Tumor-Specific Histo-Blood Group Antigens: Apropos of Two Cases

Cancer cells with immunogenic properties having altered protein glycosylation, modified blood group substances have been widely studied. Due to the genetic instability occurring during carcinogenesis the glycosyltransferases may suffer from posttranslation sequence modification. The author describes 2 autopsy cases, where in the background of the unusual metastatic tumor presentation, incompatible blood group antigenic determinants have been demonstrated using blood group specific lectins and monoclonal antibodies (mAb). In the first case, reported here, a 10-year-old girl developed an acute myeloid leukemia and died in a septic endotoxin shock after successful cytostatic treatment of a juvenile signet ring cell cancer of her colon. At autopsy there were no signs of tumor except bilateral apple-sized mucinous ovarian (Krukenberg) metastases. While she had erythrocyte phenotype of blood group A, the signet ring adenocarcinoma cells expressed blood group B incompatible antigenic determinants with lectin/mAb. In the second case, the autopsy of a 78-year-old female resulted in no macroscopic tumor sign except a moderately enlarged, ham hard spleen. Light microscopy revealed adenocarcinomatous infiltration in the splenic sinusoids. The patient had blood group O, while the metastatic cells in the spleen reacted with Breast Carcinoma Antigen (BioGenex) and incompatible anti-B Banderiaeasimplicifolia agglutinin I and anti-B mAb. It proved to be a case of an occult, completely regressed breast cancer. Based on these observations the expression of tumor specific incompatible blood group antigens might occur from time to time, mostly in adenocarcinomas. Accordingly, blood group-based specific immuno-oncotherapy could be considered in some cancer cases.

TCR-mimic antibody-drug conjugates targeting intracellular tumor-specific mutant antigen KRAS G12V mutation

Limited clinical application of antibody-drug conjugates(ADCs)targeting tumor associated antigens(TAAs)is usually caused by on-target off-tumor side effect.Tumor-specific mutant antigens(TSMAs)only expressed in tumor cells which are ideal targets for ADCs.In addition,intracellular somatic mutant proteins can be presented on the cell surface by human leukocyte antigen class I(HLA I)molecules forming tumor-specific peptide/HLA I complexes.KRAS G12 V mutation frequently occurred in varied cancer and was verified as a promising target for cancer therapy.In this study,we generated two TCR-mimic antibodydrug conjugates(TCRm-ADCs),2E8-MMAE and 2 A5-MMAE,targeting KRAS G12 V/HLAA*0201 complex,which mediated specific antitumor activity in vitro and in vivo without obvious toxicity.Our findings are the first time validate the strategy of TCRm-ADCs targeting intracellular TSMAs,which improves the safety of antibody-based drugs and provides novel strategy for precision medicine in cancer therapy.

Selective gene therapy for human lung adenocarcinoma by tumor-specific expression of herpes simplex virus thymidine kinase gene

According to the fact that CEA gene expressed only in lung adenocarcinoma but not in normal lung cells, a retroviral expression vector (pCEATK) of the herpes simplex virus thymidine kinase (HSV-TK) gene regulated by CEA promoter was constructed and introduced into CEA-producing human lung adenocarcinoma cells GL and non-CEA-producing HeLa cells. The expression of pCEATK and Ganciclovir (GCV) sensitivity of the transfected cells were tested in vitro and in vivo . pCEATK expressed only in CEA-producing GL cells but not in non-CEA-producing HeLa cells. The sensitivity to GCV of pCEATK-transfected GL was 992 times higher compared with that of the parental cell line and there was obvious "bystander effect" in vitro. HeLa cells transfected wtih pCEATK were still resistant to GCV. Injection of GCV resulted in significant regression of pCEATK-transfected GL tumors in nude mice. In addition, all mice with any fraction of GL cells expressing HSV-TK exhibited a significant reduction in tumor growth, including

Selective reversal of drug resistance in drug-resistant lung adenocarcinoma cells by tumor-specific expression of MDR1 ribozyme gene mediated by retrovirus

According to the fact that CEA gene expressed only in lung adenocarcinoma and not in normal lung cells, a retroviral vector (pCEAMR) was constructed which carried the CEA promoter coupled to MDR1 ribozyme gene. pCEAMR was introduced into drug-resistant lung adenocarcinoma cells GAOK with CEA expression and HeLaK without CEA expression; the expression of pCEAMR and drug resistance in the infected cells were analyzed in vitro and in vivo ; pCEAMR expressed only in CEA-producing GAOK cells and not in non-CEA-producing HeLa cells. The drug resistance to doxorubicin (DOX) decreased 91.5% in the infected GAOK cells and did not change in the infected HeLa cells. In nude mice, DOX could obviously inhibit the growth of the infected GAOK tumors, and had no effect on the growth of the infected HeLa cells. These results indicated that MDR1 ribozyme gene regulated by CEA promoter expressed only in human adenocarcinoma cells and reversed their drug resistance selectively. This gene-drug therapy might serve as an

Colorectal cancer vaccines: Tumor-associated antigens vs neoantigens

Therapeutic options for the treatment of colorectal cancer(CRC) are diverse but still not always satisfying. Recent success of immune checkpoint inhibition treatment for the subgroup of CRC patients suffering from hypermutated tumors suggests a permanent role of immune therapy in the clinical management of CRC. Substantial improvement in treatment outcome could be achieved by development of efficient patient-individual CRC vaccination strategies. This mini-review summarizes the current knowledge on the two general classes of targets: tumor-associated antigens(TAAs) and tumorspecific antigens. TAAs like carcinoembryonic antigen and melanoma associated antigen are present in and shared by a subgroup of patients and a variety of clinical studies examined the efficacy of different TAA-derived peptide vaccines. Combinations of several TAAs as the next step and the development of personalized TAA-based peptide vaccines are discussed. Improvements of peptidebased vaccines achievable by adjuvants and immunestimulatory chemotherapeutics are highlighted. Finally, we sum up clinical studies using tumor-specific antigens-in CRC almost exclusively neoantigens-which revealed promising results; particularly no severe adverse events were reported so far. Critical progress for clinical outcomes can be expected by individualizing neoantigen-based peptide vaccines and combining them with immunestimulatory chemotherapeutics and immune checkpoint inhibitors. In light of these data and latest developments, truly personalized neoantigen-based peptide vaccines can be expected to fulfill modern precision medicine's requirements and will manifest as treatment pillar for routine clinical management of CRC.

Alpha-fetoprotein-targeted reporter gene expression imaging in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the most common cancers in Eastern Asia, and its incidence is increasing globally. Numerous experimental models have been developed to better our understanding of the pathogenic mechanism of HCC and to evaluate novel therapeutic approaches. Molecular imaging is a convenient and up-to-date biomedical tool that enables the visualization, characterization and quantification of biologic processes in a living subject. Molecular imaging based on reporter gene expression, in particular, can elucidate tumor-specific events or processes by acquiring images of a reporter gene's expression driven by tumor-specific enhancers/promoters. In this review, we discuss the advantages and disadvantages of various experimental HCC mouse models and we present in vivo images of tumorspecific reporter gene expression driven by an alphafetoprotein(AFP) enhancer/promoter system in a mouse model of HCC. The current mouse models of HCC development are established by xenograft, carcinogen induction and genetic engineering, representing the spectrum of tumor-inducing factors and tumor locations. The imaging analysis approach of reporter genes driven by AFP enhancer/promoter is presented for these different HCC mouse models. Such molecular imaging can provide longitudinal information about carcinogenesis and tumor progression. We expect that clinical application of AFP-targeted reporter gene expression imaging systems will be useful for the detection of AFP-expressing HCC tumors and screening of increased/decreased AFP levels due to disease or drug treatment.

A novel therapeutic vaccine based on graphene oxide nanocomposite for tumor immunotherapy

With an intensive understanding of the mechanism of immune system,developing a therapeutic tumor vaccine is one of the most perspective strategy of cancer immunotherapy.In this study,we report a facile approach to prepare graphene oxide(GO)-based therapeutic cancer-nanovaccine.The model antigen(ovalbumin,OVA)and adjuvant(CpG ODN),are conjugated with GO-PEI nanosheet through electrostatic interaction.The addition of PEG can improve biocompatibility and prevent nanoparticle aggregation.The prepared GO-based nanovaccine,GO-PEI-OVA-PEG-CpG,exhibits good biocompatibility and low toxicity both in vivo and in vitro.More importantly,it can efficiently induce the maturation of dendritic cells(DCs),the enhancement of antigen cross-presentation ability,and the amplification of cytokine production of immune cells.Impressively,this nanovaccine shows a remarkable therapeutic effect against preestablished B16-OVA-melanoma tumors,which can significantly inhibit tumor growth and prolong the survival time of the OVA-expressed tumor-bearing mice.Moreover,combining GO-PEI-OVA-PEG-CpG with NLG919,an IDO-1(indoleamine-2,3-dioxygenase)inhibitor which can regulate the tumor microenvironment,displays a synergistic therapeutic effect.These findings indicate the GO-PEI-OVA-PEG-CpG nanovaccine actively induces an antigen-specific antitumor immune response and it combined with NLG919 could achieve better therapeutic outcomes.

Fluorescence-guided hepatobiliary surgery with long and short wavelength fluorophores

Importance:Fluorescence-guided surgery(FGS)is a potentially powerful tool for hepatobiliary(HPB)surgery.The high sensitivity of fluorescence navigation is especially useful in settings where tactile feedback is limited.Objective:The present narrative review evaluates literature on the use of FDA-approved fluorophores such as methylene blue(MB),5-aminolevulinic acid(5-ALA),and indocyanine green(ICG)for clinical intra-operative image-guidance during HPB surgery.Evidence Review:Approaches such as dosing,timing,imaging devices and comparative endpoints are summarized.The feasibility and safety of fluorophores in visualizing the biliary tree,identify biliary leaks,outline anatomic hepatic segments,identify tumors,and evaluate perfusion and graft function in liver transplants are discussed.Findings:Tumor-specific probes are a promising advancement in FGS with a greater degree of specificity.The current status of tumor-specific probes being evaluated in clinical trials are summarized.Conclusions and Relevance for Reviews:Relevant discussion of promising tumor-specific probes in pre-clinical development are discussed.Fluorescence-guidance in HPB surgery is relatively new,but current literature shows that the dyes are reliably able to outline desired structures with a variety of dosing,timing,and imaging devices to provide real-time intra-operative anatomic information to surgeons.Development of tumor-specific probes will further advance the field of HPB surgery especially during oncologic resections.

Fluorescent traceable nanoparticles by co-self-assembly of carbon dot-drug conjugate and biodegradable hyperbranched polymer for diagnosis and therapy

Carbon dots(CDs)have attracted more interest in tumor theranostics,but they suffer from the rapid renal clearance due to small size and high hydrophilicity.To solve such problems,hydrophobic pH-triggered carbon dot-drug conjugate(CDs-Hy-DOX)with high doxorubicin(DOX)content of 48.23%were designed by covalent conjugation of DOX onto the CDs via acid-labile linkage with hydrazine(Hy)as bridge.Then the fluorescent traceable hybrid prodrug nanoparticles were fabricated via co-self-assembly with the CDs-Hy-DOX as pH-sensitive prodrug and a pH/reduction dual-triggered degradable hyperbranched polymer PEG-PO-Cy as polyethylene glycol(PEG)-based surfactant,as well as gatekeeper for pH/reduction dual-triggered DOX release.The hybrid prodrug nanoparticles with hydrodynamic diameter of 220 nm and DOX content of 22.99%were obtained with the optimized co-self-assembling condition.They could release 68.98%of DOX in the simulated tumor microenvironment within 3 days in a sustained release mode,with a premature drug leakage of 7.58%.After the acid-triggered DOX release from the CDs-Hy-DOX,which was accelerated by the pH/reduction dual-triggered degradation of the hyperbranched polymer,the strong fluorescence of CDs-Hy was recovered,demonstrating the promising potential in future tumor nanotheranostics.

非小细胞肺癌患者外周血循环肿瘤细胞与临床病理特征和血清CEA、NSE、Cyfra21-1、pro-GRP的关系分析

目的:研究非小细胞肺癌(NSCLC)患者外周血循环肿瘤细胞(CTC)与临床病理特征及血清癌胚抗原(CEA)、神经元特异性烯醇化酶(NSE)、细胞角蛋白21-1(Cyfra21-1)、胃泌素释放肽前体(pro-GRP)的关系。方法:将中山大学附属江门医院从2018年1月~2021年1月收治的100例NSCLC患者纳入研究组,另选取同期我院收治的肺部良性病变患者50例作为对照组。检测并比较两组CTC计数及血清CEA、NSE、Cyfra21-1、pro-GRP水平,分析NSCLC患者外周血CTC与临床病理特征和血清CEA、NSE、Cyfra21-1、pro-GRP水平的关系。此外,通过受试者工作特征(ROC)曲线分析外周血CTC和血清CEA、NSE、Cyfra21-1、pro-GRP诊断NSCLC的效能。结果:研究组外周血CTC计数及血清CEA、NSE、Cyfra21-1、pro-GRP水平均高于对照组,差异有统计学意义(P<0.05)。Pearson相关性分析结果显示:NSCLC患者外周血CTC计数和血清CEA、NSE、Cyfra21-1、pro-GRP水平均呈正相关(P<0.05)。TNM分期为Ⅲ~Ⅳ期、有吸烟史的NSCLC患者CTC阳性比例明显高于TNM分期为Ⅰ~Ⅱ期、无吸烟史的NSCLC患者(P<0.05)。ROC曲线分析结果显示:CTC计数及血清CEA、NSE、Cyfra21-1、pro-GRP水平联合检测诊断NSCLC的曲线下面积最大。结论:NSCLC患者外周血CTC计数升高,与血清CEA、NSE、Cyfra21-1、pro-GRP水平均存在相关性,且CTC阳性与NSCLC恶性进展和患者吸烟史有关,联合检测上述指标诊断NSCLC可获得较为理想的效能。