metabolism of OPB-111077. We found that OPB-111077 combined with alkylating agent, cyclophosphamide or bendamustine, showed the synergistic effect on xenograft mice model using human diffuse large B‐cell lymphoma (DLBCL) cell line. To clarify this mechanism, we examined the effect of alkylating agents on mitochondrial respiration in vitro using flux analyzer and found that alkylating agents induced OXPHOS nature in the DLBCL cell line. Furthermore, the administration of alkylating agents to DLBCL cell line xenograft model mice followed by mRNA expression analysis of their tumor tissue confirmed that expression of OXPHOS-related markers was induced. These results suggest the administration of alkylating agents induced reprogramming to OXPHOS predominant nature in tumor. The tumor environment is actively reprogrammed to OXPHOS by alkylating agents, and it is changed to a state in which the antitumor effect of OPB-111077 can be more exerted. Thus, alkylating agents enhance the effect of OPB-111077 by tilting glycolytically dominant tumors to OXPHOS dominant. The alkylating agents, cyclophosphamide and bendamustine, are used as standard therapies for lymphoma. OPB-111077 could be treated in a wide range of applications as a combination therapy with the alkylating agents for lymphoma.In clinical, we have confirmed that OPB-111077 has tolerable and controllable toxicity profile of single agent in some advanced cancer patients including DLBCL. Bendamustine and rituximab (BR) therapy is indicated for the treatment of patients who are ineligible for transplantation of relapsed / refractory (R/R) DLBCL. However, there is still a high unmet need for patients with R/R DLBCL due to no standard treatment for transplant‐ineligible patients. We are conducting combination therapy of OPB-111077 with bendamustine and rituximab in Phase 1 clinical trial for R/R DLBCL in Japan. DisclosuresOhi: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. Okuno: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. Tanaka: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. Ohtani: Otsuka Pharmaceutical Co.,Ltd.: Current Employment. OffLabel Disclosure:Compound: OPB-111077 Purpose: Development of novel antitumor agent

Chemo-photodynamic therapy with light-triggered disassembly of theranostic nanoplatform in combination with checkpoint blockade for immunotherapy of hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is a common malignant tumor with high rate of metastasis and recurrence. Although immune checkpoint blockade (ICB) has emerged as a promising type of immunotherapy in advanced HCC, treatment with ICB alone achieves an objective remission rate less than 20%. Thus, combination therapy strategies is needed to improve the treatment response rate and therapeutic effect.Methods A light-triggered disassembly of nanoplatform (TB/PTX@RTK) co-loaded an aggregation induced emission (AIE) photosensitizer (TB) and paclitaxel (PTX) was prepared for on-command drug release and synergistic chemo-photodynamic therapy (chemo-PDT). Nano-micelles were characterized for drug loading content, hydrodynamic size, absorption and emission spectra, reactive oxygen species production, and PTX release from micelles. The targeted fluorescence imaging of TB/PTX@RTK micelles and the synergistic anti-tumor efficacy of TB/PTX@RTK micelles-mediated chemo-PDT combined with anti-PD-L1 were assessed both in vitro and in vivo.ResultsThe TB/PTX@RTK micelles could specifically accumulate at the tumor site through cRGD-mediated active target and facilitate image-guided PDT for tumor ablation. Once irradiated by light, the AIE photosensitizer of TB could produce ROS for PDT, and the thioketal linker could be cleaved by ROS to precise release of PTX in tumor cells. Chemo-PDT could not only synergistically inhibit tumor growth, but also induce immunogenic cell death and elicit anti-tumor immune response. Meanwhile, chemo-PDT significantly upregulated the expression of PD-L1 on tumor cell surface which could efficiently synergize with anti-PD-L1 monoclonal antibodies to induce an abscopal effect, and establish long-term immunological memory to inhibit tumor relapse and metastasis.ConclusionOur results suggest that the combination of TB/PTX@RTK micelle-mediated chemo-PDT with anti-PD-L1 monoclonal antibodies can synergistically enhance systemic anti-tumor effects, and provide a novel insight into the development of new nanomedicine with precise controlled release and multimodal therapy to enhance the therapeutic efficacy of HCC.Graphical

Posttreatment FDG-PET-CT Response via PERCIST Criteria is Predictive of Tumor Prognosis in Anal Carcinoma

We hypothesize that posttreatment F-18 fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) is useful to evaluate metabolic response in patients with anal cancer, specifically via the Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST).This was a single-institution retrospective review of 62 patients treated with Nigro Regimen chemoradiation therapy for anal squamous cell carcinoma between 2008 and 2020. All patients had pretreatment PET-CT scan and were followed with posttreatment PET-CT scans and clinical examinations. PERCIST criteria was utilized to evaluate the treatment response to chemoradiation therapy. If a target lesion shows complete resolution of FDG uptake, the response is complete metabolic response (CMR). If the decrease from baseline to follow-up is greater than or equal to 30%, the response is partial metabolic response (PMR). If the decrease is less than 30% or if the lesion shows an increase of FDG uptake less than 30%, the response is stable metabolic disease (SMD). If the target lesion shows a 30% increase or higher FDG uptake, or if there is a new lesion, the response is disease progression (DP).The median follow-up was 38 months (range, 7-114 months). Pretreatment PET-CT detected the primary tumor in 62 cases (100%), the inguinal lymph nodes were FDG avid in 33 patients, and the pelvic lymph nodes were FDG avid in 39 patients. Initial posttreatment PET-CT was obtained on average 3 months after the last day of radiation. The evaluation of the primary anal tumor on initial follow-up PET-CT showed CMR in 31 patients (50%), PMR in 26 patients (42%), and SMD in 5 patients (8%). No patients showed disease progression (DP, 0%). The evaluation of the largest inguinal node on initial post treatment PET-CT showed CMR in 30 patients (91%), PMR in 3 patients (9%), without evidence of progression of groin lymphadenopathy. The evaluation of the largest pelvic node on initial post treatment PET-CT showed CMR in 36 patients (92%), PMR in 1 patient (3%), and SMD in 2 patients (5%), without evidence of progression of pelvic lymphadenopathy.The PERCIST criteria is a reliable and useful technique in evaluating treatment response for the primary anal cancer as well as the inguinal and pelvic lymphadenopathy. The Nigro protocol is a promising combined chemoradiation therapy strategy for the anal cancer patients with most demonstrating complete metabolic response or partial metabolic response on the initial post treatment FDG PET-CT scan.

The role of metformin, statins and diet in men on active surveillance for prostate cancer.

A sound scientific basis has been emerging on the anti-neoplastic role of metformin, statins and dietary interventions. However, evidence in prostate cancer patients remains mixed owing to an absence of completed randomized trials. This overview examines the rationale for metformin, statins and dietary intervention for secondary prevention in men on active surveillance by summarizing current evidence base and biological mechanisms in influencing cancer progression and mortality. A comprehensive literature search was performed to identify studies that evaluated the role of metformin, statins and diet in the secondary prevention of prostate cancer as well as those that described the anti-cancer mechanisms of these agents. The search included Pubmed, MEDLINE, EMBASE and Cochrane library from inception till August 2021. A total of 14 trials on metformin, 21 trials on statins and 13 trials on dietary measures were evaluated. Majority were observational population-based cohort studies or meta-analysis of them. Three ongoing prospective randomized controlled trials were also reported. Overall, mixed results were obtained. The role of metformin and statins remains promising with several trials showing reduced rates of progression and cancer specific mortality. Combination therapy strategies have also been evaluated in more advanced patients showing synergism. Dietary interventions especially fruits, vegetables and fish intake has shown some benefit albeit with mixed results for others like legumes, red meat, coffee and multivitamins. Several ongoing randomized trials will provide stronger evidence in the future for secondary prevention.

Synergistic chemo-photothermal cancer therapy of pH-responsive polymeric nanoparticles loaded IR825 and DTX with charge-reversal property

IR825 is a kind of near-infrared (NIR) small molecule cyanine dye and has distinct near-infrared absorbance and excellent thermal conversion performance. Due to poor stability and insufficient therapy efficacy, various nano-systems have been developed as delivery vehicles for NIR dyes to improve their application in tumor treatment. Herein, we developed an intelligent polymer drug vehicle (Mal-PAH-PEG-DMMA/ poly (ethylene imine) – poly(ε-caprolactone) block polymers, MPPD/PEI-PCL) based on pH-responsive charge-reversal to deliver docetaxel (DTX) and photosensitizer (IR825) for chemo-photothermal combination therapy (MPPD@IR825/DTX NPs). MPPD@IR825/DTX NPs could undergo charge conversion in a slightly acidic microenvironment (pH 6.8), resulted in strong electrostatic repulsion to withdraw the shell of the polymer nanoparticles (MPPD), enhanced cellular uptake and increased drug release. MPPD@IR825/DTX NPs demonstrated nanoscale in size with good mono-dispersity and stability, triggered DTX release in response to acid environment and NIR stimulation, in the same time providing excellent photothermal conversion efficiency. In vitro and In vivo experiments confirmed that charge-reversal polymeric nanoparticles improved antitumor efficiency in 4T1 tumor cell modal than non-charge-reversal polymeric nanoparticles. Furthermore, in comparison with chemotherapy or photothermal therapy in a single treatment mode, chemo-photothermal combination therapy of MPPD@IR825/DTX NPs with laser irradiation showed highly efficient tumor ablation. In addition, the polymeric nanoparticles exhibited good biocompatibility and safety. Therefore, the design of charge-reversal polymeric nanoparticles (MPPD@IR825/DTX NPs) provides a new strategy and promising application for targeting and synergistic chemo-photothermal combination therapy.

Future Directions in Chronic Phase CML Treatment.

This review will focus on recent and emerging treatment paradigms in chronic phase CML. The discussion of each novel treatment or drug combination will include a brief overview of scientific rational and pre-clinical data, followed by recently published or ongoing clinical trial efforts. The review will be divided into three focus areas in CML treatment: new frontline approaches and approaches to deepen remission, second treatment-free remission studies, and the treatment of refractory disease. The section on new frontline approaches will highlight several strategies of combination therapy. These can be grouped into immunomodulatory approaches with interferons and immune checkpoint inhibitors, targeting of leukemia stem cells with compounds such as venetoclax and pioglitazone, and BCR-ABL1-intrinsic combination therapy with asciminib. The chance at a second treatment-free remission is an important emerging clinical trial concept, and again combination approaches are under investigation. Lastly, in advanced disease, the development of novel tyrosine kinase inhibitors remains a major focus. This review will provide an overview and perspective of treatment strategies on the horizon for chronic phase CML. Despite the already excellent clinical outcomes for most patients, challenges remain with regard to deepening initial responses, prolonging treatment-free remission, and providing efficacious and tolerable options for patients with refractory disease and resistance mutations.

A Biofilm Microenvironment-Activated Single-Atom Iron Nanozyme with NIR-Controllable Nanocatalytic Activities for Synergetic Bacteria-Infected Wound Therapy.

Biofilm microenvironment (BME)-activated antimicrobial agents display great potential for improved biofilm-related infection therapy because of their superior specificities and sensitivities, effective eliminations, and minimal side effects. Herein, BME-activated Fe-doped polydiaminopyridine nanofusiform-mediated single-atom nanozyme (FePN SAzyme) is presented for photothermal/chemodynamic synergetic bacteria-infected wound therapy. The photothermal therapy (PTT) function of SAzyme can be specifically initiated by the high level of H2 O2 and further accelerated through mild acid within the inflammatory environment through "two-step rocket launching-like" process. Additionally, the enhanced chemodynamic therapy (CDT) for the FePN SAzyme can also be endowed by producing hydroxyl radicals through reacting with H2 O2 and consuming glutathione (GSH) of the BME, thereby contributing to more efficient synergistic therapeutic effect. Meanwhile, FePN SAzyme could catalyze biofilm-overexpressed H2 O2 decomposing into O2 and overcome the hypoxia of biofilm, which significantly enhances the susceptibility of biofilm and increases the synergistic efficacy. Most importantly, the synergistic therapy of bacterial-induced infection diseases can be switched on by the internal and external stimuli simultaneously, resulting in minimal nonspecific damage to healthy tissue. These remarkable characteristics of FePN SAzyme not only develop an innovative strategy for the BME-activated combination therapy but also open a new avenue to explore other nanozyme-involved nanoplatforms for bacterial biofilm infections.

Evaluation of BLG ability for binding to 5-FU and Irinotecan simultaneously under acidic condition: A spectroscopic, molecular docking and molecular dynamic simulation study

Drug delivery system optimization is an issue that dramatically affects toxicity properties. We aim to assess the simultaneous binding effects of the two main chemotherapy drugs of 5-Fluorouracil (5-FU) and Irinotecan with milk globular whey protein, β-lactoglobulin (BLG), which is a promising candidate for oral drug delivery systems. BLG interaction with 5-FU and Irinotecan examined using spectroscopy, molecular docking, and molecular dynamics (MD) simulation methods. The experimental findings confirmed molecular docking calculations, according to which 5-FU and Irinotecan interacted with the BLG in the β-barrel cavity with two different locations. MD simulations also showed that the drugs penetrate the cavity and the amino acids at the top of the calyx fix the drugs. In addition, the results showed that the BLG intrinsic fluorescence was quenched upon interaction with the drugs under individual and simultaneous conditions which leads to the BLG secondary structural changes that were indicated by CD spectroscopy. The experimental findings cross-validate with the theoretical results since there is no difference between the number of the 5-FU and Irinotecan binding sites on BLG under individual and simultaneous conditions. MD results also verify that the densification of the BLG is not affected by the complexation process. 5-FU and Irinotecan make also a complex with the BLG at the Förster Theory distance that was in agreement with the MD data. Consequently, this work shows that the BLG can be a promising carrier for 5-FU and Irinotecan simultaneously. Considering BLG's remarkable features, it is an outstanding candidate to make an oral drug delivery system for the targeted cancer treatment in the combination therapy strategy.

An Aptamer-Modified DNA Tetrahedron-Based Nanogel for Combined Chemo/Gene Therapy of Multidrug-Resistant Tumors.

DNA-based nanogels have attracted much attention in the biomedical research field. Herein, we report a universal strategy for the fabrication of an aptamer-modified DNA tetrahedron (TET)-based nanogel for combined chemo/gene therapy of multidrug-resistant tumors. In our design, terminal extended antisense oligonucleotides (ASOs) are employed as the linker to co-assemble with two kinds of three-vertex extended TETs for the efficient construction of the DNA-based nanogel. With the incorporation of an active cell-targeting group (aptamer in one vertex of TET) and a controlled-release element (disulfide bridges in the terminals of ASOs), the functional DNA-based nanogel can achieve targeted cellular internalization and stimuli-responsive release of embedded ASOs. After loading with the chemodrug (doxorubicin (DOX), an intercalator of double-stranded DNA), the multifunctional DOX/Nanogel elicits efficient chemo/gene therapy of human MCF-7 breast tumor cells with DOX resistance (MCF-7R). This aptamer-modified DNA tetrahedron-based nanogel provides another strategy for intelligent drug delivery and combined tumor therapy.

Multifunctional nanoreactors-integrated microneedles for cascade reaction-enhanced cancer therapy

Starvation therapy based on glucose oxidase (GOx) has attracted considerable attention in tumor treatment. However, several shortcomings severely hinder its further applications, including limited therapeutic efficacy, poor enzyme stability, and potential side effects. Herein, a strategy of cascade reaction-enhanced combined therapy based on the oxygen-evolving multifunctional nanoreactors is proposed for tumor therapy. The GOx and catalase (CAT) are immobilized in metal-organic frameworks by biomimetic mineralization to improve their stability via spatial confinement. The GOx can consume glucose, reduce ATP levels, and down-regulate the expression of heat shock proteins, which consequently sensitize tumor cells to indocyanine green-based photothermal therapy. Furthermore, the hydrogen peroxide generated by GOx as well as overexpressed in tumor can be decomposed by CAT and continuously generate oxygen, which further enhance the efficacy of oxygen-dependent starvation therapy and photodynamic therapy. The nanoreactors are directly delivered to the superficial tumor by microneedles, achieving efficient tumor accumulation and dramatically strengthened antitumor efficacy without obvious side effects, which provides a valuable paradigm for the application of cascade reaction-based combined therapy.

The layered double hydroxide (LDH) nanosheets decrease anticancer potential of Satureja khuzestanica in HepG2 hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is one of the most invasive cancers and is the third cause cancer death. Due to side effects and high cost of chemotherapeutic drugs as well as increased drug resistance, plant products and natural compounds have attracted the interest of studies as an appropriate anticancer agent. Therefore, in the present study we investigated the anti-cancer activity of Satureja khuzestanica phenol-chloroform extraction in combination layered double hydroxide (LDH) nanosheets as a combination therapy strategy on HCC cell line HepG2. The phenol-chloroform extraction was prepared from fresh leaves of S. khuzestanica. The anti-cancer activity of S. khuzestanica phenol-chloroform extraction alone and by co-administration of LDH nanosheets were investigated on HCC cell line and normal human fibroblast cells using tetrazolium-based MTT assay. Moreover, apoptosis rate and mRNA expression of the anti-apoptotic (BCL2) and pro-apoptotic (BAX) genes in the treated cancer cells using Flowcytometry and Real-Time PCR method, respectively. Our study revealed that the phenol-chloroform extraction of S. khuzestanica decreased viability and proliferation of the cancer cells in a concentration- and time-dependent manner. However, use of LDH nanosheets cause to decrease the anticancer activity of S. khuzestanica against the cancer cells. Moreover, treatment of cancer cells by S. khuzestanica extraction cause to increase apoptosis rate and expression of BAX gene mRNA as well as decrease BCL2 gene mRNA expression. Generally, we demonstrated a significant anti-cancer effects of S. khuzestanica phenol-chloroform extraction against HCC cell line HepG2 through regulation of apoptosis-related genes expression and direct cells to apoptosis. However, the LDH nanosheets decrease anticancer potential of S. khuzestanica in the cancer cells.

ProspeCtive study to evaluate efficacy, safety and tOlerability of dietary supplemeNT of Curcumin (BCM95) in subjects with Active relapsing MultIple Sclerosis treated with subcutaNeous Interferon beta 1a 44 mcg TIW (CONTAIN): A randomized, controlled trial

Backgroundmultiple sclerosis (MS) is a complex disease sustained by several pathogenic mechanisms. As such, combination therapy strategies, targeting a range of disease mechanisms, might represent the ideal therapeutic approach. Here we investigated the efficacy of curcumin, a naturally occurring poly-phenolic phytochemical with potent anti-inflammatory and antioxidant properties, in subjects under treatment with IFN β-1a, to test the effects of this combination therapy on clinical and MRI parameters of inflammation and neurodegeneration in relapsing MS (RMS). Methodseighty active RMS were prospectively enrolled, randomized (1:1) to either the IFN-curcumin or the IFN-placebo group and followed up longitudinally with clinical and MRI assessments for 24 months. Primary endpoint was the efficacy of curcumin versus placebo as add-on therapy on new/enlarging T2 lesions in RMS subjects under treatment with subcutaneous IFN β-1a 44 mcg TIW. Efficacy on clinical parameters (relapses and disability progression), other MRI parameters of inflammation (T1 Gd-enhancing lesions, combined unique active-CUA lesions) and neurodegeneration (T1-hypointense lesions, grey matter loss and white matter microstructural damage) as well as safety and tolerability of curcumin were explored as secondary endpoints. Resultsten subjects dropped out from the study by month 12 (6 in the IFN-curcumin group and 4 in the IFN-placebo group), and 27 by month 24 (11 in the IFN-curcumin group and 16 in the IFN-placebo group). Although no between-group difference was present in terms of proportion of subjects free from new/enlarging T2 lesions, a lower proportion of patients with CUA lesions was noted at month 12 in the IFN-curcumin group in comparison with the IFN-placebo group (7.5% vs 17.5%, χ² test p= 0.0167). This result was not confirmed at month 24. The statistical analysis failed to reveal any difference between the two treatment groups – IFN-curcumin and IFN-placebo – in terms of relapses, disability progression, other MRI metrics of inflammation and MRI changes suggestive of ongoing neurodegeneration. No difference in the rate and nature of adverse events was observed between the two treatment groups. ConclusionAlthough the study drop-out rate was too high to allow definite conclusions, our findings suggest that curcumin might add to IFN β-1a efficacy on radiological signs of inflammation in MS, while it did not seem to exert any neuroprotective effect as assessed by clinical and MRI parameters. (NCT01514370)

High-dose VitC plus oncolytic adenoviruses enhance immunogenic tumor cell death and reprogram tumor immune microenvironment

Preclinical and clinical studies have validated the antitumor effects of several oncolytic viruses (OVs). However, the efficacy of OVs is limited when they are administered as monotherapies. Combination therapy is a promising direction for oncolytic virotherapy in the future. A high dose of vitamin C (VitC) exerts anticancer effects by triggering the accretion of substantial amounts of reactive oxygen species (ROS). OVs can induce immunogenic tumor cell death and elicit an antitumor immune response. ROS play an important role in immunogenic cell death (ICD). This study aimed to explore whether high-dose VitC in combination with oncolytic adenoviruses (oAds) exhibited a synergistic antitumor effect. High-dose VitC synergized with oAds against tumor by enhancing immunogenic tumor cell death. Combination therapy with high-dose VitC and oAds significantly increased the number of Tcells in the tumor microenvironment (TME) and promoted the activation of Tcells. Furthermore, the antitumor effect of the combination therapy was CD8+ Tcell dependent. In addition, combination therapy with high-dose VitC and oAds reprogramed the immunosuppressive TME. Our study provides a new strategy for combination therapy of OVs.