Evaluation Of Antitumor Efficacy Research Articles

Preparation of cardamonin and IR780 Co-loaded on Lycium barbarum polysaccharide nanoparticles and anti-tumor efficacy evaluation

To improve the therapeutic efficacy of cardamonin (CRD) in the treatment of breast cancer, Lycium barbarum polysaccharide (LBP) was selected as a nanocarrier for CRD and IR780 to prepare CRD-IR780@LBP nanoparticles (NPs) via antisolvent precipitation. CRD-IR780@LBP NPs demonstrated superior characteristics, such as sustainable drug release, high photothermal conversion, and good antitumor efficacy and secretion levels of cytokines (TNF-α, IL-6 and IL-2). The IC50 value of CRD-IR780@LBP NPs was 2.31 μg/mL, which was significantly lower than that of the pure CRD group (P < 0.0001). The tumor inhibition rate of CRD-IR780@LBP NPs was 80.03 %, which was a 1.58-fold increase compared to that of PTX injection. Furthermore, the ELISA results suggested that LBP can exert therapeutic effects by upregulating the expression levels of TNF-α, IL-6 and IL-2 (P < 0.01) without causing any apparent adverse effects on major tissues and organs. In conclusion, the CRD-IR780@LBP NPs prepared in this study can enhance the therapeutic efficacy of CRD against breast cancer via multiple synergistic anti-tumor mechanisms.

Abstract LB441: An intravenous compatible oncolytic vaccinia virus treated hepatic metastasis of colon cancer through extensive cancer cell killing and activation of cytotoxic effector differentiation

Abstract Colorectal cancer (CRC) is the third most common cancer worldwide and nearly 50% of CRC patients develop liver metastasis during the course of their disease. Treatment of colorectal cancer liver metastasis (CRLM) has been particularly challenging due to tolerogenic nature of liver immune microenvironment as well as an eventual development of therapy resistance to standard chemotherapy regimen. One promising area of cancer immunotherapy is oncolytic virotherapy that can selectively destroy tumor cells and stimulate anti-tumor immune response. In this study, we systemically administered mSJ-650, an intravenous compatible oncolytic Wyeth strain vaccinia virus that expresses human complement regulatory protein CD55 and murine GM-CSF in place of viral thymidine kinase gene and has a deletion of the viral K2L gene, and evaluated its anti-tumor efficacy in CRLM. Mouse CRLM was induced by intrasplenic injection of 5×105 MC38-OVA cancer cells. Following tumor nodules formation in the liver, low dose (1×106 pfu) or high dose (3×106 pfu) of mSJ-650 was administered multiple times via tail vein and liver was harvested for evaluation of anti-tumor efficacy. Flow cytometry analysis was performed to investigate changes in hepatic and tumor immune microenvironment upon mSJ-650 treatment. Liver and tumor tissue were stained for immunofluorescence imaging of viral replication within the tumor cells and subsequent oncolysis by the virus. Systemic administration of mSJ-650 showed potent anti-tumor efficacy and led to significant reduction in metastatic nodule formation in liver even at low dose. The anti-tumor efficacy was mediated by tumor cell-specific viral distribution and replication, followed by lytic egress of mSJ-650 from infected tumor cells. Anti-tumor efficacy of mSJ-650 also accompanied a dramatic shift in immunologically tolerant hepatic microenvironment to immune-stimulatory one by decreasing proportion of myeloid-derived suppressor cells, Kupffer cells, and monocyte-derived macrophages (MDMs) in the liver while increasing CD8+ T cell infiltration by 2~3 folds. Moreover, mSJ-650 treatment was associated with phenotypic change in hepatic immune cells, as evidenced by Kupffer cell and MDM polarization to M1 phenotype and elevated expression of activation markers and cytotoxic molecules in CD8+ T cells. Changes in hepatic immune microenvironment were also observed in tumor nodules, especially in those completely surrounded by adjacent liver tissue, suggesting that anti-tumor immune response in tumor bed is potentiated by reprogramming of tumor-adjacent hepatic immune microenvironment. Systemic administration of mSJ-650 demonstrated superior anti-tumor efficacy in CRLM which was mediated by direct tumor cell killing and tumor-adjacent hepatic immune microenvironment reprogramming by the virus. Citation Format: Eunhye Kim, Yeonsoo Yang, Solchan Won, Namhee Lee, Songyi Lee, Mi-Ju Park, Byung-Jin Jung, Yun-Kyoung Hong, Hang-Rae Kim, Dong-Sup Lee, Keunhee Oh. An intravenous compatible oncolytic vaccinia virus treated hepatic metastasis of colon cancer through extensive cancer cell killing and activation of cytotoxic effector differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB441.

ZGGS15, a Novel IgG4 Bispecific Monoclonal Antibody Targeting Both LAG-3 and Tigit, Demonstrates Outstanding Anti-Tumor Activity and Can be Used As Monotherapy or in Combination with Anti-PD-1 Antibodies for Cancer Immunotherapy

Background This study aims to evaluate the anti-tumor efficacy of ZGGS15, a novel IgG4 bispecific monoclonal antibody (BsAb) targeting TIGIT and LAG-3, for cancer immunotherapy. Methods: ZGGS15 was generated in-house with the standard recombinant BsAb technology. ZGGS15 proteins were purified with protein A affinity column chromatography and evaluated for purity by size-exclusion high-performance liquid chromatography. The ZGGS15 affinity was assessed using a biolayer interferometry (BLI) assay. The EC50s of ZGGS15 binding to TIGIT and LAG-3 were determined using the ELISA technique. The EC50s of ZGGS15 binding to REH, Hela, MCF-7, and HCC1954 cells were measured by flow cytometry. Antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities were also evaluated by flow cytometry. BALB/c-hPD-1/hLAG-3 and BALB/c-hPD-1/hTIGIT subcutaneously transplanted with CT26.WT tumor mouse models, and peripheral blood mononuclear cells (PBMC) -humanized NOG bearing A375 tumor mouse model were used for in vivo anti-tumor efficacy evaluation. Results ZGGS15 binds specifically to activated CD4 + and CD8 + T cells and human LAG-3 and TIGIT proteins expressed by CHO-K1 cells identically with a dose-dependent nanomolar affinity of 0.69 nM and 1.87 nM for human LAG-3 and TIGIT, respectively. In vitro kinetic analysis BLI results revealed ZGGS15 has high affinity for human LAG-3 and human TIGIT proteins, with KDs of 3.05 nM and 2.65 nM, respectively. ZGGS15 binds to human LAG-3 and human TIGIT simultaneously with similar affinity. Furthermore, ZGGS15 competitively inhibited the binding of LAG-3 to MHC-II (IC50 = 0.77 nM) and the binding of TIGIT to CD155 (IC50=0.24 nM). ZGGS15 induced better T cell activation than single anti-LAG3 or anti-TIGIT mAb agent or combined with different stimuli with or without cancer cells. When combined with nivolumab, ZGGS15 can further enhance the T cell activation in a dose-dependent manner. ADCC/CDC assay results showed that ZGGS15 binding to target cells does not induce ADCC or CDC. ZGGS15 interacts with the human neonatal Fc receptor in a pH-dependent manner, which can promote recirculation of ZGGS15 with a prolonged half-life in plasma. Besides, ZGGS15 interacts with human Fc-γ receptors and the human complement component, C1q, with low binding affinities. However, ZGGS15 does not induce obvious cytokine production from PBMCs, including IFN-γ, IL-2, IL-6, IL-10, and TNF-α. In vivo anti-tumor efficacy for ZGG15 in PBMC humanized NOG mice bearing A375 tumors showed that ZGGS15 had significant anti-tumor effects in the subcutaneous A375 xenograft model. ZGGS15 showed a better anti-tumor inhibition than single anti-LAG-3 or anti-TIGIT agent and a synergetic effect when combined with nivolumab. On day 18 post-treatment, the ZSAB015 plus nivolumab treatment demonstrated a significantly tumor growth inhibition (TGI) of 95.80% ( p =0.001), compared with the vehicle group. In vivo efficacy tests in BALB/c-hPD-1/hLAG-3 mice subcutaneously transplanted with CT26.WT tumor model showed that both high and low doses of ZGGS15 could inhibit the growth of CT26.WT colon cancer. The combination of high-dose ZGGS15 plus nivolumab has better efficacy than high-dose ZGGS15 and is slightly better than nivolumab alone. The tumor volume inhibition rate (TGITV) for ZGGS15 at 2 mg/kg was 69.70%, and for ZGGS15 at 5 mg/kg plus nivolumab at 1 mg/kg, it was 94.03% ( p &amp;lt; 0.001). During the experiment, the tumor-bearing mice tolerated it well, and no adverse reactions were observed. In vivo efficacy tests of ZGG15 in BALB/c-hPD-1/hTIGIT mice subcutaneously transplanted with CT26.WT tumor model showed that ZGGS15 at a low dose (1.5 mg/kg) demonstrated a significant tumor inhibitory effect, with the TGITV of 51.42% ( p &amp;lt; 0.01). The combination of ZGGS15 high-dose with nivolumab (5 mg/kg + 1 mg/kg) showed a better tumor inhibitory effect compared with ZGGS15 high-dose (5 mg/kg), with the TGITV of 81.15% and 41.54%, respectively ( p &amp;lt; 0.05). Conclusions ZGGS15 has excellent anti-tumor activity by inhibiting LAG-3 and TIGIT as a new IgG4 BsAb. ZGGS15 also exhibits potent anti-tumor efficacy in transgenic mouse models combined with nivolumab. Additionally, ZGGS15 does not elicit ADCC or CDC, therefore avoiding the cross-reaction of non-target binding. Finally, ZGGS15 does not induce cytokine production, mitigating any potential adverse effects of CRS.

Design, synthesis and anti-tumor efficacy evaluation of novel 1,3-diaryl propane-based polyphenols obtained from Claisen rearrangement reaction

Polyphenols such as resveratrol, honokiol and nordihydroguaiaretic acid are widely existing in nature products or synthetic compounds with interesting biological activities. Inspired by their structural feature, a total of 49 1,3-diaryl propane-based polyphenols were designed and synthesized through Claisen rearrangement reaction. New compounds were initially assessed for their anti-proliferative activities against various cancer cell lines (PC-3, U87MG, U251, HCT116) at a concentration of 50 μM, and the results guided the SAR of this series of compounds. Further screening of selected compounds against seven cancer cell lines (three additional colon cancer cell lines namely COLO205, HT29 and SW480 were chosen) led to the identification of two advanced leads 2t and 3t with IC50 values ranging from 8.2 ± 0.1 to 19.3 ± 1.9 μM. Both compounds also showed promising anti-proliferative activities against COLO205 in dose- and time-dependent manners. Furthermore, 2t and 3t exhibited good anti-tumor efficacy in COLO205 xenografted mice model with TGI values ranging from 38% to 58%. These results warrant the further investigation of this series of compounds.

Chicken embryo model for in vivo acute toxicological and antitumor efficacy evaluation of lipid nanocarrier containing doxorubicin

Nanoencapsulation of chemotherapeutics, including doxorubicin, can endow the formulations with unique properties, such as a decrease in adverse effects and toxicity. The chicken embryo model is an alternative and well-accepted strategy for evaluating the toxicity and efficacy of drugs and nanoformulations. Therefore, this study proposes the development of a new lipid nanocarrier for doxorubicin delivery (NanoLip-Dox) and posterior evaluation of toxicological profile and antitumoral efficacy against a breast tumor in chicken embryos. NanoLip-Dox showed a unimodal particle size (< 150 nm), negative zeta potential (−19.5 mV), absence of drug crystals, drug content of 0.099 mg·mL−1, and high entrapment efficiency (95%). NanoLip-Dox did not cause toxicity in the chicken embryos; in contrast, doxorubicin hydrochloride induced moderate irritation in the chorioallantoic membrane (at 862.1 μmol·L−1), a survival rate of 50% (at 1.7 μmol·L−1), and an increase in aspartate aminotransferase (at 862.1, 344.8, and 172.4 μmol·L−1). In addition, NanoLip-Dox (at 1.7 μmol·L−1) showed potent antitumor efficacy with a high tumor remission percentage (40.9 ± 9.7%) compared to the control group (8.6 ± 14.8%). These findings together with the absence of toxicity concerning morphological characteristics, weights of embryos and organs, hematologic parameters, and enzymatic activity (alanine aminotransferase, aspartate aminotransferase, and creatinine) suggest the safety and efficacy of NanoLip-Dox.

Targeted Fisetin-Encapsulated β-Cyclodextrin Nanosponges for Breast Cancer.

Fisetin (FS) is considered a safer phytomedicine alternative to conventional chemotherapeutics for breast cancer treatment. Despite its surpassing therapeutic potential, its clinical utility is hampered by its low systemic bioavailability. Accordingly, as far as we are aware, this is the first study to develop lactoferrin-coated FS-loaded β-cyclodextrin nanosponges (LF-FS-NS) for targeted FS delivery to breast cancer. NS formation through cross-linking of β-cyclodextrin by diphenyl carbonate was confirmed by FTIR and XRD. The selected LF-FS-NS showed good colloidal properties (size 52.7 ± 7.2 nm, PDI < 0.3, and ζ-potential 24 mV), high loading efficiency (96 ± 0.3%), and sustained drug release of 26 % after 24 h. Morphological examination using SEM revealed the mesoporous spherical structure of the prepared nanosponges with a pore diameter of ~30 nm, which was further confirmed by surface area measurement. Additionally, LF-FS-NS enhanced FS oral and IP bioavailability (2.5- and 3.2-fold, respectively) compared to FS suspension in rats. Antitumor efficacy evaluation in vitro on MDA-MB-231 cells and in vivo on an Ehrlich ascites mouse model demonstrated significantly higher activity and targetability of LF-FS-NS (30 mg/kg) compared to the free drug and uncoated formulation. Consequently, LF-FS-NS could be addressed as a promising formulation for the effective management of breast cancer.

Abstract 6360: In vivo antitumor efficacy evaluation of ASC63, an oral small molecule PD-L1 inhibitor, in a humanized mouse tumor model

Abstract Background: ASC63 is an oral small molecule programmed cell death-ligand 1 (PD-L1) inhibitor. After oral dosing, ASC63 is rapidly absorbed and converted to its pharmacologically active metabolite ASC63-A in vivo. In vitro studies showed that ASC63-A could activate PD-L1 dimerization and internalization from cell membrane, thus interfere PD-1/PD-L1 interaction and enhance T-cell activation. Here we report the in vivo antitumor efficacy of ASC63 in a humanized mouse tumor model. Methods: 0.5×106 human PD-L1 knock in CT26 cells (CT26-hPD−L1) were implanted subcutaneously into BALB/c mice for tumor development. When the average tumor volume reached approximately 100 mm3, mice were randomly assigned (post-grouping, PG) and treated with vehicle, reference drug (10 mg/kg Atezolizumab intravenous injection twice a week [BIW]), 50 or 100 mg/kg ASC63 oral dosing twice a day (BID) for 18 days. Body weights and tumor volumes were measured regularly, and tumor growth inhibitions (TGI) of different groups were compared. TGI was calculated using the formula: TGI (%) =[1-(TRTV-1)/(CRTV-1)] ×100, where TRTV= mean relative tumor volume (RTV) of treatment group; CRTV= mean of control group. Results: At PG-D18, the tumor volume of vehicle group reached 1548 mm3, and Atezolizumab, 50 and 100 mg/kg AS63 groups showed TGI values of 35.17, 17.12 and 36.87%, respectively. Atezolizumab 10 mg/kg BIW and ASC63 100 mg/kg BID produced similar antitumor activities. One mouse in 100 mg/kg ASC63 group had body weight loss more than 10% at PG-D6, and was back to normal at PG-D9 after extra nutrition was provided, while the rest of mice showed a gradually increase in body weight during the study. No significant difference of body weight or body weight change was found among different groups of mice. Conclusion: Results of this study show that ASC63 is in general well tolerated in CT26-hPD−L1 humanized mouse tumor model, and ASC63 has comparable antitumor efficacy as the FDA-approved PD-L1 antibody, Atezolizumab. ASC63 is an oral small molecule PD-L1 inhibitor, and thus will have better patient compliance than injective PD-1/PD-L1 antibody. Results of this study support the continued investigation of ASC63. Citation Format: Jinzi J. Wu, Handan He. In vivo antitumor efficacy evaluation of ASC63, an oral small molecule PD-L1 inhibitor, in a humanized mouse tumor model [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 6360.

Evaluation of antitumor efficacy of Cerium oxide nanoparticle on Ehrlich tumour cells in mice

Evaluation of antitumor efficacy of Cerium oxide nanoparticle on Ehrlich tumour cells in mice

Design, synthesis and antitumor efficacy evaluation of a series of novel β-elemene-based macrocycles

β-Elemene is the major constituent of the antitumor drugs elemene extract approved in China. By incorporating macrocyclization strategy into the β-elemene skeleton, we designed a series of novel macrocycles retaining three key carbon–carbon double bonds. Four different methods have been successfully developed for these challenging ring systems. A total of twenty-eight 14- to 24-membered macrocycles were synthesized. Most of these macrocycles exhibited good antitumor activity against several cancer cell lines (PC-3, A549, U87MG, U251 and HCT116), with up to 40 folds improvement of activity comparing to β-elemene. Additionally, X-ray single crystal structures of compounds Ic, Ip, and IIh were successfully solved as the proof of macrocycle formation. The results warrant the further investigation of this novel class macrocycles in pharmacokinetic and pharmacodynamics studies, which will be reported in due course.

A caspase-3-activatable bimodal probe for photoacoustic and magnetic resonance imaging of tumor apoptosis in vivo

Multimodal imaging probes have shown promise in both biomedical research and clinical diagnosis. However, the development of molecular probes capable of being switched on multimodality imaging signals in response to a biomarker of interest remains challenging. In this paper, we report a caspase-3-activatable small-molecule bimodal probe (Gd-IR780) for photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) of tumor apoptosis via caspase-3-triggered intramolecular macrocyclization and in situ self-assembly process. Upon interaction with caspase-3, Gd-IR780 can be efficiently converted into a macrocyclic product, Gd-IR780-MC, which subsequently self-assembles into near-infrared absorptive and paramagnetic nanoparticles (Gd-IR780-NPs), allowing to concurrently switch on PAI (∼4.3-fold at 855 nm) and MRI (r1 relaxivity increases from 7.98 ± 0.03 mM−1 s−1 to 19.66 ± 0.7 mM−1 s−1 at 0.5 T) bimodal signals in caspase buffer. Noninvasive in vivo imaging results show that Gd-IR780 can enter apoptotic U87MG tumor tissues after systemic administration, and produce markedly enhanced PAI and MRI signals for high sensitivity and spatial-resolution visualization of caspase-3 activity in the doxorubicin-treated apoptotic U87MG tumor tissues. Gd-IR780 holds a good potential to report tumor apoptosis via combined PAI and MRI, which is beneficial for the early evaluation of antitumor efficacy in vivo.

Efficacy and safety of serplulimab (an anti-PD-1 antibody) combined with albumin-bound paclitaxel in patients with advanced cervical cancer who have progressive disease or intolerable toxicity after first-line standard chemotherapy (074)

<b>Objectives:</b> Limited effective treatments are available for advanced cervical cancer patients who have failed first-line chemotherapy. Historical data indicate that PD-1 antibodies and albumin-bound paclitaxel monotherapy have certain antitumor activity (ORR: 14.3% for pembrolizumab and 28.6% for albumin-bound paclitaxel) in recurrent/advanced cervical cancer patients. This study aimed to determine the efficacy and safety of serplulimab (a recombinant humanized anti-PD-1 monoclonal antibody) plus albumin-bound paclitaxel in patients with advanced cervical cancer who have progressed on or are intolerant to first-line standard chemotherapy. <b>Methods:</b> This is an ongoing, single-arm, open-label, multi-center phase II study (NCT04150575). Twenty eligible patients aged between 18 and 75 years, who had ECGO PS 0 or 1, with histologically or cytologically diagnosed cervical cancer and positive PD-L1 expression (combined positive score [CPS] ≥1) were planned to be enrolled and given intravenous infusions of serplulimab (4.5 mg/kg) plus albumin-bound paclitaxel (260 mg/m²) every three weeks. The primary endpoints of this study were the adverse events, serious adverse events, and ORR (assessed by independent radiological review committee [IRRC] per RECIST v1.1). After all patients completed two tumor evaluations (every six weeks), a safety evaluation and a preliminary evaluation of antitumor efficacy were conducted. <b>Results:</b> By cut-off date July 15, 2021, 21 eligible patients were enrolled with a median age of 50.8 years (range: 31-64) and an average CPS of 39.3 (1 ≤CPS <20: <i>n</i>=7 [33.3%], CPS ≥20: <i>n</i>=14 [66.7%]). The median follow-up duration was 12.5 months; 71.4% patients had ECOG PS 1. The ORR assessed by IRRC and investigators were 57.1% (<i>n</i>=12; 95% CI: 34.0%-78.2%) and 47.6% (<i>n</i>=10; 95% CI: 25.7%-70.2%), respectively. The disease control rate (DCR) assessed by IRRC and investigators were both 76.2% (<i>n</i>=16; 95% CI: 52.8%-91.8%). The median PFS assessed by IRRC was 5.7 months (95% CI: 3.0-not reached). The median OS was not reached (95% CI: 10.5 months-not reached). The most common grade 3 or worse treatment-emergent adverse events (TEAEs) were decreased neutrophil count (<i>n</i>=7, 33.3%), decreased white blood cell count (<i>n</i>=6, 28.6%) and anemia (<i>n</i>=5, 23.8%). The most common immune-related adverse events (irAEs) were hypothyroidism (<i>n</i>=6, 28.6%), hyperthyroidism (<i>n</i>=3, 14.3%) and pruritus (<i>n</i>=3, 14.3%), all of which were grade 1 to 2. No TEAEs leading to drug discontinuation were observed. <b>Conclusions:</b> The results demonstrated a manageable safety profile and encouraging efficacy (IRRC-ORR: 57.1%) of serplulimab plus albumin-bound paclitaxel in advanced cervical cancer patients who have progressive disease or intolerable toxicity to first-line standard chemotherapy, representing a novel potential treatment option that warranted further investigation.

Establishment of an Ex Vivo Tissue Culture Model for Evaluation of Antitumor Efficacy in Clear Cell Renal Cell Carcinoma.

There are many potential immunotherapeutic targets for cancer immunotherapy, which should be assessed for efficacy before they enter clinical trials. Here we established an ex vivo cultured patient-derived tumor tissue model to evaluate antitumor effectiveness of one VISTA inhibitor, given that our previous study showed that VISTA was selectively highly expressed in human clear cell renal cell carcinoma (ccRCC) tumors. We observed that all the tested patients responded to the anti-VISTA monoclonal antibody as manifested by TNF-α production, but only a small fraction were responders to the anti-PD-1 antibody. Co-blockade of VISTA and PD-1 resulted in a synergistic effect in 20% of RCC patients. Taken together, these findings indicate that this ex vivo tumor slice culture model represents a viable tool to evaluate antitumor efficacies for the inhibitors of immune checkpoints and further supports that VISTA could serve as a promising target for immunotherapy in ccRCC.

FimH confers mannose-targeting ability to Bacillus Calmette-Guerin for improved immunotherapy in bladder cancer

BackgroundBladder cancer is a common disease worldwide with most patients presenting with the non-muscle-invasive form (NMIBC) at initial diagnosis. Postoperational intravesical instillation of BCG is carried out for patients with...

Tailoring a Near‐Infrared Macrocyclization Scaffold Allows the Control of In Situ Self‐Assembly for Photoacoustic/PET Bimodal Imaging

AbstractEnzyme‐triggered macrocyclization and in situ self‐assembly of small molecules into nanoparticles has shown promise to design activatable probes for molecular imaging. However, controlling macrocyclization and self‐assembly to concurrently augment positron emission tomography (PET) and photoacoustic (PA) signals for bimodality imaging is challenging. Herein, we report the engineering of a triazole‐IR780 fluorophore as a versatile macrocyclization scaffold for controlling in situ self‐assembly and design a caspase‐3‐activatable PA/PET bimodal probe ([18F]‐IR780‐1) for in vivo imaging of tumor apoptosis. By leveraging the high‐sensitivity whole‐body imaging signals offered by PET with the high‐resolution imaging signals offered by PA, [18F]‐IR780‐1 can provide a promising tool for the early evaluation of antitumor efficacy, helpful for optimizing the therapeutic protocol for patients. This scaffold may be adopted to design other activatable bimodal probes for in vivo imaging.

Tailoring a Near-Infrared Macrocyclization Scaffold Allows the Control of In Situ Self-Assembly for Photoacoustic/PET Bimodal Imaging.

Enzyme-triggered macrocyclization and in situ self-assembly of small molecules into nanoparticles has shown promise to design activatable probes for molecular imaging. However, controlling macrocyclization and self-assembly to concurrently augment positron emission tomography (PET) and photoacoustic (PA) signals for bimodality imaging is challenging. Herein, we report the engineering of a triazole-IR780 fluorophore as a versatile macrocyclization scaffold for controlling in situ self-assembly and design a caspase-3-activatable PA/PET bimodal probe ([18 F]-IR780-1) for in vivo imaging of tumor apoptosis. By leveraging the high-sensitivity whole-body imaging signals offered by PET with the high-resolution imaging signals offered by PA, [18 F]-IR780-1 can provide a promising tool for the early evaluation of antitumor efficacy, helpful for optimizing the therapeutic protocol for patients. This scaffold may be adopted to design other activatable bimodal probes for in vivo imaging.

Clinical efficacy evaluation of Erlotinib Combined with Concurrent Chemoradiotherapy in the treatment of locally advanced Pancreatic Cancer.

ABSTRACTObjective:To evaluate the clinical effects of erlotinib combined with concurrent chemoradiotherapy in the treatment of locally advanced pancreatic cancer.Methods:Eighty patients with locally advanced pancreatic cancer who attended Shijiazhuang People’s Hospital or Anhui Cancer Hospital between January 2018 and January 2020 were randomly divided into two groups, with 40 cases in each group. Patients in the control group were treated with concurrent chemoradiotherapy, while those in the experimental group were treated with erlotinib tablets based on the treatment regimen of the control group. Anti-tumor efficacy evaluation was conducted for all patients in both groups, and the adverse drug reactions, improvement of performance status after treatment were compared and analyzed between the two groups.Results:The overall response rate of the experimental group was 47.5%, which was significantly better than the 25% of the control group (p=0.03). The incidence of adverse drug reactions in the experimental group was 40%, while that in the control group was 30%. The incidence of adverse drug reactions in the experimental group was higher than that in the control group, but there was no statistical significance (p=0.34). Moreover, the improvement rate of performance status score in the experimental group was significantly higher than that in the control group (p=0.00).Conclusion:Erlotinib combined with concurrent chemoradiotherapy has been preliminarily proved to be safe and effective in the treatment of locally advanced pancreatic cancer, which can improve the physical condition of patients to a certain extent without significantly increasing adverse reactions.

Efficacy and safety evaluation of HLX10 (a recombinant humanized anti-PD-1 monoclonal antibody) combined with albumin-bound paclitaxel in patients with advanced cervical cancer who have progressive disease or intolerable toxicity after first-line standard chemotherapy: A single-arm, open-label, phase 2 study.

e17510 Background: Limited effective treatments are available for advanced cervical cancer patients who progress after first-line chemotherapy. Historic data indicate PD-1 antibodies have significant activity in advanced cervical cancer patients. This study was designed to determine the efficacy and safety of HLX10 (a recombinant humanized anti-PD-1 monoclonal antibody) plus albumin-bound paclitaxel in patients with advanced cervical cancer who have progressed on or are intolerant to first-line standard chemotherapy. Methods: This is an ongoing single-arm, open-label, multicenter, two-stage phase 2 study (NCT04150575). 143 eligible patients aged between 18 and 75, with histologically or cytologically diagnosed cervical cancer and positive PD-L1 expression (combined positive score [CPS] ≥1) were planned to be enrolled and given intravenous infusion of HLX10 (4.5 mg/kg) plus albumin-bound paclitaxel (260 mg/m2) every 3 weeks. Stage one (N = 20) was a safety run-in and preliminary efficacy exploration study with primary endpoints of adverse events, serious adverse events and objective response rate (ORR, assessed by IRRC per RECIST v1.1). In this stage, after all patients completed two tumor evaluations (every 6 weeks), a safety evaluation and a preliminary evaluation of anti-tumor efficacy were conducted to determine whether to proceed to the second stage (N = 123). Stage two is a single-arm, open-label, multicenter, phase 2 study with primary endpoint of ORR assessed by IRRC per RECIST v1.1. Results: Here we report the stage one results (safety and preliminary efficacy) of HLX10 in advanced cervical cancer patients. By cut-off date Oct 14, 2020, 21 eligible patients with median age of 50 (range: 31–65) and average CPS of 39.33 were enrolled; the median follow-up duration was 4.34 months. 71.4% patients had ECOG PS 1. The ORR assessed by IRRC and investigators were 52.4% (95% CI: 29.8%, 74.3%) and 42.9% (95% CI: 21.8%, 66.0%), respectively. The most common grade 3 or worse treatment-emergent adverse events (TEAEs) were decreased neutrophil counts (n = 7, 33.3%), decreased white blood cell count (n = 6, 28.6%) and anemia (n = 4, 19.0%). No TEAEs leading to drug discontinuation were observed. One death (multiple organ dysfunction syndrome) possibly related to treatment was reported. Conclusions: Stage one results demonstrated a manageable safety profile and encouraging efficacy (ORR 52.4%) of HLX10 plus albumin-bound paclitaxel in advanced cervical cancer patients who have progressive disease or intolerable toxicity to first-line standard chemotherapy, representing a novel potential treatment option that warranted further investigation. Clinical trial information: NCT04150575.

Bruton's tyrosine kinase inhibitors in primary central nervous system lymphoma-evaluation of anti-tumor efficacy and brain distribution.

BackgroundPrimary central nervous system lymphoma (PCNSL) is an aggressive lymphoma confined to central nervous system. Current treatments including surgery, chemotherapy and whole-brain radiotherapy often fail to achieve satisfactory effect, especially in elderly. As a regimen in targeted therapy, Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has been tested in several clinical trials against PCNSL, offering hope for patients unfit for chemotherapy. We aim to evaluate and compare the anti-PCNSL ability of three different BTK inhibitors, ibrutinib, zanubrutinib and tirabrutinib, providing direct evidence for the targeted therapy of PCNSL.MethodsRetrospective study was done on patients who received ibrutinib-based therapy in our hospital. Cerebrospinal fluid (CSF) from one patient was collected to measure the concentration of ibrutinib. Inhibition assay and apoptosis assay were done on lymphoma cells to determine the anti-tumoral effects of three inhibitors. Pharmacokinetic study was conducted to evaluate their ability in penetrating blood brain barrier and distributing in brain.ResultsIn retrospective study, we found three patients with PCNSL who had good clinical response to ibrutinib-based therapy (2 complete remission, 1 partial remission), which further support the use of BTK inhibitors in PCNSL. In vitro studies show that ibrutinib has the best anti-tumoral ability among three inhibitors. In vivo study on pharmacokinetic profiles indicate that both ibrutinib and tirabrutinib are good in distributing in brain parenchyma.ConclusionsIn conclusion, our study results suggest that BTK inhibitors can be promising candidates for PCNSL treatment, preferring the use of ibrutinib and tirabrutinib as anti-PCNSL agents among the three inhibitors.

Evaluation of antitumor efficacy of folate-poly(2-ethyl-2-oxazoline)-distearoyl phosphatidyl ethanolamine based liposome

This study aims to explore and evaluate the antitumor efficacy of doxorubicin (DOX)-loaded liposomes containing the novel tri-block polymer folate-poly (2-ethyl-2-oxazoline)-distearoyl phosphatidyl ethanolamine (F-PEOz-DSPE), compared with folate-polyethylene glycol-distearoyl phosphatidyl ethanolamine (F-PEG-DSPE) to offer an alternative for PEG decorated carriers. PEOz, a pH-sensitive polymer, exhibits similar solubility and segmental flexibility to PEG. In our previous study, PEOz was employed to an F-PEOz-DSPE which was segmentally similar to F-PEG-DSPE and exhibited selective targeting and pH-sensitivity in tumor cells. In this work, DOX-loaded liposomes containing F-PEOz-DSPE (F-PEOz liposome) or F-PEG-DSPE (F-PEG liposome) were prepared. In vivo/vitro antitumor efficacy and biodistribution were compared between the two liposomes. F-PEOz liposome showed higher in vitro antitumor activity and significantly stronger inhibition of tumor growth in HeLa tumor-bearing nude mice (tumor inhibition rate, 81.20 vs 52.99% with the treatment of 9 mg/kg DOX-loaded F-PEOz liposome/F-PEG liposome) and much less toxicity than free DOX. In vivo fluorescence imaging experiment confirmed that F-PEOz liposome accumulated much more than F-PEG liposome in tumor. Based on the above, F-PEOz liposome may be a promising carrier in tumor chemotherapy to achieve better therapeutic efficacy.

Redox-sensitive polyglutamic acid-platinum(IV) prodrug grafted nanoconjugates for efficient delivery of cisplatin into breast tumor

Targeting cisplatin to the sites of action and decreasing its side effects are still major challenges. Here, we introduced a polyglutamic acid-platinum(IV) prodrug nanoconjugates (γ-PGA-CA-Pt(IV)) constructed by polyglutamic acid and modified platinum(IV) prodrug to reserve the anti-tumor efficacy of cisplatin with decreased side effects. We describe the synthesis, physico-chemical characterization, and redox- and pH-sensitive releasing behavior of the nanoconjugate. In vitro studies revealed that, when incubated with glutathione in advance, the γ-PGA-CA-Pt(IV) nanoconjugate induced significant apoptosis in human breast carcinoma MCF-7 cells. From in vivo antitumor efficacy evaluation, the γ-PGA-CA-Pt(IV) nanoconjugate obviously improved the survival rate of tumor-bearing mice with inhibition of the tumor growth compared with cisplatin. Meanwhile, the nanoconjugates showed remarkable improved safety profile than the free cisplatin.