Adoptive cellular therapy is rapidly improving immunotherapy in hematologic malignancies and several solid tumors.Remarkable clinical success has been achieved in chimeric antigen receptor(CAR)-T cell therapy which re...Adoptive cellular therapy is rapidly improving immunotherapy in hematologic malignancies and several solid tumors.Remarkable clinical success has been achieved in chimeric antigen receptor(CAR)-T cell therapy which represents a paradigm-shifting strategy for the treatment of hematological malignancies.However,many challenges such as resistance,antigen heterogeneity,poor immune cell infiltration,immunosuppressive microenvironment,metabolic obstructive microenvironment,and T cell exhaustion remain as barriers to broader application especially in solid tumors.Encouragingly,the development of new approaches such as multidimensional omics and biomaterials technologies was aided to overcome these barriers.Here,in this perspective,we focus on the most recent clinical advancements,challenges,and strategies of immune cellular therapy in solid tumor treatment represented by CAR-T cell therapy,to provide new ideas to further overcome the bottleneck of immune cell therapy and anticipate future clinical advances.展开更多
We reported a biopsy proved case of minimal change nephrotic syndrome in a 72-year-old patient. The minimal change nephrotic syndrome has been steroid sensitive, but the patient had 7 relapses over a span of 5 years. ...We reported a biopsy proved case of minimal change nephrotic syndrome in a 72-year-old patient. The minimal change nephrotic syndrome has been steroid sensitive, but the patient had 7 relapses over a span of 5 years. Each time the dose of steroid is tapered, a relapse of the nephrotic syndrome occurred. Eventually, the patient was complaining of dysphagia and difficulty swallowing. Hospital work-up with barium swallow, endoscopy, and CT of the chest, abdomen and pelvis, revealed a focal stenotic lesion with mild to moderate esophageal dysmotility 7/15/2022. A diagnosis of an ulcerating lesion with biopsy confirmed a neuro-endocrine carcinoma of the gastro-esophageal junction was entertained. The CT of the chest/abdomen/pelvis, 7/19/2022, has shown, an esophageal mass of 5.1 × 5.6 × 7 cm of the gastro-esophageal junction with ulceration. No evidence of spread beyond the esophagus and stomach. The histology revealed a poorly differentiated neuroendocrine tumor of the gastro-esophageal junction. The patient underwent several rounds of chemotherapy, radiation, and surgery culminating in tumor control. His nephrotic syndrome was resolved after the tumor has been controlled by surgery and chemotherapy.展开更多
Background: Programmed cell death protein 4(PDCD4) is a novel tumor suppressor protein involved in pro?grammed cell death. Its association with cancer progression has been observed in multiple tumor models, but eviden...Background: Programmed cell death protein 4(PDCD4) is a novel tumor suppressor protein involved in pro?grammed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical signiicance and prognostic value of PDCD4 in solid tumors.Methods: A systematic literature review was performed to retrieve publications with available clinical informa?tion and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta?analysis Of Observational Studies in Epidemiology group. Pooled odds ratios(ORs), hazard ratios(HRs), and 95% conidence intervals(CIs) for survival analysis were calculated. Publication bias was examined by Begg's and Egger's tests.Results: Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was signiicantly associated with the diferentiation status of head and neck cancer(OR 4.25, 95% CI 1.87–9.66) and digestive system cancer(OR 2.87, 95% CI 1.84–4.48). Down?regulation of PDCD4 was signiicantly associated with short overall survival of patients with head and neck(HR: 3.44, 95% CI 2.38–4.98), breast(HR: 1.86, 95% CI 1.36–2.54), digestive system(HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers(HR: 3.16, 95% CI 1.06–9.41).Conclusions: The current evidence suggests that PDCD4 down?regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be conirmed by large?scale prospective studies.展开更多
The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.Howeve...The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.However,accumulating evidence suggests that PD-1/PD-L1 is also widely expressed on immune cells,and that regulation is also critical for tumor immune responses.In this review,we emphasized that under solid tumor conditions,the immunoregulatory effects of immune cells expressing PD-1 or PD-L1,affected the prognoses of cancer patients.Therefore,a better understanding of the mechanisms that regulate PD-1 or PD-L1 expression on immune cells would provide clear insights into the increased efficacy of anti-PD antibodies and the development of novel tumor immunotherapy strategies.展开更多
Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-E...Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-Esc and D-Ex)trial in patients with advanced solid cancer.Methods:This was a 3+3 phaseⅠD-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies,and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid)at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding,safety,pharmacokinetics,and antitumor activity.Results:Seventy-nine patients were enrolled from March,2015 to January,2018[OC(47,59.5%);breast cancer(BC)(16,20.3%);colorectal cancer(8,10.1%),other tumors(8,10.1%)];48 patients were treated in the D-Esc arm and 31 in the D-Ex arm.The maximum tolerated dose(MTD)was 150 mg bid,with a half-life of 9.14 h.Grade 3/4 adverse events included anemia(7.6%)and neutropenia(5.1%).The objective response rate(ORR)was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13)in patients with BC.Among patients treated with fluzoparib≥120 mg/d,median progression-free survival(m PFS)was 7.2[95%confidence interval(95%CI),1.8-9.3]months in OC,9.3(95%CI,7.2-9.3)months in platinum-sensitive OC,and 3.5(range,2.0-28.0)months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC;2/16 BC),m PFS was 8.9 months for OC(range,1.0-23.2;95%CI,1.0-16.8)and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions:The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC,particularly in BRCAMut and platinum-sensitive OC.展开更多
Objective:This study evaluated the safety and preliminary efficacy of vorolanib,a novel tyrosine kinase inhibitor,for treatment of patients with advanced solid tumors.Methods:During dose escalation,patients received i...Objective:This study evaluated the safety and preliminary efficacy of vorolanib,a novel tyrosine kinase inhibitor,for treatment of patients with advanced solid tumors.Methods:During dose escalation,patients received increasing doses of oral vorolanib(50-250 mg once daily)in cycles of four weeks for up to one year.During dose expansion,patients received recommended doses(100 and 200 mg)in 4-week cycles.The primary endpoint was to determine the safety and maximum tolerated dose and/or the recommended phase II dose(RP2 D).The severity and type of adverse drug reactions(ADRs)were assessed using the Common Terminology Criteria for Adverse Events version 4.0.The second endpoint was preliminary efficacy in terms of objective response and progression-free survival(PFS).Results:No dose-limiting toxicity occurred during dose escalation(50-250 mg).Five(26.3%)patients in the escalation cohort(n=19)and 12(48.0%)in the expansion cohort(n=25)experienced grade 3 ADRs.The most common ADRs were hair color changes,fatigue,portal hypertension,hypertriglyceridemia,and proteinuria.During dose expansion,the patients treated with 200 mg and 100 mg(once daily)showed an objective response rate of 22.2%and 5.9%,respectively;the disease control rate was 88.9%and 73.3%,respectively;the median PFS was9.9[95%confidence interval(95%CI):7.4-not reached]months and 3.8(95%CI:1.9-not reached)months,respectively.Conclusions:Oral vorolanib at a dose of 200 mg(once daily)exhibited an acceptable safety profile and favorable clinical benefit for patients with advanced solid tumors.The RP2 D for vorolanib was determined to be 200 mg as a daily regimen.展开更多
In 2017,immune response evaluation criteria in solid tumors(iRECIST)were introduced to validate radiologic and clinical interpretations and to better analyze tumor’s response to immunotherapy,considering the differen...In 2017,immune response evaluation criteria in solid tumors(iRECIST)were introduced to validate radiologic and clinical interpretations and to better analyze tumor’s response to immunotherapy,considering the different time of following and response,between this new therapy compared to the standard one.However,even if the iRECIST are worldwide accepted,to date,different aspects should be better underlined and well reported,especially in clinical practice.Clinical experience has demonstrated that in a non-negligible percentage of patients,it is challenging to determine the correct category of response(stable disease,progression disease,partial or complete response),and consequently,to define which is the best management for those patients.Approaching radiological response in patients who underwent immunotherapy,a new uncommon kind of target lesions behavior was found.This phenomenon is mainly due to the different mechanisms of action of immunotherapeutic drug.Therefore,new groups of response have been described in clinical practice,defined as“atypical responses,”and categorized into three new groups:pseudoprogression,hyperprogression,and dissociated response.This review summarizes and reports these patterns,helping clinicians and radiologists get used to atypical responses,in order to identify patients that respond best to treatment.展开更多
Despite the significant resources dedicated to the development of monoclonal antibody(m Ab)therapies for solid tumors,the clinical success,thus far,has been modest.Limited efficacy of m Ab in solid tumors likely relat...Despite the significant resources dedicated to the development of monoclonal antibody(m Ab)therapies for solid tumors,the clinical success,thus far,has been modest.Limited efficacy of m Ab in solid tumors likely relates to unique aspects of tumor physiology.Solid tumors have an aberrant vasculature and a dense extracellular matrix that slow both the convective and diffusive transport of m Abs into and within tumors.For m Abs that are directed against cellular antigens,high antigen expression and rapid antigen turnover can result in perivascular cells binding to and eliminating a significant amount of extravasated m Ab,limiting m Ab distribution to portions of the tumor that are distant from functional vessels.Many preclinical investigations have reported strategies to improve m Ab uptake and distribution;however,to our knowledge,none have translated into the clinic.Here,we provide an overview of several barriers in solid tumors that limit m Ab uptake and distribution and discuss approaches that have been utilized to overcome these barriers in preclinical studies.展开更多
Objective:To assess the anti-tumor effects of Pistacia atlantica methanolic extract(PAME)compared with cyclophosphamide against Ehrlich solid tumors in mice.Methods:Swiss albino mice(n=40)were divided into five groups...Objective:To assess the anti-tumor effects of Pistacia atlantica methanolic extract(PAME)compared with cyclophosphamide against Ehrlich solid tumors in mice.Methods:Swiss albino mice(n=40)were divided into five groups:normal control mice,mice with Ehrlich solid tumors treated with normal saline,mice with Ehrlich solid tumors treated with cyclophosphamide intraperitoneally once a day for 14 d,or 50mg/kg or 100 mg/kg PAME orally once a day for 14 d.Tumor growth inhibition,body weight,tumor markers,liver and kidney enzymes,oxidative stress markers,antioxidant enzymes,tumor necrosis factor-alpha level(TNF-α),and apoptosis-regulatory gene expression were evaluated.Results:Treatment of mice bearing Ehrlich solid tumors with PAME at 50 and 100 mg/kg orally significantly decreased tumor volume,body weight,tumor markers,liver and kidney enzymes,oxidative stress markers and TNF-αlevel in comparison with mice with Ehrlich solid tumors receiving normal saline.whereas PAME at 50 and 100 mg/kg/day significantly elevated the level of antioxidant enzymes(P<0.05).Conclusions:Pistacia atlantica methanolic extract has potent antitumor activity in mice.Therefore,the extract might be considered as an alternative anticancer agent against tumors,however,additional studies especially in the clinical setting are required to confirm this finding.展开更多
BACKGROUND There are currently three coronavirus disease 2019(COVID-19)vaccines approved by the United States Food and Drug Administration to prevent coronavirus infection.However,robust data are unavailable on the ad...BACKGROUND There are currently three coronavirus disease 2019(COVID-19)vaccines approved by the United States Food and Drug Administration to prevent coronavirus infection.However,robust data are unavailable on the adverse events of the vaccines in patients with solid tumor malignancies undergoing systemic therapies.AIM To evaluate the safety of COVID-19 vaccines in patients with solid tumors undergoing systemic therapies.METHODS The study included patients with solid tumors treated in an academic tertiary care center who received COVID-19 vaccination between January 1,2021 and August 15,2021,while undergoing systemic therapy.Electronic medical records were accessed to collect information on patient characteristics,systemic therapies,type of vaccine received,and adverse effects associated with the vaccine administration.Adverse events(AEs)were graded according to Common Terminology Criteria for Adverse Events,version 5.0.RESULTS The analysis included 210 patients;the median age was 70 years,and 51%of patients were female.The most common chemotherapy,immunotherapy,and targeted therapy administered were taxane-based regimens 14.2%(30/210),antiprogrammed death 1(PD-1)agents 22.8%(48/210),and antiangiogenic agents 7.1%(15/210),respectively.The most common cancers were gastrointestinal 43.8%(92/210),thoracic 30.4%(64/210),and genitourinary 17.6%(37/210).Patients received the following vaccines:2 doses of BNT162b2 by Pfizer 52%(110/210),2 doses of mRNA-1273 by Moderna 42%(89/210),and 1 dose of JNJ-78436735 by Johnson&Johnson 5%(11/210).At least 1 AE attributable to the vaccine was observed in 37 patients 17.6%(37/210).The total number of AEs attributable to vaccines was 62:Fifty-three grade 1 and nine grade 2.Most adverse events occurred after the second dose 59.7%(37/62).The most frequent grade 1 AEs included fatigue 17%(9/53),fever 15%(8/53),injection site reaction 13.2%(7/53),and chills 9.4%(5/53).The most frequent grade 2 AEs were fatigue 33.3%(3/9)and generalized weakness 22.2%(2/9).Therapy was delayed by 2 wk because of the AEs possibly related to vaccine administration in 3 patients 1.4%(3/210).CONCLUSION The present study demonstrates that the adverse events associated with COVID-19 vaccination are infrequent,mild,and rarely delay treatment in patients with solid tumors receiving systemic therapies.展开更多
This paper is concerned with the bifurcation analysis for a free boundary problem modeling the growth of solid tumor with inhibitors.In this problem,surface tension coefficient plays the role of bifurcation parameter,...This paper is concerned with the bifurcation analysis for a free boundary problem modeling the growth of solid tumor with inhibitors.In this problem,surface tension coefficient plays the role of bifurcation parameter,it is proved that there exists a sequence of the nonradially stationary solutions bifurcate from the radially symmetric stationary solutions.Our results indicate that the tumor grown in vivo may have various shapes.In particular,a tumor with an inhibitor is associated with the growth of protrusions.展开更多
The management of hepatic metastatic disease from solid tumors in adults has been extensively described and resection of metastatic liver lesions from colorectal adenocarcinoma, renal adenocarcinoma, breast cancer, te...The management of hepatic metastatic disease from solid tumors in adults has been extensively described and resection of metastatic liver lesions from colorectal adenocarcinoma, renal adenocarcinoma, breast cancer, testicular cancer, and neuroendocrine tumors(NET) havedemonstrated therapeutic benefits in select patients. However, there are few reports in the literature on the management of hepatic metastatic disease in the pediatric and adolescent populations and the effectiveness of hepatic metastasectomy. This may be due to the much lower incidence of pediatric malignancies and the higher chemosensitivity of childhood tumors which make hepatic metastasectomy less likely to be required. We review liver involvement with metastatic disease from the main pediatric solid tumors, including neuroblastoma and Wilms tumor focusing on the management and treatment options. We also review other solid malignant tumors which may have liver metastases including germ cell tumors, gastrointestinal stromal tumors, osteosarcoma, desmoplastic small round cell tumors and NET. However, these histological subtypes are so rare in the pediatric and adolescent populations that the exact incidence and best management of hepatic metastatic disease are unknown and can only be extrapolated from adult series.展开更多
Solid pseudopapillary tumor of the pancreas(SPTP)is a rare neoplasm predom-inantly observed in young females.Pathologically,CTNNB1 mutations,β-catenin nuclear accumulation,and subsequent Wnt-signaling pathway activat...Solid pseudopapillary tumor of the pancreas(SPTP)is a rare neoplasm predom-inantly observed in young females.Pathologically,CTNNB1 mutations,β-catenin nuclear accumulation,and subsequent Wnt-signaling pathway activation are the leading molecular features.Accurate preoperative diagnosis often relies on imaging techniques and endoscopic biopsies.Surgical resection remains the mainstay treatment.Risk models,such as the Fudan Prognostic Index,show promise as predictive tools for assessing the prognosis of SPTP.Establishing three types of metachronous liver metastasis can be beneficial in tailoring individu-alized treatment and follow-up strategies.Despite advancements,challenges persist in understanding its etiology,establishing standardized treatments for unresectable or metastatic diseases,and developing a widely recognized grading system.This comprehensive review aims to elucidate the enigma by consolidating current knowledge on the epidemiology,clinical presentation,pathology,molecular characteristics,diagnostic methods,treatment options,and prognostic factors.展开更多
Solid-pseudopapillary tumor of the pancreas (SPT) or Frantz’s tumor is a rare epithelial neoplasm that represents 0.3% to 2.7% of exocrine pancreatic tumors. These tumors occur mainly in young women and have a good p...Solid-pseudopapillary tumor of the pancreas (SPT) or Frantz’s tumor is a rare epithelial neoplasm that represents 0.3% to 2.7% of exocrine pancreatic tumors. These tumors occur mainly in young women and have a good prognosis. We present a case of a 19-year-old female patient who presented to the emergency for abdominal pain. Physical examination reveals a left hypochondrium mass. Ultrasound imaging showed an encapsulated caudal pancreatic mass with cystic components. The patient underwent tumor excision and lymph node removal. Macroscopically, the tumor was encapsulated and measuring 12 × 8 × 7 cm. It has a solid-cystic and hemorrhagic appearance inside. Histologically, the tumor had two components: solid and papillary. Tumor tissue showed monomorphic tumor cells radiating around blood vessels. Perineural invasion and vascular emboli were not seen. Three lymph nodes without metastases were observed. The diagnosis of solid-pseudopapillary tumor of the pancreas (SPT) or Frantz’s tumor was retained. Solid-pseudo-papillary tumor of the pancreas is rare and not always suspected by the physician. The clinical and imaging patterns are not specific. Anatomopathological examination confirmed the diagnosis. The patient underwent curative surgery.展开更多
Previous studies demonstrated that three-dimensional(3D) multicellular tumor spheroids(MCTS) could more closely mimic solid tumors than two-dimensional(2D) cancer cells in terms of the spatial structure, extracellular...Previous studies demonstrated that three-dimensional(3D) multicellular tumor spheroids(MCTS) could more closely mimic solid tumors than two-dimensional(2D) cancer cells in terms of the spatial structure, extracellular matrix-cell interaction, and gene expression pattern. However, no study has been reported on the differences in lipid metabolism and distribution among 2D cancer cells, MCTS, and solid tumors. Here, we used Hep G2 liver cancer cell lines to establish these three cancer models. The variations of lipid profiles and spatial distribution among them were explored by using mass spectrometry-based lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging(MSI). The results revealed that MCTS, relative to 2D cells, had more shared lipid species with solid tumors. Furthermore,MCTS contained more comparable characteristics than 2D cells to solid tumors with respect to the relative abundance of most lipid classes and mass spectra patterns. MSI data showed that 46 of 71 lipids had similar spatial distribution between solid tumors and MCTS, while lipids in 2D cells had no specific spatial distribution. Interestingly, most of detected lipid species in sphingolipids and glycerolipids preferred locating in the necrotic region to the proliferative region of solid tumors and MCTS. Taken together, our study provides the evidence of lipid metabolism and distribution demonstrating that MCTS are a more suitable in vitro model to mimic solid tumors, which may offer insights into tumor metabolism and microenvironment.展开更多
Poor permeation of drugs and“immune-cold”tumor microenvironment in solid tumors are the two major challenges which lead to the inefficient therapeutic efficacy for cancer treatment.Here,light-activated penetrable na...Poor permeation of drugs and“immune-cold”tumor microenvironment in solid tumors are the two major challenges which lead to the inefficient therapeutic efficacy for cancer treatment.Here,light-activated penetrable nanoparticles(PEGVAL&DOX&ICG@RNPs)for co-delivery of the chemotherapeutic drug doxorubicin(DOX),the photosensitizer agent indocyanine green(ICG),and the angiotensin II receptor blockers valsartan(VAL)were developed to achieve deep drug penetration and synergistic photo-chemo-immunotherapy of solid tumor.Studies showed that under the first-wave of laser irradiation,the polyethylene glycol(PEG)hydrophilic layer as an“inert”surface could detach from the nanoparticles,release VAL and expose the arginine-rich peptide modified-cores that can facilitate deep drug penetration via a transcytosis pathway.When exposed to the second-wave of laser irradiation,the synergistic chemo-photo-immunotherapy can be achieved.As expected,in 4T1 tumorbearing mice,PEG-VAL&DOX&ICG@RNPs treatment could effectively inhibit the growth of tumors,down-regulateα-smooth muscle actin expression level of cancer-associated fibroblasts cells in tumors,induce dendritic cells(DCs)maturation,and promote intratumoral infiltration of cytotoxic T lymphocytes.Moreover,combination therapy by PEG-VAL&DOX&ICG@RNPs and anti-PD-1 monoclonal antibody can elicit memory T cell response for preventing tumor recurrence and metastasis in vivo.This work provides a promising delivery strategy to overcome the current limitations of nanomedicine for achieving more effective therapeutic index of“immune-cold”solid tumor treatment.展开更多
Minimal residual disease(MRD)is termed as the small numbers of remnant tumor cells in a subset of patients with tumors.Liquid biopsy is increasingly used for the detection of MRD,illustrating the potential of MRD dete...Minimal residual disease(MRD)is termed as the small numbers of remnant tumor cells in a subset of patients with tumors.Liquid biopsy is increasingly used for the detection of MRD,illustrating the potential of MRD detection to provide more accurate management for cancer patients.As new techniques and algorithms have enhanced the performance of MRD detection,the approach is becoming more widely and routinely used to predict the prognosis and monitor the relapse of cancer patients.In fact,MRD detection has been shown to achieve better performance than imaging methods.On this basis,rigorous investigation of MRD detection as an integral method for guiding clinical treatment has made important advances.This review summarizes the development of MRD biomarkers,techniques,and strategies for the detection of cancer,and emphasizes the application of MRD detection in solid tumors,particularly for the guidance of clinical treatment.展开更多
Insufficient infiltration of T cells severely compromises the antitumor efficacy of adoptive cell therapy(ACT)against solid tumors.Here,we present a facile immune cell surface engineering strategy aiming to substantia...Insufficient infiltration of T cells severely compromises the antitumor efficacy of adoptive cell therapy(ACT)against solid tumors.Here,we present a facile immune cell surface engineering strategy aiming to substantially enhance the anti-tumor efficacy of Th9-mediated ACT by rapidly identifying tumor-specific binding ligands and improving the infiltration of infused cells into solid tumors.Non-genetic decoration of Th9 cells with tumor-targeting peptide screened from phage display not only allowed precise targeted ACT against highly heterogeneous solid tumors but also substantially enhanced infiltration of CD8+T cells,which led to improved antitumor outcomes.Mechanistically,infusion of Th9 cells modified with tumor-specific binding ligands facilitated the enhanced distribution of tumor-killing cells and remodeled the immunosuppressive microenvironment of solid tumors via IL-9 mediated immunomodulation.Overall,we presented a simple,cost-effective,and cell-friendly strategy to enhance the efficacy of ACT against solid tumors with the potential to complement the current ACT.展开更多
Chimeric antigen receptor(CAR)T cell therapy is a relatively new form of targeted therapy that has demonstrated impressive success in treating hematological malignancies.It has been challenging to translate this succe...Chimeric antigen receptor(CAR)T cell therapy is a relatively new form of targeted therapy that has demonstrated impressive success in treating hematological malignancies.It has been challenging to translate this success to solid tumors.Reasons for this include barriers to delivery,tumor heterogeneity,cancer cells'ability to evade the immune system as well as identifying the optimal target.Most CAR T clinical trials have targeted well‐characterized cancer targets with significant preclinical and in some cases clinical validation.Published results from some of these trials show signs of anti‐cancer activity that warrant encouragement,but also caution,given instances of unacceptable toxicity.The narrow therapeutic window is complicated by the ability of CAR T cells to expand in patients regardless of dose.Here,we review those trials showing encouraging results in the context of target selection.It is clear that more specific tumor targeting is required,either by affinity tuning to avoid low‐level target expression in healthy cells,logic gating,or the identification of new targets that are more cancer specific.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.82203548)National Key Research and Development Program(No.2022YFE0141000)+1 种基金Henan Province Medical Science and Technology Research Project(No.LHGJ20220385)the Central Government of Henan Province guides local science and technology development fund projects(No.Z20221343036)。
文摘Adoptive cellular therapy is rapidly improving immunotherapy in hematologic malignancies and several solid tumors.Remarkable clinical success has been achieved in chimeric antigen receptor(CAR)-T cell therapy which represents a paradigm-shifting strategy for the treatment of hematological malignancies.However,many challenges such as resistance,antigen heterogeneity,poor immune cell infiltration,immunosuppressive microenvironment,metabolic obstructive microenvironment,and T cell exhaustion remain as barriers to broader application especially in solid tumors.Encouragingly,the development of new approaches such as multidimensional omics and biomaterials technologies was aided to overcome these barriers.Here,in this perspective,we focus on the most recent clinical advancements,challenges,and strategies of immune cellular therapy in solid tumor treatment represented by CAR-T cell therapy,to provide new ideas to further overcome the bottleneck of immune cell therapy and anticipate future clinical advances.
文摘We reported a biopsy proved case of minimal change nephrotic syndrome in a 72-year-old patient. The minimal change nephrotic syndrome has been steroid sensitive, but the patient had 7 relapses over a span of 5 years. Each time the dose of steroid is tapered, a relapse of the nephrotic syndrome occurred. Eventually, the patient was complaining of dysphagia and difficulty swallowing. Hospital work-up with barium swallow, endoscopy, and CT of the chest, abdomen and pelvis, revealed a focal stenotic lesion with mild to moderate esophageal dysmotility 7/15/2022. A diagnosis of an ulcerating lesion with biopsy confirmed a neuro-endocrine carcinoma of the gastro-esophageal junction was entertained. The CT of the chest/abdomen/pelvis, 7/19/2022, has shown, an esophageal mass of 5.1 × 5.6 × 7 cm of the gastro-esophageal junction with ulceration. No evidence of spread beyond the esophagus and stomach. The histology revealed a poorly differentiated neuroendocrine tumor of the gastro-esophageal junction. The patient underwent several rounds of chemotherapy, radiation, and surgery culminating in tumor control. His nephrotic syndrome was resolved after the tumor has been controlled by surgery and chemotherapy.
文摘Background: Programmed cell death protein 4(PDCD4) is a novel tumor suppressor protein involved in pro?grammed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical signiicance and prognostic value of PDCD4 in solid tumors.Methods: A systematic literature review was performed to retrieve publications with available clinical informa?tion and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta?analysis Of Observational Studies in Epidemiology group. Pooled odds ratios(ORs), hazard ratios(HRs), and 95% conidence intervals(CIs) for survival analysis were calculated. Publication bias was examined by Begg's and Egger's tests.Results: Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was signiicantly associated with the diferentiation status of head and neck cancer(OR 4.25, 95% CI 1.87–9.66) and digestive system cancer(OR 2.87, 95% CI 1.84–4.48). Down?regulation of PDCD4 was signiicantly associated with short overall survival of patients with head and neck(HR: 3.44, 95% CI 2.38–4.98), breast(HR: 1.86, 95% CI 1.36–2.54), digestive system(HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers(HR: 3.16, 95% CI 1.06–9.41).Conclusions: The current evidence suggests that PDCD4 down?regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be conirmed by large?scale prospective studies.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81974416 and 81872166)the Key Project of Tianjin Health Industry(Grant No.15KG145).
文摘The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.However,accumulating evidence suggests that PD-1/PD-L1 is also widely expressed on immune cells,and that regulation is also critical for tumor immune responses.In this review,we emphasized that under solid tumor conditions,the immunoregulatory effects of immune cells expressing PD-1 or PD-L1,affected the prognoses of cancer patients.Therefore,a better understanding of the mechanisms that regulate PD-1 or PD-L1 expression on immune cells would provide clear insights into the increased efficacy of anti-PD antibodies and the development of novel tumor immunotherapy strategies.
文摘Objective:Fluzoparib(SHR3162)is a novel,potent poly(ADP-ribose)polymerases(PARP)1,2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phaseⅠ,first-in-human,dose-escalation and expansion(D-Esc and D-Ex)trial in patients with advanced solid cancer.Methods:This was a 3+3 phaseⅠD-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies,and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid)at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding,safety,pharmacokinetics,and antitumor activity.Results:Seventy-nine patients were enrolled from March,2015 to January,2018[OC(47,59.5%);breast cancer(BC)(16,20.3%);colorectal cancer(8,10.1%),other tumors(8,10.1%)];48 patients were treated in the D-Esc arm and 31 in the D-Ex arm.The maximum tolerated dose(MTD)was 150 mg bid,with a half-life of 9.14 h.Grade 3/4 adverse events included anemia(7.6%)and neutropenia(5.1%).The objective response rate(ORR)was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13)in patients with BC.Among patients treated with fluzoparib≥120 mg/d,median progression-free survival(m PFS)was 7.2[95%confidence interval(95%CI),1.8-9.3]months in OC,9.3(95%CI,7.2-9.3)months in platinum-sensitive OC,and 3.5(range,2.0-28.0)months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC;2/16 BC),m PFS was 8.9 months for OC(range,1.0-23.2;95%CI,1.0-16.8)and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions:The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC,particularly in BRCAMut and platinum-sensitive OC.
文摘Objective:This study evaluated the safety and preliminary efficacy of vorolanib,a novel tyrosine kinase inhibitor,for treatment of patients with advanced solid tumors.Methods:During dose escalation,patients received increasing doses of oral vorolanib(50-250 mg once daily)in cycles of four weeks for up to one year.During dose expansion,patients received recommended doses(100 and 200 mg)in 4-week cycles.The primary endpoint was to determine the safety and maximum tolerated dose and/or the recommended phase II dose(RP2 D).The severity and type of adverse drug reactions(ADRs)were assessed using the Common Terminology Criteria for Adverse Events version 4.0.The second endpoint was preliminary efficacy in terms of objective response and progression-free survival(PFS).Results:No dose-limiting toxicity occurred during dose escalation(50-250 mg).Five(26.3%)patients in the escalation cohort(n=19)and 12(48.0%)in the expansion cohort(n=25)experienced grade 3 ADRs.The most common ADRs were hair color changes,fatigue,portal hypertension,hypertriglyceridemia,and proteinuria.During dose expansion,the patients treated with 200 mg and 100 mg(once daily)showed an objective response rate of 22.2%and 5.9%,respectively;the disease control rate was 88.9%and 73.3%,respectively;the median PFS was9.9[95%confidence interval(95%CI):7.4-not reached]months and 3.8(95%CI:1.9-not reached)months,respectively.Conclusions:Oral vorolanib at a dose of 200 mg(once daily)exhibited an acceptable safety profile and favorable clinical benefit for patients with advanced solid tumors.The RP2 D for vorolanib was determined to be 200 mg as a daily regimen.
文摘In 2017,immune response evaluation criteria in solid tumors(iRECIST)were introduced to validate radiologic and clinical interpretations and to better analyze tumor’s response to immunotherapy,considering the different time of following and response,between this new therapy compared to the standard one.However,even if the iRECIST are worldwide accepted,to date,different aspects should be better underlined and well reported,especially in clinical practice.Clinical experience has demonstrated that in a non-negligible percentage of patients,it is challenging to determine the correct category of response(stable disease,progression disease,partial or complete response),and consequently,to define which is the best management for those patients.Approaching radiological response in patients who underwent immunotherapy,a new uncommon kind of target lesions behavior was found.This phenomenon is mainly due to the different mechanisms of action of immunotherapeutic drug.Therefore,new groups of response have been described in clinical practice,defined as“atypical responses,”and categorized into three new groups:pseudoprogression,hyperprogression,and dissociated response.This review summarizes and reports these patterns,helping clinicians and radiologists get used to atypical responses,in order to identify patients that respond best to treatment.
基金funded by the National Institutes of Health/National Cancer Institute(Grant Nos.CA204192 and CA246785)。
文摘Despite the significant resources dedicated to the development of monoclonal antibody(m Ab)therapies for solid tumors,the clinical success,thus far,has been modest.Limited efficacy of m Ab in solid tumors likely relates to unique aspects of tumor physiology.Solid tumors have an aberrant vasculature and a dense extracellular matrix that slow both the convective and diffusive transport of m Abs into and within tumors.For m Abs that are directed against cellular antigens,high antigen expression and rapid antigen turnover can result in perivascular cells binding to and eliminating a significant amount of extravasated m Ab,limiting m Ab distribution to portions of the tumor that are distant from functional vessels.Many preclinical investigations have reported strategies to improve m Ab uptake and distribution;however,to our knowledge,none have translated into the clinic.Here,we provide an overview of several barriers in solid tumors that limit m Ab uptake and distribution and discuss approaches that have been utilized to overcome these barriers in preclinical studies.
文摘Objective:To assess the anti-tumor effects of Pistacia atlantica methanolic extract(PAME)compared with cyclophosphamide against Ehrlich solid tumors in mice.Methods:Swiss albino mice(n=40)were divided into five groups:normal control mice,mice with Ehrlich solid tumors treated with normal saline,mice with Ehrlich solid tumors treated with cyclophosphamide intraperitoneally once a day for 14 d,or 50mg/kg or 100 mg/kg PAME orally once a day for 14 d.Tumor growth inhibition,body weight,tumor markers,liver and kidney enzymes,oxidative stress markers,antioxidant enzymes,tumor necrosis factor-alpha level(TNF-α),and apoptosis-regulatory gene expression were evaluated.Results:Treatment of mice bearing Ehrlich solid tumors with PAME at 50 and 100 mg/kg orally significantly decreased tumor volume,body weight,tumor markers,liver and kidney enzymes,oxidative stress markers and TNF-αlevel in comparison with mice with Ehrlich solid tumors receiving normal saline.whereas PAME at 50 and 100 mg/kg/day significantly elevated the level of antioxidant enzymes(P<0.05).Conclusions:Pistacia atlantica methanolic extract has potent antitumor activity in mice.Therefore,the extract might be considered as an alternative anticancer agent against tumors,however,additional studies especially in the clinical setting are required to confirm this finding.
文摘BACKGROUND There are currently three coronavirus disease 2019(COVID-19)vaccines approved by the United States Food and Drug Administration to prevent coronavirus infection.However,robust data are unavailable on the adverse events of the vaccines in patients with solid tumor malignancies undergoing systemic therapies.AIM To evaluate the safety of COVID-19 vaccines in patients with solid tumors undergoing systemic therapies.METHODS The study included patients with solid tumors treated in an academic tertiary care center who received COVID-19 vaccination between January 1,2021 and August 15,2021,while undergoing systemic therapy.Electronic medical records were accessed to collect information on patient characteristics,systemic therapies,type of vaccine received,and adverse effects associated with the vaccine administration.Adverse events(AEs)were graded according to Common Terminology Criteria for Adverse Events,version 5.0.RESULTS The analysis included 210 patients;the median age was 70 years,and 51%of patients were female.The most common chemotherapy,immunotherapy,and targeted therapy administered were taxane-based regimens 14.2%(30/210),antiprogrammed death 1(PD-1)agents 22.8%(48/210),and antiangiogenic agents 7.1%(15/210),respectively.The most common cancers were gastrointestinal 43.8%(92/210),thoracic 30.4%(64/210),and genitourinary 17.6%(37/210).Patients received the following vaccines:2 doses of BNT162b2 by Pfizer 52%(110/210),2 doses of mRNA-1273 by Moderna 42%(89/210),and 1 dose of JNJ-78436735 by Johnson&Johnson 5%(11/210).At least 1 AE attributable to the vaccine was observed in 37 patients 17.6%(37/210).The total number of AEs attributable to vaccines was 62:Fifty-three grade 1 and nine grade 2.Most adverse events occurred after the second dose 59.7%(37/62).The most frequent grade 1 AEs included fatigue 17%(9/53),fever 15%(8/53),injection site reaction 13.2%(7/53),and chills 9.4%(5/53).The most frequent grade 2 AEs were fatigue 33.3%(3/9)and generalized weakness 22.2%(2/9).Therapy was delayed by 2 wk because of the AEs possibly related to vaccine administration in 3 patients 1.4%(3/210).CONCLUSION The present study demonstrates that the adverse events associated with COVID-19 vaccination are infrequent,mild,and rarely delay treatment in patients with solid tumors receiving systemic therapies.
基金The NSF(11361029)of Chinathe NSF(20142BAB211001)of Jiangxi Province
文摘This paper is concerned with the bifurcation analysis for a free boundary problem modeling the growth of solid tumor with inhibitors.In this problem,surface tension coefficient plays the role of bifurcation parameter,it is proved that there exists a sequence of the nonradially stationary solutions bifurcate from the radially symmetric stationary solutions.Our results indicate that the tumor grown in vivo may have various shapes.In particular,a tumor with an inhibitor is associated with the growth of protrusions.
文摘The management of hepatic metastatic disease from solid tumors in adults has been extensively described and resection of metastatic liver lesions from colorectal adenocarcinoma, renal adenocarcinoma, breast cancer, testicular cancer, and neuroendocrine tumors(NET) havedemonstrated therapeutic benefits in select patients. However, there are few reports in the literature on the management of hepatic metastatic disease in the pediatric and adolescent populations and the effectiveness of hepatic metastasectomy. This may be due to the much lower incidence of pediatric malignancies and the higher chemosensitivity of childhood tumors which make hepatic metastasectomy less likely to be required. We review liver involvement with metastatic disease from the main pediatric solid tumors, including neuroblastoma and Wilms tumor focusing on the management and treatment options. We also review other solid malignant tumors which may have liver metastases including germ cell tumors, gastrointestinal stromal tumors, osteosarcoma, desmoplastic small round cell tumors and NET. However, these histological subtypes are so rare in the pediatric and adolescent populations that the exact incidence and best management of hepatic metastatic disease are unknown and can only be extrapolated from adult series.
文摘Solid pseudopapillary tumor of the pancreas(SPTP)is a rare neoplasm predom-inantly observed in young females.Pathologically,CTNNB1 mutations,β-catenin nuclear accumulation,and subsequent Wnt-signaling pathway activation are the leading molecular features.Accurate preoperative diagnosis often relies on imaging techniques and endoscopic biopsies.Surgical resection remains the mainstay treatment.Risk models,such as the Fudan Prognostic Index,show promise as predictive tools for assessing the prognosis of SPTP.Establishing three types of metachronous liver metastasis can be beneficial in tailoring individu-alized treatment and follow-up strategies.Despite advancements,challenges persist in understanding its etiology,establishing standardized treatments for unresectable or metastatic diseases,and developing a widely recognized grading system.This comprehensive review aims to elucidate the enigma by consolidating current knowledge on the epidemiology,clinical presentation,pathology,molecular characteristics,diagnostic methods,treatment options,and prognostic factors.
文摘Solid-pseudopapillary tumor of the pancreas (SPT) or Frantz’s tumor is a rare epithelial neoplasm that represents 0.3% to 2.7% of exocrine pancreatic tumors. These tumors occur mainly in young women and have a good prognosis. We present a case of a 19-year-old female patient who presented to the emergency for abdominal pain. Physical examination reveals a left hypochondrium mass. Ultrasound imaging showed an encapsulated caudal pancreatic mass with cystic components. The patient underwent tumor excision and lymph node removal. Macroscopically, the tumor was encapsulated and measuring 12 × 8 × 7 cm. It has a solid-cystic and hemorrhagic appearance inside. Histologically, the tumor had two components: solid and papillary. Tumor tissue showed monomorphic tumor cells radiating around blood vessels. Perineural invasion and vascular emboli were not seen. Three lymph nodes without metastases were observed. The diagnosis of solid-pseudopapillary tumor of the pancreas (SPT) or Frantz’s tumor was retained. Solid-pseudo-papillary tumor of the pancreas is rare and not always suspected by the physician. The clinical and imaging patterns are not specific. Anatomopathological examination confirmed the diagnosis. The patient underwent curative surgery.
基金supported by National Natural Science Foundation of China (Nos. 22036001, 22106130 and 91843301)Research Grant Council (Nos. 463612 and 14104314) of Hong Kong。
文摘Previous studies demonstrated that three-dimensional(3D) multicellular tumor spheroids(MCTS) could more closely mimic solid tumors than two-dimensional(2D) cancer cells in terms of the spatial structure, extracellular matrix-cell interaction, and gene expression pattern. However, no study has been reported on the differences in lipid metabolism and distribution among 2D cancer cells, MCTS, and solid tumors. Here, we used Hep G2 liver cancer cell lines to establish these three cancer models. The variations of lipid profiles and spatial distribution among them were explored by using mass spectrometry-based lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging(MSI). The results revealed that MCTS, relative to 2D cells, had more shared lipid species with solid tumors. Furthermore,MCTS contained more comparable characteristics than 2D cells to solid tumors with respect to the relative abundance of most lipid classes and mass spectra patterns. MSI data showed that 46 of 71 lipids had similar spatial distribution between solid tumors and MCTS, while lipids in 2D cells had no specific spatial distribution. Interestingly, most of detected lipid species in sphingolipids and glycerolipids preferred locating in the necrotic region to the proliferative region of solid tumors and MCTS. Taken together, our study provides the evidence of lipid metabolism and distribution demonstrating that MCTS are a more suitable in vitro model to mimic solid tumors, which may offer insights into tumor metabolism and microenvironment.
基金We acknowledge financial support from National Natural Science Foundation of China(Nos.82172089,22178270 and 22078246)the Fundamental Research Funds for the Central Universities(No.2019PT320028)CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-058).
文摘Poor permeation of drugs and“immune-cold”tumor microenvironment in solid tumors are the two major challenges which lead to the inefficient therapeutic efficacy for cancer treatment.Here,light-activated penetrable nanoparticles(PEGVAL&DOX&ICG@RNPs)for co-delivery of the chemotherapeutic drug doxorubicin(DOX),the photosensitizer agent indocyanine green(ICG),and the angiotensin II receptor blockers valsartan(VAL)were developed to achieve deep drug penetration and synergistic photo-chemo-immunotherapy of solid tumor.Studies showed that under the first-wave of laser irradiation,the polyethylene glycol(PEG)hydrophilic layer as an“inert”surface could detach from the nanoparticles,release VAL and expose the arginine-rich peptide modified-cores that can facilitate deep drug penetration via a transcytosis pathway.When exposed to the second-wave of laser irradiation,the synergistic chemo-photo-immunotherapy can be achieved.As expected,in 4T1 tumorbearing mice,PEG-VAL&DOX&ICG@RNPs treatment could effectively inhibit the growth of tumors,down-regulateα-smooth muscle actin expression level of cancer-associated fibroblasts cells in tumors,induce dendritic cells(DCs)maturation,and promote intratumoral infiltration of cytotoxic T lymphocytes.Moreover,combination therapy by PEG-VAL&DOX&ICG@RNPs and anti-PD-1 monoclonal antibody can elicit memory T cell response for preventing tumor recurrence and metastasis in vivo.This work provides a promising delivery strategy to overcome the current limitations of nanomedicine for achieving more effective therapeutic index of“immune-cold”solid tumor treatment.
基金supported by National Key R&D Program of China(Nos.2021YFC2500900 and 2021YFC2501004)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(Nos.2021-1-I2M-018 and 2021-I2M-1-067)Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2022-RC310-08).
文摘Minimal residual disease(MRD)is termed as the small numbers of remnant tumor cells in a subset of patients with tumors.Liquid biopsy is increasingly used for the detection of MRD,illustrating the potential of MRD detection to provide more accurate management for cancer patients.As new techniques and algorithms have enhanced the performance of MRD detection,the approach is becoming more widely and routinely used to predict the prognosis and monitor the relapse of cancer patients.In fact,MRD detection has been shown to achieve better performance than imaging methods.On this basis,rigorous investigation of MRD detection as an integral method for guiding clinical treatment has made important advances.This review summarizes the development of MRD biomarkers,techniques,and strategies for the detection of cancer,and emphasizes the application of MRD detection in solid tumors,particularly for the guidance of clinical treatment.
基金This work was supported by National Natural Science Foundation of China(81872173,82072959,31870959,and 82102855)Zhejiang Province Natural Science Foundation(LY20H160018,LD21H160002,and LY19H160045).
文摘Insufficient infiltration of T cells severely compromises the antitumor efficacy of adoptive cell therapy(ACT)against solid tumors.Here,we present a facile immune cell surface engineering strategy aiming to substantially enhance the anti-tumor efficacy of Th9-mediated ACT by rapidly identifying tumor-specific binding ligands and improving the infiltration of infused cells into solid tumors.Non-genetic decoration of Th9 cells with tumor-targeting peptide screened from phage display not only allowed precise targeted ACT against highly heterogeneous solid tumors but also substantially enhanced infiltration of CD8+T cells,which led to improved antitumor outcomes.Mechanistically,infusion of Th9 cells modified with tumor-specific binding ligands facilitated the enhanced distribution of tumor-killing cells and remodeled the immunosuppressive microenvironment of solid tumors via IL-9 mediated immunomodulation.Overall,we presented a simple,cost-effective,and cell-friendly strategy to enhance the efficacy of ACT against solid tumors with the potential to complement the current ACT.
文摘Chimeric antigen receptor(CAR)T cell therapy is a relatively new form of targeted therapy that has demonstrated impressive success in treating hematological malignancies.It has been challenging to translate this success to solid tumors.Reasons for this include barriers to delivery,tumor heterogeneity,cancer cells'ability to evade the immune system as well as identifying the optimal target.Most CAR T clinical trials have targeted well‐characterized cancer targets with significant preclinical and in some cases clinical validation.Published results from some of these trials show signs of anti‐cancer activity that warrant encouragement,but also caution,given instances of unacceptable toxicity.The narrow therapeutic window is complicated by the ability of CAR T cells to expand in patients regardless of dose.Here,we review those trials showing encouraging results in the context of target selection.It is clear that more specific tumor targeting is required,either by affinity tuning to avoid low‐level target expression in healthy cells,logic gating,or the identification of new targets that are more cancer specific.
