Treatment Of Solid Tumors Research Articles

Clinical research progress of callisperes® of drug-loaded microsphere arterial chemoembolisation in the treatment of solid tumors.

The incidence and mortality of cancer is ever-increasing, which poses a significant challengesto human health and a substantial economic burden to patients. At present, chemotherapy is still a primary treatment for various cancers. However, chemotherapy kills tumors but also induces the related side effects, whichadversely impacting patient quality of life and exacerbating suffering. Therefore, there is an urgent need for new and effective treatments that can control tumor growth while reducing the side effects for patients. Arterial chemoembolization has been attracted much attentionwhich attributed to the advantage of ability to embolize tumor vessels to block blood and nutrition supplies. Thus, to achieve local tumor control, it has become an effective means of local tumor control and has been widely used in clinical practice. Despite its efficacy, conventional arterial chemoembolization techniques, limited by embolization materials, have been associated with incomplete embolization and suboptimal drug delivery outcomes. Gradually, researchers have shifted their attention to a new type of embolic material called CalliSperes® drug-eluting embolic bead (DEB). DEB can not only load high doses of drugs, but also has strong sustained drug release ability and good biocompatibility. The integration of DEBs with traditional arterial chemoembolization (DEB-TACE) promises targeted vascular embolization, mitigated tumor ischemia and hypoxia, and direct intravascular chemotherapy delivery. It can prevent cancer cell differentiation and accelerate their death, meanwhile, directly injecting chemotherapy drugs into the target blood vessels reduced the blood concentration of the whole body, thus reduced the toxic and side effects of chemotherapy. Furthermore, DEB-TACE's sustained drug release capability elevates local drug concentrations at the tumor site, amplifying its antitumor efficacy. Therefore, DEB-TACE has become a hot spot in clinical research worldwide. This review introduces the pathogenesis of solid tumors, the background of research and biological characteristics of DEB, and the action mechanism of DEB-TACE, as well as its clinical research in various solid tumors and future prospects. This review aims to provide new ideas for the treatment of DEB-TACE in various solid tumors.

Hypoxia makes EZH2 inhibitor not easy—advances of crosstalk between HIF and EZH2

Hypoxia makes EZH2 inhibitor not easy—advances of crosstalk between HIF and EZH2

Sustained Secretion of CCL21 via an Implantable Cell Reservoir Hydrogel Enhances the Systemic Antitumor Effect of Radiotherapy.

The combination of radiotherapy (RT) and immunotherapy shows promise in improving the clinical treatment of solid tumors; however, it faces challenges of low response rates and systemic toxicity. Herein, an implantable alginate/collagen hydrogel encapsulating C-C motif ligand 21 (CCL21)-expressing dendritic cells (CCL21-DCs@gel) was developed to potentiate the systemic antitumor effects of RT. The hydrogel functioned as a suitable reservoir for in vivo culture and proliferation of CCL21-DCs, thereby enabling sustained CCL21 release. The local CCL21 gradient induced by CCL21-DCs@gel significantly enhanced the efficacy of RT in suppressing primary tumor growth and inhibiting distant metastasis across several mouse models. Furthermore, the combination of RT with CCL21-DCs@gel provided complete prophylactic protection to mice. Mechanistic investigations revealed that CCL21-DCs@gel potentiated RT by promoting tumor lymphangiogenesis and attracting immune cell infiltration into the tumor. Collectively, these results suggest that CCL21-DCs@gel is a promising adjunct to RT for effectively eradicating tumors and preventing tumor recurrence.

Antibody-drug conjugates in solid tumors; new strategy for cancer therapy.

Antibody-drug conjugates (ADCs) have emerged as a novel class of anticancer treatment. ADCs are composed of three parts: a monoclonal antibody, a linker and a payload. A monoclonal antibody binds to the specific antigen present at the cancer cells, allowing selective delivery of the cytotoxic agents to the tumor site. Several ADCs are approved by the US Food and Drug Administration for the treatment of hematologic cancers and solid tumors with clinically meaningful survival benefit. However, the development of ADCs faces a lot of challenges and there is a need to get better understanding of ADCs in order to improve patient outcomes. Here, we briefly discuss the structure and mechanism of ADCs, as well as the clinical data of current approved ADCs in solid tumors.

Global research trends in CAR-T cell therapy for solid tumors: A comprehensive visualization and bibliometric study (2012–2023)

ABSTRACT CAR-T cell therapy has emerged as a significant approach for the management of hematological malignancies. Over the past few years, the utilization of CAR-T cells in the investigation and treatment of solid tumors has gained momentum, thereby establishing itself as a prominent area of research. This descriptive study involved the retrieval of articles about CAR-T cell therapy for solid tumors from the Web of Science Core Collection (WoSCC) database. Subsequently, bibliometric analysis and knowledge map analysis were conducted on these articles. The field under consideration is currently experiencing a period of swift advancement, as evidenced by the escalating number of publications in this domain each year. The United States holds an indisputable position as the foremost leader in this particular field, with the University of Pennsylvania emerging as the most active institution. The authors with the highest citation frequency and co-citation frequency are Carl H. June and Shannon L. Maude, respectively. The research hotspots in this field mainly focus on five aspects. Additionally, 10 emerging themes were identified. This study undertakes a comprehensive, systematic, and objective analysis and exploration of the field of CAR-T cell treatment for solid tumors, utilizing bibliometric methods. The findings of this study are expected to serve as a valuable reference and enlightenment for future research endeavors in this particular domain.

KRAS G12C inhibitor combination therapies: current evidence and challenge

Although KRAS G12C inhibitors have proven that KRAS is a “druggable” target of cancer, KRAS G12C inhibitor monotherapies have demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer. Many clinical trials of combinations of KRAS G12C inhibitors with other targeted therapies, such as SOS1, ERK, CDK4/6, and wild-type RAS, are ongoing. Furthermore, preclinical data have suggested additional promising KRAS G12C combinations with YAP/TAZ-TEAD inhibitors, FAK inhibitors, and farnesyltransferase inhibitors. The combinations of KRAS G12C inhibitors with immunotherapies and chemotherapies have also been investigated, and the preliminary results were reported. More recently, KRAS-targeted therapies not limited to KRAS G12C are being developed, potentially broadening the treatment landscape of KRAS-mutated cancers. Rationally combining KRAS inhibitors with other therapeutics is likely to play a significant role in future treatment for KRAS-mutated solid tumors.

Abstract PO2-03-05: Neoadjuvant anthracycline followed by Toripalimab combined with nab-paclitaxel in patients with stage IIA-IIIC triple negative breast cancer (NeoTENNIS): efficacy and safety results of a phase II study

Abstract Background: Immune checkpoint inhibitors(ICIs)have shown promising antitumor activity in triple negative breast cancer (TNBC) patients. Toripalimab, a novel PD-1 antibody, has been approved for the treatment in multiple solid tumors. However, the neoadjuvant use of toripalimab with chemotherapy has not been evaluated in TNBC patients. In addition, whether chemotherapy could sensitize the ICI treatment has not drawn conclusion yet. In this phase II trial, a sequential use of chemotherapy and anti-PD1 therapy was given in a neoadjuvant setting. The efficacy and safety of toripalimab were evaluated. Patients and methods: Female patients with histologically confirmed stage IIA to IIIC TNBC were included. Eligible patients received neoadjuvant therapy with four cycles of epirubicin-cyclophosphamide every 2 weeks followed by toripalimab (240 mg) every 3 weeks plus nab-paclitaxel weekly for 12 weeks. The primary endpoint was pathologic complete response (tpCR; ypT0/is ypN0) rate. Key secondary endpoints were breast pCR (bpCR; ypT0/is) rate, biomarker analysis, and safety. Results: Among 70 enrolled patients (median age, 51 years; 62.9% stage III), 66 patients completed study treatment without progression and received surgery after study treatment. Overall, the percentages of patients with a tpCR and bpCR were 55.7% (39 of 70 patients) and 58.6 % (41 of 70 patients), respectively. For women with CD8–positive and negative tumors, the tpCR rates were 66.0% and 30.0% (P = 0.006), respectively. Significant upregulation of CD8 positive cells after 4 cycles of epirubicin-cyclophosphamide induction chemotherapy (P = 0.011) were shown in sequential biopsy samples. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 30 patients (42.9%), the most common of which were neutropenia (15.7%), leukopenia (14.3%) and alanine aminotransferase increase (4.3%). Most common immune-related AEs were hepatobiliary disorders (Grade 3, 7.2%), creatinine increase (all Grade 1-2, 2.8%) and hypothyroidism (all Grade 1-2, 2.8%). Conclusions: The addition of toripalimab to neoadjuvant chemotherapy is efficacious and safe in patients with locally advanced TNBC. Anthracycline-based chemotherapy could sensitize the ICI treatment with upregulated tumor immune response. The event-free survival results are expected with further follow up. Mechanisms of chemotherapy sensitization are still under investigation (ClinicalTrials.gov number: NCT04418154). Citation Format: Min He, Linxiaoxi Ma, Shuang Hao, Benlong Yang, Bingqiu Xiu, Ya-Yun Chi, Ruo-Hong Shui, Zhong-Hua Wang, Zhi-Ming Shao, Jiong Wu. Neoadjuvant anthracycline followed by Toripalimab combined with nab-paclitaxel in patients with stage IIA-IIIC triple negative breast cancer (NeoTENNIS): efficacy and safety results of a phase II study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-03-05.

Abstract PO4-16-05: Identification of functional HLA-A*11:01-restricted driver gene PIK3CA mutation specific T-cell receptors

Abstract The adoptive transfer of genetically engineered T-cell receptors (TCR-T) has emerged as a promising therapeutic strategy for the treatment of solid tumors. Recent clinical trials have demonstrated the safety and efficacy of TCR-T cell therapies against certain types of metastatic solid cancers. In our study, we aimed to investigate the potential of TCR-T cell therapies targeting neoantigens, which are exclusively expressed in cancer cells, with a focus on metastatic breast cancer (MBC). Specifically, we identified four driver missense mutations (PIK3CA E542K, E545K, H1047L, and H1047R) frequently observed in MBC patients and utilized computational tools to predict the generation of neoantigens. Utilizing NetMHCpan V.4.1, we performed screening of peptides spanning the mutation region and predicted a neoantigen epitope, PIK3CA_H1047L, to bind with HLA-A*11:01. To validate the presentation and stability of the neoantigen epitope, we employed TAP1-deficient K562 cells and observed stable expression of the mutant peptide-major histocompatibility complex (MHC) complex on the cell membrane. Subsequently, we isolated T cells from healthy donors possessing the HLA-A11:01 genotype, and subjected them to successive stimulations with neopeptide-pulsed dendritic cells. T cells stimulated with neopeptide were examined for neoantigen specificity using an IFN-γ ELISpot assay. Employing pMHC tetramer staining and single-cell sorting via flow cytometry, we successfully isolated five HLA-A11:01-restricted PIK3CA_H1047L-specific TCRs. Through lentivirus transduction of these TCRs into T cells, we achieved the generation of TCR-T cells that exhibited potent and specific activity exclusively against the PIK3CA_H1047L neoantigen. The functionality of the TCR-T cells was confirmed through assessments of CD137 expression, IFN-γ secretion, and cytotoxicity assays. In conclusion, our study demonstrates T cell responses towards neoantigens derived from PIK3CA, a commonly observed driver mutation in MBC. Furthermore, we successfully isolated five distinct neoantigen-specific TCRs that specifically recognized the PIK3CA_H1047L mutation and were restricted to the prevalent HLA-A*11:01 allele. The transfer of these TCRs into T cells resulted in the generation of TCR-T products exhibiting remarkable activity against the PIK3CA_H1047L neoantigen. These findings strongly encourage further investigation into TCRs targeting driver mutations in MBC, with the aim of advancing neoantigen-targeted TCR-T therapies into clinical trials. Additionally, the PIK3CA_H1047L neoantigen holds great promise as a potential candidate for the development of effective cancer vaccines. Citation Format: Meiying Shen, Xiaojian Han, Siyin Chen, Aishun Jin, Shengchun Liu. Identification of functional HLA-A*11:01-restricted driver gene PIK3CA mutation specific T-cell receptors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-16-05.

Acidity-targeting transition-aided universal chimeric antigen receptor T-cell (ATT-CAR-T) therapy for the treatment of solid tumors

The use of CAR-T cells in treating solid tumors frequently faces significant challenges, mainly due to the heterogeneity of tumor antigens. This study assessed the efficacy of an acidity-targeting transition-aided universal chimeric antigen receptor T (ATT-CAR-T) cell strategy, which is facilitated by an acidity-targeted transition. Specifically, the EGFRvIII peptide was attached to the N-terminus of a pH-low insertion peptide. Triggered by the acidic conditions of the tumor microenvironment, this peptide alters its structure and selectively integrates into the membrane of solid tumor cells. The acidity-targeted transition component effectively relocated the EGFRvIII peptide across various tumor cell membranes; thus, allowing the direct destruction of these cells by EGFRvIII-specific CAR-T cells. This method was efficient even when endogenous antigens were absent. In vivo tests showed marked antigen modification within the acidic tumor microenvironment using this component. Integrating this component with CAR-T cell therapy showed high effectiveness in combating solid tumors. These results highlight the capability of ATT-CAR-T cell therapy to address the challenges presented by tumor heterogeneity and expand the utility of CAR-T cell therapy in the treatment of solid tumors.

Biomaterial-based scaffolds for direct in situ programming of tumor-infiltrating T lymphocytes

Adoptive cell therapy with tumor-infiltrating T cells (TILs) has generated exciting clinical trial results for the treatment of unresectable solid tumors. However, solid tumors remain difficult targets for adoptively transferred T cells, due in part to poor migration of TILs to the tumor, physical barriers to infiltration, and active suppression of TILs by the tumor. Furthermore, a highly skilled team is required to obtain tumor tissue, isolate and expand the TILs ex vivo, and reinfuse them into the patient, which drives up costs and limits patient access. Here, we describe a cell-free polymer implant designed to recruit, genetically reprogram and expand host T cells at tumor lesions in situ. Importantly, the scaffold can be fabricated on a large scale and is stable to lyophilization. Using a mouse breast cancer model, we show that the implants quickly and efficiently amass cancer-specific host lymphocytes at the tumor site in quantities sufficient to bring about long-term tumor regression. Given that surgical care is the mainstay of cancer treatment for many patients, this technology could be easily implemented in a clinical setting as an add-on to surgery for solid tumors. Furthermore, the approach could be broadened to recruit and genetically reprogram other therapeutically desirable host cells, such as macrophages, natural killer cells or dendritic cells, potentially boosting the antitumor effectiveness of the implant even more.

Brief Report: Updated Data From IMscin001 Part 2, a Randomized Phase III Study of Subcutaneous Versus Intravenous Atezolizumab in Patients With Locally Advanced/Metastatic NSCLC

IntroductionSubcutaneous atezolizumab is approved for the treatment of various solid tumors. Previous results from the IMscin001 study (NCT03735121) demonstrated that the pharmacokinetics, efficacy, immunogenicity, and safety of subcutaneous and intravenous atezolizumab were consistent (data cutoff: April 26, 2022). We present updated data from this trial (data cut-off: 16 January 2023). MethodsEligible patients aged ≥18 years with locally advanced/metastatic NSCLC were randomized (2:1) to receive atezolizumab subcutaneously (1875 mg, n=247) or intravenously (1200 mg, n=124) every 3 weeks. Here we present updated efficacy (overall survival [OS]; progression-free survival; objective response rate; duration of response), safety, and immunogenicity endpoints, alongside patient-reported outcomes (PROs) and healthcare practitioner (HCP) perspectives. ResultsIn this updated analysis, the median survival follow-up was 9.5 months. Median subcutaneous injection time was 7.1 minutes, with an average subcutaneous injection time of 4–8 minutes in most patients (75.7%). OS data were mature: median OS was similar between treatment arms, at 10.7 and 10.1 months in the subcutaneous and intravenous arms, respectively (HR: 0.88; 95% CI: 0.67–1.16). Other efficacy endpoints, as well as immunogenicity, PROs, and safety, were similar between arms. Most HCPs found subcutaneous administration convenient (79.5%), easy to administer (89.7%), and were satisfied with the treatment (84.6%); 75.0% of HCPs agreed that administering atezolizumab subcutaneously compared with intravenously could save time. ConclusionsIn this analysis, mature OS data were similar between treatments. The updated efficacy and safety profile of subcutaneous atezolizumab is consistent with previous findings and equivalent to intravenous atezolizumab.

Pharmacokinetics and safety of LEAD-452, an EGFR-specific 4-1BB-agonistic trimerbody in non-human primates

LEAD-452 is a humanized bispecific EGFR-targeted 4-1BB-agonistic trimerbody with a unique trimeric configuration compared to other 4-1BB-specific antibodies that are currently in development. Indeed, enhanced tumor-specific costimulation and very remarkable safety and efficacy profiles have been observed in mouse models. Here, we conducted for the first time a preclinical pharmacokinetic and toxicity study in non-human primates (NHP) (Macaca fascicularis). LEAD-452 exhibits comparable binding affinity for human and macaque targets, indicating its pharmacological significance for safety testing across species. The NHP were administered LEAD-452 in a series of ascending doses, ranging from 0.1 mg/kg to 10 mg/kg, and repeated doses up to 20 mg/kg. The administration of LEAD-452 was found to be clinically well tolerated, with no major related adverse effects observed. Furthermore, there have been no reported cases of liver toxicity, thrombocytopenia, and neutropenia, which are commonly associated with treatments using conventional anti-4-1BB IgG-based antibodies. In addition, neither IgM nor IgG-based anti-drug antibodies were detected in serum samples from NHP during the study, regardless of the dose of LEAD-452 administered. These results support the clinical development of LEAD-452 for the treatment of solid tumors.

Outer Membrane Vesicle-Wrapped Manganese Nanoreactor for Augmenting Cancer Metalloimmunotherapy through Hypoxia Attenuation and Immune Stimulation

Tumor hypoxia, high oxidative stress, and low immunogenic create a deep-rooted immunosuppressive microenvironment, posing a major challenge to the therapeutic efficiency of cancer immunotherapy for solid tumor. Herein, an intelligent nanoplatform responsive to the tumor microenvironment (TME) capable of hypoxia relief and immune stimulation has been engineered for efficient solid tumor immunotherapy. The MnO2@OxA@OMV nanoreactor, enclosing bacterial-derived outer membrane vesicles (OMVs)-wrapped MnO2 nanoenzyme and the immunogenic cell death inducer oxaliplatin (OxA), demonstrated intrinsic catalase-like activity within the TME, which effectively catalyzed the endogenous H2O2 into O2 to enable a prolonged oxygen supply, thereby alleviating the tumor's oxidative stress and hypoxic TME, and expediting OxA release. The combinational action of OxA-caused ICD effect and Mn2+ from nanoreactor enabled the motivation of the cGAS-STING pathway to significantly improve the activation of STING and dendritic cells (DCs) maturation, resulting in metalloimmunotherapy. Furthermore, the immunostimulant OMVs played a crucial role in promoting the infiltration of activated CD8+ T cells into the solid tumor. Overall, the nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy. Statement of SignificanceA tailor-made nanoreactor was fabricated by enclosing bacterial-derived outer membrane vesicles (OMVs) onto MnO2 nanoenzyme and loading with immunogenic cell death inducer oxaliplatin (OxA) for tumor metalloimmunotherapy. The nanoreactor possesses intrinsic catalase-like activity within the tumor microenvironment, which effectively enabled a prolonged oxygen supply by catalyzing the conversion of endogenous H2O2 into O2, thereby alleviating tumor hypoxia and expediting OxA release. Furthermore, the TME-responsive release of nutritional Mn2+ sensitized the cGAS-STING pathway and collaborated with OxA-induced immunogenic cell death (ICD). Combing with immunostimulatory OMVs enhances the uptake of nanoreactors by DCs and promotes the infiltration of activated CD8+ T cells. This nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy.

A Sensitive Assay for Unbound Docetaxel Using Ultrafiltration plus HPLC-MS and Its Application to a Clinical Study

Introduction: Docetaxel, a taxane used in the treatment of solid tumours, exerts pharmacological activity when in its unbound form. We report a sensitive assay to quantify unbound docetaxel after oral administration of docetaxel plus encequidar (oDox+E). Unbound drug quantification is important due to its direct correlation with drug-related toxicity and therapeutic efficacy. We improve on the sensitivity of current assay methods and demonstrate the utility of the assay on a novel formulation of oral docetaxel. Methods: Ultrafiltration followed by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) was utilized. Long-term stability, precision, accuracy, and recovery experiments were conducted to validate the assay. Additionally, patient samples from a Phase I dose-escalation pharmacokinetic study were analyzed using the developed assay. Results: The assay method exhibited long-term stability with an observed change between 0.8 and 6.9% after 131 days of storage at −60 °C. Precision and accuracy quality controls met the FDA acceptance criteria. An average recovery of 88% was obtained. Patient sample analysis demonstrated successful implementation of the assay. Conclusion: A validated sensitive assay was developed with an LLOQ of 0.084 ng/mL using 485 µL of human plasma. The sensitivity of the assay allowed quantification of unbound docetaxel concentrations in an early-phase oDox+E clinical study to compare it against IV docetaxel using pharmacokinetic modelling. Successful development of oDox+E represents an opportunity to replace the current IV docetaxel regimen with an oral regimen with lower cost, decreased side effects, and improve patient quality of life and experience.

Bromodomain inhibition targeting BPTF in the treatment of melanoma and other solid tumors.

Epigenetic mechanisms have been shown to play an important role in the development of cancer. These include the activation of chromatin remodeling factors in various malignancies, including bromodomain plant homeodomain (PHD) finger transcription factor (BPTF), the largest component of the human nucleosome remodeling factor (NURF). In the last few years, BPTF has been identified as a pro-tumorigenic factor in melanoma, stimulated by research into the molecular mechanisms underlying BPTF function. Developing therapy targeting the BPTF bromodomain would represent a significant advance. Melanoma therapy has been revolutionized by the efficacy of immunotherapeutic and targeted strategies, but the development of drug resistance calls for alternative therapeutic approaches. Recent work has shown both a biomarker as well as functional role for BPTF in melanoma progression and as a possible target for its therapy. BPTF was shown to stimulate the mitogen-activated protein kinase pathway, which is targeted by selective BRAF inhibitors. The advent of small molecule inhibitors that target bromodomain motifs has shown that bromodomains are druggable. By combining the bromodomain inhibitor bromosporine with existing treatments that target mutant BRAF, BPTF targeting has emerged as a novel and promising therapeutic approach for metastatic melanoma. This article summarizes the functional role of BPTF in tumor progression, reviews the clinical experience to date with bromodomain inhibitors, and discusses the promise of BPTF targeting in melanoma and other solid tumors.

CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition

Chimeric antigen receptor (CAR)-T cell therapy for solid tumors faces significant hurdles, including T-cell inhibition mediated by the PD-1/PD-L1 axis. The effects of disrupting this pathway on T-cells are being actively explored and controversial outcomes have been reported. Here, we hypothesize that CAR-antigen affinity may be a key factor modulating T-cell susceptibility towards the PD-1/PD-L1 axis. We systematically interrogate CAR-T cells targeting HER2 with either low (LA) or high affinity (HA) in various preclinical models. Our results reveal an increased sensitivity of LA CAR-T cells to PD-L1-mediated inhibition when compared to their HA counterparts by using in vitro models of tumor cell lines and supported lipid bilayers modified to display varying PD-L1 densities. CRISPR/Cas9-mediated knockout (KO) of PD-1 enhances LA CAR-T cell cytokine secretion and polyfunctionality in vitro and antitumor effect in vivo and results in the downregulation of gene signatures related to T-cell exhaustion. By contrast, HA CAR-T cell features remain unaffected following PD-1 KO. This behavior holds true for CD28 and ICOS but not 4-1BB co-stimulated CAR-T cells, which are less sensitive to PD-L1 inhibition albeit targeting the antigen with LA. Our findings may inform CAR-T therapies involving disruption of PD-1/PD-L1 pathway tailored in particular for effective treatment of solid tumors.

A Multivalent DNA Nanoparticle/Peptide Hybrid Molecular Modality for the Modulation of Protein–Protein Interactions in the Tumor Microenvironment

Despite success in the treatment of some blood cancers and melanoma, positive response to immunotherapies remains disappointingly low in the treatment of solid tumors. The context of the molecular crosstalk within the tumor microenvironment can result in dysfunctional immune cell activation, leading to tumor tolerance and progression. Although modulating these protein–protein interactions (PPIs) is vital for appropriate immune cell activation and recognition, targeting nonenzymatic PPIs has proven to be fraught with challenges. To address this, a synthetic, multivalent molecular modality comprised of small interfering peptides precisely hybridized to a semirigid DNA scaffold is introduced. Herein, a prototype of this modality that targets the IL‐33/ST2 signaling axis, which is associated with tumor tolerance and immunotherapy treatment failure is described. Using peptides that mimic the specific high‐energy “hotspot” residues with which the IL‐33/ST2 coreceptor, IL‐1RAcP, interacts with the initial binary complex, this platform is shown to effectively bind IL‐33/ST2 with a KD of 110 nm. Additionally, this molecule effectively abrogates signal transduction in cell models at high nanomolar concentrations and is exquisitely selective for this complex over structurally similar PPIs within the same cytokine superfamily.

Inhibition of human UDP-glucuronosyltransferase enzyme by entrectinib: Implications for drug-drug interactions

As a new type of oral tyrosine kinase inhibitor, entrectinib can act on multiple targets and exert efficacy and has been approved for the treatment of non-small cell lung cancer (NSCLC) and solid tumors. However, whether entrectinib affects the activities of recombinant human UDP-glucuronosyltransferases (UGTs) remains unclear. Herein, we aimed to investigate the inhibitory effects of entrectinib on human UGTs and to assess the potential risk of causing drug-drug interactions (DDIs) based on the inhibition against UGTs. High-performance liquid chromatography (HPLC) was used to evaluate the inhibitory effects of entrectinib on UGTs according to the product formation rate of UGT substrate with or without entrectinib, and the inhibition kinetics experiment was conducted to assess the inhibitory type of entrectinib on UGTs. Our results showed that entrectinib exhibited extensive inhibitory effects on most human UGTs, and especially inhibited the activities of UGT1A7, UGT1A8, and UGT2B15 with Ki (Inhibition constant) of lower than 5 μM (0.95–4.38 μM). Furthermore, the results from quantitative prediction research suggested that the combination of entrectinib at 600 mg/day with substrates primarily metabolized by hepatic UGT2B15 or intestinal UGT1A7 and UGT1A8 might cause clinical DDIs. Thus, special attention should be paid to avoid adverse reactions induced by DDIs when co-administration of entrectinib and drugs metabolized by UGTs.

Polymer Backpack-Loaded Tissue Infiltrating Monocytes for Treating Cancer.

Adoptive cell therapies are dramatically altering the treatment landscape of cancer. However, treatment of solid tumors remains a major unmet need, in part due to limited adoptive cell infiltration into the tumor and in part due to the immunosuppressive tumor microenvironment. The heterogeneity of tumors and presence of nonresponders also call for development of antigen-independent therapeutic approaches. Myeloid cells offer such an opportunity, given their large presence in the immunosuppressive tumor microenvironment, such as in triple negative breast cancer. However, their therapeutic utility is hindered by their phenotypic plasticity. Here, the impressive trafficking ability of adoptively transferred monocytes is leveraged into the immunosuppressive 4T1 tumor to develop an antitumor therapy. To control monocyte differentiation in the tumor microenvironment, surface-adherent "backpacks" stably modified with interferon gamma (IFNγ) are developed to stimulate macrophage plasticity into a pro-inflammatory, antitumor phenotype, a strategy as referred to as Ornate Polymer backpacks on Tissue Infiltrating Monocytes (OPTIMs). Treatment with OPTIMs substantially reduces tumor burden in a mouse 4T1 model and significantly increases survival. Cytokine and immune cell profiling reveal that OPTIMs remodeled the tumor microenvironment into a pro-inflammatory state.

FLT3 agonists and secondary hematopoietic malignancies: a potential class effect.

Expansion of cDC cells via FLT3 agonism has promising therapeutic potential in the treatment of advanced solid tumors. Here, we discuss the results of a clinical trial using GS-3583, an FLT3 agonist, that was stopped after a patient in the study developed acute myeloid leukemia.