Strong Antitumor Activity Research Articles

Alkylgold(III) Complexes Undergo Unprecedented Photo-Induced β-Hydride Elimination and Reduction for Targeted Cancer Therapy.

Spatiotemporally controllable activation of prodrugs within tumors is highly desirable for cancer therapy to minimize toxic side effects. Herein we report that stable alkylgold(III) complexes can undergo unprecedented photo-induced β-hydride elimination, releasing alkyl ligands and forming gold(III)-hydride intermediates that could be quickly converted into bioactive [AuIII -S] adducts; meanwhile, the remaining alkylgold(III) complexes can photo-catalytically reduce [AuIII -S] into more bioactive AuI species. Such photo-reactivities make it possible to functionalize gold complexes on the auxiliary alkyl ligands without attenuating the metal-biomacromolecule interactions. As a result, the gold(III) complexes containing glucose-functionalized alkyl ligands displayed efficient and tumor-selective uptake; notably, after one- or two-photon activation, the complexes exhibited high thioredoxin reductase (TrxR) inhibition, potent cytotoxicity, and strong antiangiogenesis and antitumor activities in vivo.

Alkylgold(III) Complexes Undergo Unprecedented Photo‐Induced β‐Hydride Elimination and Reduction for Targeted Cancer Therapy

AbstractSpatiotemporally controllable activation of prodrugs within tumors is highly desirable for cancer therapy to minimize toxic side effects. Herein we report that stable alkylgold(III) complexes can undergo unprecedented photo‐induced β‐hydride elimination, releasing alkyl ligands and forming gold(III)‐hydride intermediates that could be quickly converted into bioactive [AuIII−S] adducts; meanwhile, the remaining alkylgold(III) complexes can photo‐catalytically reduce [AuIII−S] into more bioactive AuIspecies. Such photo‐reactivities make it possible to functionalize gold complexes on the auxiliary alkyl ligands without attenuating the metal–biomacromolecule interactions. As a result, the gold(III) complexes containing glucose‐functionalized alkyl ligands displayed efficient and tumor‐selective uptake; notably, after one‐ or two‐photon activation, the complexes exhibited high thioredoxin reductase (TrxR) inhibition, potent cytotoxicity, and strong antiangiogenesis and antitumor activities in vivo.

Abstract OT2-28-01: A phase 2 study of sitravatinib in metastatic, pre-treated, triple negative breast cancer, NCT # 04123704

Abstract Background:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, disproportionally affecting African American and Hispanic patients, and germline BRCA1/2 mutation carriers. Prognosis of relapsed, metastatic disease is extremely poor and effective well-tolerated therapies are urgently needed. Our collaborators have discovered that TNBCs often lose feedback control of receptor tyrosine kinases (RTKs) including PDGFR and MET, locking these receptors in a chronically active state. These receptors share a common negative regulator called Protein Tyrosine Phosphatase, Non-Receptor Type 12 (PTPN12). Baylor investigators have shown that PTPN12- deficient TNBCs may be responsive to combined RTK inhibition. Sitravatinib is a spectrum selective RTK inhibitor that has shown strong antitumor activity in patient derived xenografts (PDXs) of TNBC with low levels of PTPN12. We have therefore designed a phase II, multi-institution, two cohort trials to evaluate the efficacy of sitravatinib in patients with metastatic TNBC (mTNBC). Methods: Patients with diagnosis of mTNBC who have received at least one line of chemotherapy +/- atezolizumab for advanced disease would be considered for enrollment. Patients would need to have tissue from metastatic site available for evaluation or agree to undergo biopsy if banked tumor tissue is not available. Sitravatinib at 100 mg daily, the recommended phase 2 dose for sitravatinib monotherapy, will be started at the initiation of the study and continued until progression or unacceptable toxicity. The study will employ a modified optimal Simon’s two stage design. Patients will be recruited into two cohorts: PTPN12 low or PTPN12 high/normal cohorts simultaneously and independently. Seven patients will be enrolled to each arm during the first stage. After the first stage, depending on the observed number of responses, the study will proceed to the 2nd stage. The primary endpoint is progression-free survival status at 24 weeks (PFS24). Current Trial status: The trial is funded by Mirati Therapeutics and opened to enrollment at Dan L Duncan Comprehensive Cancer Center (DLDCCC) clinics as of 6/8/21. Trial is due to open at UT Southwestern Dallas by 11/2021. The correlative science is funded by an institutional SPORE grant. Conclusion: This trial aims to show that sitravatinib is safe and to investigate whether it could be a treatment option in mTNBC. Citation Format: Maryam Nemati Shafaee, Kristen Otte, Nicholas J Neill, Kent C Osborne, Thomas F Westbrook, Susan Hilseneck, Matthew J Ellis. A phase 2 study of sitravatinib in metastatic, pre-treated, triple negative breast cancer, NCT # 04123704 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-28-01.

Adiponectin suppresses tumor growth of nasopharyngeal carcinoma through activating AMPK signaling pathway

BackgroundAdiponectin is an adipocyte-secreted cytokine that enhances insulin sensitivity and attenuates inflammation. Although circulating adiponectin level is often inversely associated with several malignancies, its role in the development of nasopharyngeal carcinoma (NPC) remains unclear. Here, we investigated the clinical association between circulating adiponectin level and NPC, and examined the impact of adiponectin, as well as the underlying mechanisms, on NPC growth both in vitro and in vivo.MethodsThe association between circulating adiponectin level and the risk of developing NPC was assessed in two different cohorts, including a hospital-based case–control study with 152 cases and 132 controls, and a nested case–control study with 71 cases and 142 controls within a community-based NPC screening cohort. Tumor xenograft model, cell proliferation and cycle assays were applied to confirm the effects of adiponectin on NPC growth in cultured cells and in xenograft models. We also investigated the underlying signaling mechanisms with various specific pharmacological inhibitors and biochemistry analysis.ResultsHigh adiponectin levels were associated with a monotonic decreased trend of NPC risk among males in both the hospital-based case–control study and a nested case–control study. In vitro, recombinant human full-length adiponectin significantly inhibited NPC cell growth and arrested cell cycle, which were dependent on AMPK signaling pathway. The growth of xenograft of NPC tumor was sharply accelerated in the nude mice carrying genetic adiponectin deficiency. An adiponectin receptor agonist, AdipoRon, displayed strong anti-tumor activity in human xenograft models.ConclusionsThese findings demonstrated for the first time that circulating adiponectin is not only inversely associated with NPC, but also controls the development of NPC via AMPK signaling pathway. Stimulation of adiponectin function may become a novel therapeutic modality for NPC.

Novel dihydroartemisinin derivative Mito-DHA5 induces apoptosis associated with mitochondrial pathway in bladder cancer cells

BackgroundBladder cancer is the second most common genitourinary malignancy and the eleventh most common cancer worldwide. Dihydroartemisinin (DHA), a first-line antimalarial drug, has been found to have potent antitumor activity. In our previous study, a novel dihydroartemisinin derivative Mito-DHA5 synthesized in our laboratory has a stronger anti-tumor activity than DHA. In this study, we investigated the apoptotic effect of Mito-DHA5 on bladder cancer T24 cells and molecular mechanisms underlying.MethodsAntitumor activity in vitro was evaluated by MTT, wound healing and cloning formation assays. Mitochondrial membrane potential (MMP) was detected by JC-1 probe and ROS levels were measured by specific kit. The expression of caspase-3, cleaved-caspase3, mitochondrial Cyt-C, Bcl-2, Bax and PARP in T24 cells was evaluated by Western blotting.ResultsThe results showed that Mito-DHA5 reduced cell viability with an IC50 value of 3.2 µM and induced T24 cell apoptosis in a dose-dependent manner, increased the production of ROS and decreased MMP. Mito-DHA5 could down-regulate the expression of Bcl-2, mitochondrial Cyt-C, Caspase-3, PARP and up-regulate the expression of Bax and cleaved Caspase-3.ConclusionsThese data suggested that Mito-DHA5 had a potent inhibitory effect on T24 bladder cancer cell growth and induced these cells apoptosis associated with mitochondrial pathway.

Tumor-Microenvironment-Activatable Polymer Nano-Immunomodulator for Precision Cancer Photoimmunotherapy.

Cancer nanomedicine combined with immunotherapy has become a promising strategy for treating cancer in terms of safety and potency; however, precise regulation of the activation of antitumor immunity remains challenging. Herein, a smart semiconducting polymer nano-immunomodulator (SPNI), which responds to the acidic tumor microenvironment (TME), for precision photodynamic immunotherapy of cancer, is reported. The SPNI is self-assembled by a near-infrared (NIR)-absorbing semiconducting polymer and an amphipathic polymer conjugated with a Toll-like receptor 7 (TLR7) agonist via an acid-labile linker. Upon arrival at tumor site, SPNI undergoes hydrolysis and triggers an efficient liberation of TLR7 agonist in response to the acidic TME for dendritic cell activation. Moreover, SPNI exerts photodynamic effects for direct tumor eradication and immunogenic cancer cell death under NIR photoirradiation. The synergistic action of released immunogenic factors and acidic-TME-activated TLR7 agonist can serve as an in situ generated cancer vaccine to evoke strong antitumor activities. Notably, such localized immune activation boosts systemic antitumor immune responses, resulting in enhanced cytotoxic CD8+ T infiltration to inhibit tumor growth and metastasis. Thereby, this work presents a general strategy to devise prodrug of immunotherapeutics for precise regulation of cancer immunotherapy.

Evaluation of Nonviral piggyBac and lentiviral Vector in Functions of CD19chimeric Antigen Receptor T Cells and Their Antitumor Activity for CD19+ Tumor Cells.

Nonviral transposon piggyBac (PB) and lentiviral (LV) vectors have been used to deliver chimeric antigen receptor (CAR) to T cells. To understand the differences in the effects of PB and LV on CAR T-cell functions, a CAR targeting CD19 was cloned into PB and LV vectors, and the resulting pbCAR and lvCAR were delivered to T cells to generate CD19pbCAR and CD19lvCAR T cells. Both CD19CAR T-cell types were strongly cytotoxic and secreted high IFN-γ levels when incubated with Raji cells. TNF-α increased in CD19pbCAR T cells, whereas IL-10 increased in CD19lvCAR T cells. CD19pbCAR and CD19lvCAR T cells showed similar strong anti-tumor activity in Raji cell-induced mouse models, slightly reducing mouse weight while enhancing mouse survival. High, but not low or moderate, concentrations of CD19pbCAR T cells significantly inhibited Raji cell-induced tumor growth in vivo. These CD19pbCAR T cells were distributed mostly in mesenteric lymph nodes, bone marrow of the femur, spleen, kidneys, and lungs, specifically accumulating at CD19-rich sites and CD19-positive tumors, with CAR copy number being increased on day 7. These results indicate that pbCAR has its specific activities and functions in pbCAR T cells, making it a valuable tool for CAR T-cell immunotherapy.

Antitumorska aktivnost rutenijum (II) kompleksa na HCT 116 ćelije in vitro

In the field of non-platinum complexes, ruthenium complexes have shown very strong antitumor activity on various types of cisplatin-resistant tumors. In addition, Ru(II) and Ru(III) complexes have shown a high degree of selectivity towards cancer cells as well as antimetastatic effects. Importantly, ruthenium compounds can bind to the DNA molecule of a tumor cell and thus reduce the viability of cancer cells. Moreover, ruthenium complexes can bind to human serum albumin and transferrin, which makes their transfer to tumor cells more efficient than platinum compounds. Consequently, the research aim was to investigate the antitumor effect of two synthesized Ru(II) complexes [Ru(Cl-Ph-tpy)(phen)Cl]Cl (K1) and [Ru(Cl-Ph-tpy)(o-bqdi)Cl]Cl (K2) on the HCT 116 cell line, and to define the mechanism of cell death that these compounds induce in HCT 116 cancer cells. Results of our research clearly showed that the two investigated ruthenium complexes K1 and K2 showed very strong antitumor activity against the HCT 116 tumor cell line. Additionally, ruthenium complex K1 showed higher antitumor activity than ruthenium K2 complex and cisplatin after 72 hours of treatment. Our findings demonstrated that both K1 and K2 ruthenium compounds exhibited strong antitumor activity against HCT 116 cell line by induction of early apoptosis.

A highly-specific fully-human antibody and CAR-T cells targeting CD66e/CEACAM5 are cytotoxic for CD66e-expressing cancer cells in vitro and in vivo.

Neuro-endocrine prostate cancer (NEPC) accounts for about 20% of lethal metastatic castration-resistant prostate cancer (CRPC). NEPC has the most aggressive biologic behavior of all prostate cancers and is associated with poor patient outcome. Effective treatment for NEPC is not available because NEPC exhibit distinct cell-surface expression profiles compared to other types of prostate cancer. Recently, the carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) (known as CEA or CD66e) was suggested to be a specific surface protein marker for NEPC. Therefore, we identified a new, fully-human anti-CEACAM5 monoclonal antibody, 1G9, which bound to the most proximal membrane domains, A3 and B3, of CEACAM5 with high affinity and specificity. It shows no off-target binding to other CEACAM family members, membrane distal domains of CEACAM5, or 5800 human membrane proteins. IgG1 1G9 exhibited CEACAM5-specific ADCC activity toward CEACAM5-positive prostate cancer cells in vitro and in vivo. Chimeric antigen receptor T cells (CAR-T) based on scFv 1G9 induced specific and strong antitumor activity in a mouse model of prostate cancer. Our results suggest that IgG1 and CAR-T cells based on 1G9 are promising candidate therapeutics for CEACAM5-positive NEPC and other cancers.

Ursolic Acid Derivative UA232 Promotes Tumor Cell Apoptosis by Inducing Endoplasmic Reticulum Stress and Lysosomal Dysfunction.

Due to increased drug and radiation tolerance, there is an urgent need to develop novel anticancer agents. In our previous study, we performed a series of structural modifications of ursolic acid (UA), a natural product of pentacyclic triterpenes, and found UA232, a derivative with stronger anti-tumor activity. In vitro experiments showed that UA232 inhibited proliferation, induced G0/G1 arrest, and promoted apoptosis in human breast cancer and cervical cancer cells. Mechanistic studies revealed that UA232 promoted apoptosis and induced protective autophagy via the protein kinase R-like endoplasmic reticulum kinase/activating transcription factor 4/C/EBP homologous protein-mediated endoplasmic reticulum stress. In addition, we also found that UA232 induced lysosomal biogenesis, increased lysosomal membrane permeability, promoted lysosomal protease release, and led to lysosome-dependent cell death. Furthermore, UA232 suppressed tumor growth in a mouse xenograft model. In conclusion, our study revealed that UA232 exerts multiple pharmacological effects against breast and cervical cancers by simultaneously triggering endoplasmic reticulum stress and lysosomal dysfunction. Thus, UA232 may be a promising drug candidate for cancer treatment.

Thermo-responsive palladium-ruthenium nanozyme synergistic photodynamic therapy for metastatic breast cancer management.

Reactive oxygen species (ROS) have become an effective "weapon" for cancer therapy due to their strong oxidation and high anti-tumor activity. Photodynamic therapy (PDT) is one of the classical methods to induce reactive oxygen species. Therefore, an ultraminiature palladium ruthenium alloy (sPdRu) and Ru(II) were combined with thermally responsive phase change materials (PCMs). Polypyridyl-complex (RCE) co-encapsulation was performed to obtain thermally responsive nanoparticles (PdRu-RCE@PCMNPs) for multimodal synergistic anti-breast cancer therapy. On the one hand, the thermosensitive PCM protective layer can realize the slow release of sPdRu, and then catalyze the production of oxygen from tumor endogenous H2O2 to perform RCE-mediated PDT. At the same time, sPdRu further increased ROS levels through peroxidase (POD) activity. On the other hand, sPdRu has high photothermal conversion efficiency and can be effectively used for photothermal therapy and photodynamic therapy. Importantly, PdRu-RCE@PCM NPs not only can effectively inhibit primary tumor growth, but also can inhibit tumor metastasis. In addition, due to the effective accumulation of sPdRu and RCE, PdRu-RCE@PCM NPs also show excellent fluorescence and photothermal imaging capabilities of tumors, which can be used for tumor tracing and evaluation of treatment. Accordingly, PdRu-RCE@PCM NPs are useful in treating primary tumors and inhibiting tumor metastasis.

Galectin-1-Dependent Mitochondria Apoptosis Plays an Essential Role in the Potential Protein Targets of DBDCT-Induced Hepatotoxicity as Revealed by Quantitative Proteomic Analyses.

Di-n-butyl-di-(4-chlorobenzohydroxamato) tin(IV) (DBDCT), a new patent agent, exhibited strong antitumor activity. In some cases, its activity was close to or even higher than cisplatin, a first-line clinical metallic agent. Similar to platinum compounds, it also showed toxicity. However, the effective targets and mechanisms for specific toxicity and biological activity are still unclear. In this study, proteomic analysis revealed that 146 proteins (98 upregulated and 48 downregulated) were differentially identified by label-free LC-MS/MS after DBDCT treatment. Meanwhile, network analysis of these differential proteins suggested that protein Galectin-1 (Gal-1) could regulate the apoptosis process (15 related proteins), which played an essential role in the potential targets of DBDCT-induced hepatotoxicity. Furthermore, it was demonstrated that DBDCT might promote ROS production, activate NF-κB p65, inhibit Ras and p-ERK1/2 expressions, increase the level of Gal-1, subsequently upregulate the expressions of Bax, p53, Fas, and FasL, and downregulate the expression of Bcl-2. As a result of these modulations, caspase cascades were finally activated, which executed apoptosis in HL7702 liver cells. Correspondingly, NAC (inhibitor of ROS), PDTC (inhibitor of NF-κB), EGF (ERK1/2 activator), and OTX008 (inhibitor of Gal-1) were found to reverse and abolish the DBDCT-associated cytotoxicity partially. In conclusion, Gal-1 might be the potential target for toxicity and biological activity. Moreover, the present study will lay the groundwork for future research about di-n-butyl-di-(4-chlorobenzohydroxamato) tin structure optimization and developing it into a new potential anticancer agent.

Multinuclear silver N‐heterocyclic carbene complexes provoke potent anticancer activity via mitochondrial dysfunction and cell necrosis induction

AbstractThree silver N‐heterocyclic carbene (NHC) complexes (Ag1–Ag3) were designed and synthesized using quinoline‐functionalized benzoimidazole salts (L1–L3). Both NHC precursors and resultant silver‐NHC complexes were characterized by NMR, FT‐IR spectroscopy, and elemental analysis. X‐ray diffraction analysis was additionally performed to investigate the crystal structures of these silver‐NHC complexes. The results showed that Ag1 is a dinuclear silver complex with a deviated linear geometry. Ag2 has a disilver core in which two silver atoms are coordinated by two quinoline‐functionalized carbene ligands and one acetonitrile molecule. The silver‐NHC complex Ag3 is composed of a silver‐triangle formed by three silver atoms and three carbene ligands. The in vitro cytotoxic studies revealed that silver‐NHC complexes had stronger antitumor activity than their corresponding NHC precursors. Notably, after a 24‐h exposure to cancer cells, Ag2 presented the highest cytotoxicity with a half maximal inhibitory concentration (IC50) at 1.74 ± 0.08 μM in A2780 cells, which was approximately 14‐fold lower than that of the clinically approved metallodrug cisplatin (IC50 = 24.74 ± 1.35 μM). Detailed mechanistic studies suggested that the complex Ag2 provoked intracellular reactive oxygen species (ROS) overproduction and mitochondrial membrane depolarization, which eventually resulted in mitochondrial dysfunction and cell potent necrosis. Overall, our studies show that NHC‐coordinated silver complexes can be readily constructed and used as an attractive class of anticancer agents, which is conductive for further investigation of their therapeutic potential for treating cisplatin‐resistant cancers.

Inhibition of triple‑negative breast cancer proliferation and motility by reactivating p53 and inhibiting overactivated Akt.

Mutations of p53 tumor suppressors occur more frequently in cancers at advanced stages or in more malignant cancer subtypes such as triple‑negative breast cancer. Thus, restoration of p53 tumor suppressor function constitutes a valuable cancer therapeutic strategy. In the present study, it was revealed that a specific inhibitor of histone deacetylase6, ACY‑1215, caused increased acetylation of p53 in breast cancer cells with mutated p53, which was accompanied by increased expression of p21. These results suggested that ACY‑1215 may lead to enhanced transcriptional activity of p53. It was also determined that ACY‑1215 treatment resulted in G1 cell cycle arrest and apoptosis in these cancer cells. Furthermore, ACY‑1215 displayed a synergistic effect with specific inhibitors of ATM, an activator of Akt, in inducing cancer cell apoptosis and inhibiting their motility. More importantly, it was observed that combination of ACY‑1215 and ATM inhibitors exhibited markedly more potent antitumor activity than the individual compound in xenograft mouse models of breast cancer with mutant p53. Collectively, our results demonstrated that ACY‑1215 is a novel chemotherapeutic agent that could restore mutant p53 function in cancer cells with strong antitumor activity, either alone or in combination with inhibitors of the ATM protein kinase.

Synthesis of ring opening of evodiamine derivatives and evaluation on their biological activity.

As a main bioactive component extracted from Evodiae fructus, evodiamine has a variety of pharmacological activities. In this paper, evodiamine was chosen as starting material to react with different halides. Upon treatment of TFA, a series of novel ring-opening evodiamine derivatives 3a-o were successfully synthesized in a moderate to high yields. These obtained compounds exhibit a moderate to good antitumor activity against BGC803 and SW480 in vitro test by MTT assay. The results showed that hexyl substituted evodiamine derivative (3j, R=hexyl) has a strong antitumor activity against BGC803 and SW480.

Reactive Oxygen Species-Responsive Miktoarm Amphiphile for Triggered Intracellular Release of Anti-Cancer Therapeutics.

Reactive oxygen species (ROS)-responsive nanocarriers have received considerable research attention as putative cancer treatments because their tumor cell targets have high ROS levels. Here, we synthesized a miktoarm amphiphile of dithioketal-linked ditocopheryl polyethylene glycol (DTTP) by introducing ROS-cleavable thioketal groups as linkers between the hydrophilic and hydrophobic moieties. We used the product as a carrier for the controlled release of doxorubicin (DOX). DTTP has a critical micelle concentration (CMC) as low as 1.55 μg/mL (4.18 × 10−4 mM), encapsulation efficiency as high as 43.6 ± 0.23% and 14.6 nm particle size. The DTTP micelles were very responsive to ROS and released their DOX loads in a controlled manner. The tocopheryl derivates linked to DTTP generated ROS and added to the intracellular ROS in MCF-7 cancer cells but not in HEK-293 normal cells. In vitro cytotoxicity assays demonstrated that DOX-encapsulated DTTP micelles displayed strong antitumor activity but only slightly increased apoptosis in normal cells. This ROS-triggered, self-accelerating drug release device has high therapeutic efficacy and could be a practical new strategy for the clinical application of ROS-responsive drug delivery systems.

Validity of Anti-PSMA ScFvD2B as a Theranostic Tool: A Narrative-Focused Review

Prostate cancer (PCa) is the second leading cause of cancer among men, and its diagnosis and adequate staging are fundamental. Among the biomarkers identified in recent years for PCa management, prostate-specific-membrane-antigen (PSMA), physiologically expressed at a low level on healthy prostate and in other normal tissues and highly overexpressed in PCa, represents a reliable marker ideal for imaging and therapy. The development of anti-PSMA antibodies, such as D2B, demonstrated slow clearance of intact antibodies compared with fragments resulting in low tumor-to-blood ratios; however, the modular structural and functional nature of antibodies allowed the generation of smaller fragments, such as scFvs. In this review of the anti-PSMA antibody fragment scFvD2B, we combined further characterization of its biomolecular and tissue cross-reactivity characteristics with a comprehensive summary of what has already been performed in preclinical models to evaluate imaging and therapeutic activities. A molecular dynamics study was performed, and ScFvD2B occupied a limited conformational space, characterized by low-energy conformational basins, confirming the high stability of the protein structure. In the cross-reactivity study, the weak/absent immunoreactivity in non-tumor tissues was comparable to the PSMA expression reported in the literature. Biodistribution studies and therapeutic treatments were conducted in different animal models obtained by subcutaneous or locoregional injection of PSMA-positive-versus-negative xenografts. The maximum tumor uptake was observed for 123I(SPECT), 124I(PET), and optical imaging, which avoids kidney accumulation (compared with radiometals) and leads to an optimal tumor-to-kidney and tumor-to-background ratios. Regarding its possible use in therapy, experimental data suggested a strong and specific antitumor activity, in vitro and in vivo, obtained using CAR-T or NK-92/CAR cells expressing scFvD2B. Based on presented/reviewed data, we consider that scFvD2B, due to its versatility and robustness, seems to: (i) overcome some problems observed in other studied scFvs, very often relatively unstable and prone to form aggregates; (ii) have sufficient tumor-to-background ratios for targeting and imaging PSMA-expressing cancer; (iii) significantly redirect immune killing cells to PSMA-positive tumors when inserted in second-generation CAR-T or NK-92/CAR cells. These data suggest that our product can be considered the right reagent to fill the gap that still exists in PCa diagnosis and treatment.

Chimeric antigen receptor T cells targeting CD147 for non-small cell lung cancer therapy

Non-small cell lung cancer (NSCLC) is a highly malignant tumor, with a significant mortality and morbidity. With the development of tumor immunotherapy, chimeric antigen receptor T cells (CART) gets increasingly attention and achieves prominent contributions in the treatment of hematologic malignancies. However, CART therapy for NSCLC proceeds slowly and further researches need to be investigated. In our study, we performed bioinformatics analysis to evaluate the significant role of CD147 in NSCLC. The expression level of CD147 was detected in human NSCLC cell lines and NSCLC tissues. Meanwhile, CD147-CART was constructed and identified. Cell cytotoxicity and cytokine secretion were performed to evaluate the efficacy of CD147-CART. We also constructed cell-derived xenograft (CDX) model and patient-derived xenograft (PDX) model, which was used to further investigate the safety and efficacy of CD147-CART in vivo. Our observations show that CD147 is a specific tumor antigen of NSCLC and plays an essential role in NSCLC progression, which can be used as a target for CART therapy in NSCLC. CD147-CART cells exhibit robust cytotoxicity and cytokine production in vitro, suggesting a strong anti-tumor activity against NSCLC tumor cells. Importantly, CD147-CART cells have strong anti-tumor activity against NSCLC cells in vivo in both CDX and PDX models and no adverse side effects. Our findings show that CD147-CART immunotherapy for NSCLC is safe and effective, which is an ideal and promising medical patch for treating NSCLC.

A Squalene-Based Nanoemulsion for Therapeutic Delivery of Resiquimod.

Agonists for toll-like receptors (TLRs) have shown promising activities against cancer. In the present study, a squalene-based nanoemulsion (NE) was loaded with resiquimod, a TLR7/8 agonist for therapeutic delivery. R848 NE was developed and characterized for long-term stability. In vitro and in vivo antitumor immunity of R848 NE were also evaluated in combination with SD-101, a CpG-containing TLR9 agonist. In vitro studies demonstrated strong long-term stability and immune responses to R848 NE. When combined with SD-101, strong antitumor activity was observed in MC38 murine colon carcinoma model with over 80% tumor growth inhibition. The combination treatment showed a 4-fold increase in systemic TNFa production and a 2.6-fold increase in Cd8a expression in tumor tissues, suggesting strong cell-mediated immune responses against the tumor. The treatment not only demonstrated a strong antitumor immunity by TLR7/8 and TLR9 activations but also induced PD-L1 upregulation in tumors, suggesting a potential therapeutic synergy with immune checkpoint inhibitors.

Abstract P001: The anti-angiogenic antibody BD0801 demonstrates better anti-tumor activity than bevacizumab and synergize with chemotherapies in multiple tumor models

Abstract Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play a fundamental role in tumor growth and angiogenesis. An increasing number of evidences have suggested enhanced anti-tumor activity when combining anti-angiogenic agents with chemotherapies in the clinic. To support the clinical development of BD0801, a humanized rabbit anti-VEGF monoclonal antibody, we assessed anti-tumor activities of BD0801 using a series of preclinical tumor mouse models including human ovarian cancer OVCAR-8 and SK-OV-3, human non-small cell lung cancer (NSCLC) NCI-H460, and human renal cancer Caki-1 models, with bevacizumab being used as a benchmark. We also investigated the pharmacological kinetics (PK) of BD0801 in cynomolgus monkeys. BD0801 or bevacizumab were intravenously injected into tumor bearing mice at 0.8 mg/kg, 2.5 mg/kg or 7.5 mg/kg twice a week. Combinations of chemotherapy and BD0801 or bevacizumab were also investigated in some of the tumor models. BD0801 presented more potent anti-tumor activities than bevacizumab in ovarian cancer, NSCLC and renal cancer mouse models in a dose-dependent manner. The tumor growth inhibition of BD0801 was 2-20%, 34-66%, or 32-84% when dosed at 0.8 mg/kg, 2.5 mg/kg or 7.5 mg/kg, respectively. Besides, combination of 2.5 mg/kg BD0801 and 10 mg/kg paclitaxel presented a statistically stronger antitumor activity in human ovarian cancer models compared to both single treatments (P<0.05). Combination of 2.5 mg/kg BD0801, 10 mg/kg paclitaxel, and 80 mg/kg carboplatin also presented a stronger antitumor activity than BD0801 or chemotherapy alone in the human NSCLC model. In cynomolgus monkeys received a single intravenous injection of BD0801 at 1.5, 5, and 15 mg/kg, the half-life (t1/2) of BD0801 was 39.4-142 h, the clearance (Cl) was 0.321-0.900 mL/h/kg, and the apparent volume of distribution (Vd) was 49.5-64.4 mL/kg. The peak concentrations (Cmax) of BD0801 were proportional to the doses administered. No difference on the PK parameters was observed between female and male monkeys. Taken together, this study has demonstrated BD0801 as a more potent molecule than bevacizumab in some preclinical tumor models, supporting further clinical development plans for BD0801, especially in combination with chemotherapeutics. Citation Format: Liting Xue, Jianxing Tang, Yuyin Ding, Lei Song, Shansen Xu, Yue Huang, Yan Wu, Wenjie Song, Renhong Tang, Wenqing Yang. The anti-angiogenic antibody BD0801 demonstrates better anti-tumor activity than bevacizumab and synergize with chemotherapies in multiple tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P001.