Exosome-based anticancer vaccines: From Bench to bedside.

Exosomes, a subset of extracellular vesicles, are released by all active cells and play a crucial role in intercellular communications. Exosomes could facilitate the transfer of various biologically active molecules, such as DNA, non-coding RNAs, and proteins, from donor to recipient cells, thereby participating in diverse biological and pathological processes. Besides, exosomes possess unique characteristics, including non-toxicity, low-immunogenicity, and stability within biological systems, rendering them highly advantageous for cancer drug development. Meanwhile, accumulating evidence suggests that exosomes originating from tumor cells and immune cells possess distinct composition profiles that play a direct role in anticancer immunotherapy. Of note, exosomes can transport their contents to specific cells, thereby exerting an impact on the phenotype and immune-regulatory functions of targeted cells. Therapeutic cancer vaccines, an emerging therapeutics of immunotherapy, could enhance antitumor immune responses by delivering a large number of tumor antigens, thereby augmenting the immune response against tumor cells. Therefore, the therapeutic rationale of cancer vaccines and exosome-based immunotherapy are almost similar to some extent, but some challenges have hindered their application in the clinical setting. Here, in this review, we first summarized the biogenesis, structure, compositions, and biological functions of exosomes. Then we described the roles of exosomes in cancer biology, particularly in tumor immunity. We also comprehensively reviewed current exosome-based anticancer vaccine development and we divided them into three types. Finally, we give some insights into clinical translation and clinical trial progress of exosome-based anticancer vaccines for future direction.

Nanoparticle drug delivery system for the treatment of brain tumors: Breaching the blood-brain barrier.

The current status of clinical trials utilizing nanoparticle drug delivery system (NDDS) for brain tumors was summarized.Image 1.

Identification of the Efficient Enhancer Elements in FVIII-Padua for Gene Therapy Study of Hemophilia A.

Hemophilia A (HA) is a common X-linked recessive hereditary bleeding disorder. Coagulation factor VIII (FVIII) is insufficient in patients with HA due to the mutations in the F8 gene. The restoration of plasma levels of FVIII via both recombinant B-domain-deleted FVIII (BDD-FVIII) and B-domain-deleted F8 (BDDF8) transgenes was proven to be helpful. FVIII-Padua is a 23.4 kb tandem repeat mutation in the F8 associated with a high F8 gene expression and thrombogenesis. Here we screened a core enhancer element in FVIII-Padua for improving the F8 expression. In detail, we identified a 400 bp efficient enhancer element, C400, in FVIII-Padua for the first time. The core enhancer C400 extensively improved the transcription of BDDF8 driven by human elongation factor-1 alpha in HepG2, HeLa, HEK-293T and induced pluripotent stem cells (iPSCs) with different genetic backgrounds, as well as iPSCs-derived endothelial progenitor cells (iEPCs) and iPSCs-derived mesenchymal stem cells (iMSCs). The expression of FVIII protein was increased by C400, especially in iEPCs. Our research provides a novel molecular target to enhance expression of FVIII protein, which has scientific value and application prospects in both viral and nonviral HA gene therapy strategies.

TGF-ß phospho antibody array identifies altered SMAD2, PI3K/AKT/SMAD, and RAC signaling contribute to the pathogenesis of myxomatous mitral valve disease.

Background: TGFß signaling appears to contribute to the pathogenesis of myxomatous mitral valve disease (MMVD) in both dogs and humans. However, little is known about the extent of the downstream signaling changes that will then affect cell phenotype and function in both species. Objective: Identify changes in downstream signals in the TGFß pathway in canine MMVD and examine the effects of antagonism of one significant signal (SMAD2 was selected). Materials and methods: Canine cultures of normal quiescent valve interstitial cells (qVICs) and disease-derived activated myofibroblasts (aVICs) (n = 6) were examined for TGFß signaling protein expression using a commercial antibody array. Significant changes were confirmed, and additional proteins of interest downstream in the TGFß signaling pathway and markers of cell phenotype were examined (PRAS40, S6K, elF4E IRS-1, αSMA, and VIM), using protein immunoblotting. RT-PCR examined expression of gene markers of VIC activation (ACTA2, TAGLN, and MYH10; encoding the proteins αSMA, SM22, and Smemb, respectively). Attenuation of pSMAD2 in aVICs was examined using a combination of RNA interference technology (siRNA) and the SMAD7 (antagonizes SMAD2) agonist asiaticoside. Results: The antibody array identified significant changes (P < 0.05) in 19 proteins, of which six were phosphorylated (p). There was increased expression of pSMAD2 and pRAC1 and decreased expression of pmTOR, pERK1/2, and pAKT1. Expression of pPRAS40 and pIRS-1 was increased, as was the mTOR downstream transcription factor pS6K, with increased expression of peIF4E in aVICs, indicating negative feedback control of the PI3K/AKT/mTOR pathway. SMAD2 antagonism by siRNA and the SMAD7 agonist asiaticoside decreased detection of pSMAD by at least 50%, significantly decreased expression of the aVIC gene markers ACTA2, TAGLN, and MYH10, and pαSMA, pAKT2, and pERK1, but had no effect on pS6K, pERK2, or pVIM expression in aVICs. SMAD2 antagonism transitioned diseased aVICs to normal qVICs, while maintaining a mesenchymal phenotype (VIM+) while concurrently affecting non-canonical TGFß signaling. Conclusion: MMVD is associated with changes in both the canonical and non-canonical TGFß signaling pathway. Antagonism of SMAD2 transitions diseased-activated myofibroblasts back to a normal phenotype, providing data that will inform studies on developing novel therapeutics to treat MMVD in dogs and humans.

Adverse events of PD-(L)1 inhibitors plus anti-VEGF(R) agents compared with PD-(L)1 inhibitors alone for cancer patients: a systematic review and meta-analysis.

Background: Anti-PD-(L)1 antibody monotherapy or in combination with VEGF(R) blockade has been applied widely for cancer treatment. Whether combination therapy increases irAEs still remains controversial. Methods: A systematic review and meta-analysis comparing PD-(L)1 and VEGF(R) blockade combination therapy with PD-(L)1 inhibitors alone was performed. Phase II or III randomized clinical trials reporting irAEs or trAEs were included. The protocol was registered with PROSPERO, CRD42021287603. Results: Overall, 77 articles were included in the meta-analysis. A total of 31 studies involving 8,638 participants were pooled and an incidence for PD-(L)1 inhibitor monotherapy with any grade and grade ≥3 irAEs of 0.25 (0.20, 0.32) and 0.06 (0.05, 0.07), respectively, were reported. Two studies with 863 participants pooled for PD-(L)1 and VEGF(R) blockade showed that an incidence of any grade and grade ≥3 irAEs were 0.47 (0.30, 0.65) and 0.11 (0.08, 0.16), respectively. Regarding pairwise comparisons for irAEs, only one study was included, indicating no significant difference between the two regimens in terms of colitis, hyperthyroidism, and hypothyroidism for any grade and grade ≥3, while there was a trend of higher incidence for any grade hyperthyroidism under the combination therapy. The incidence of reactive cutaneous capillary endothelial proliferation (RCCEP) was as high as 0.80 under camrelizumab monotherapy. Conclusion: Total incidences of any grade and grade ≥3 irAEs were higher in the combination treatment group. Direct comparisons indicated no significant difference between the two regimens for any grade and grade ≥3 specific irAEs. RCCEP and thyroid disorders need to be paid attention to clinically. Moreover, trials with direct comparisons are needed and the safety profiles of the two regimens should be further explored. Exploration of the mechanism of action and regulatory management of adverse events should be enhanced. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=287603, identifier CRD42021287603.

CRISPR-Mediated In Situ Introduction or Integration of F9-Padua in Human iPSCs for Gene Therapy of Hemophilia B.

Hemophilia B (HB) is an X-linked recessive disease caused by F9 gene mutation and functional coagulation factor IX (FIX) deficiency. Patients suffer from chronic arthritis and death threats owing to excessive bleeding. Compared with traditional treatments, gene therapy for HB has obvious advantages, especially when the hyperactive FIX mutant (FIX-Padua) is used. However, the mechanism by which FIX-Padua works remains ambiguous due to a lack of research models. Here, in situ introduction of F9-Padua mutation was performed in human induced pluripotent stem cells (hiPSCs) via CRISPR/Cas9 and single-stranded oligodeoxynucleotides (ssODNs). The hyperactivity of FIX-Padua was confirmed to be 364% of the normal level in edited hiPSCs-derived hepatocytes, providing a reliable model for exploring the mechanism of the hyperactivity of FIX-Padua. Moreover, the F9 cDNA containing F9-Padua was integrated before the F9 initiation codon by CRISPR/Cas9 in iPSCs from an HB patient (HB-hiPSCs). Integrated HB-hiPSCs after off-target screening were differentiated into hepatocytes. The FIX activity in the supernatant of integrated hepatocytes showed a 4.2-fold increase and reached 63.64% of the normal level, suggesting a universal treatment for HB patients with various mutations in F9 exons. Overall, our study provides new approaches for the exploration and development of cell-based gene therapy for HB.

Rare tumors: a blue ocean of investigation.

Advances in novel drugs, therapies, and genetic techniques have revolutionized the diagnosis and treatment of cancers, substantially improving cancer patients' prognosis. Although rare tumors account for a non-negligible number, the practice of precision medicine and development of novel therapies are largely hampered by many obstacles. Their low incidence and drastic regional disparities result in the difficulty of informative evidence-based diagnosis and subtyping. Sample exhaustion due to difficulty in diagnosis also leads to a lack of recommended therapeutic strategies in clinical guidelines, insufficient biomarkers for prognosis/efficacy, and inability to identify potential novel therapies in clinical trials. Herein, by reviewing the epidemiological data of Chinese solid tumors and publications defining rare tumors in other areas, we proposed a definition of rare tumor in China, including 515 tumor types with incidences of less than 2.5/100 000 per year. We also summarized the current diagnosis process, treatment recommendations, and global developmental progress of targeted drugs and immunotherapy agents on the status quo. Lastly, we pinpointed the current recommendation chance for patients with rare tumors to be involved in a clinical trial by NCCN. With this informative report, we aimed to raise awareness on the importance of rare tumor investigations and guarantee a bright future for rare tumor patients.

TGF-ß-induced PI3K/AKT/mTOR pathway controls myofibroblast differentiation and secretory phenotype of valvular interstitial cells through the modulation of cellular senescence in a naturally occurring in vitro canine model of myxomatous mitral valve disease.

PI3K/AKT/mTOR signalling contributes to several cardiovascular disorders. The aim of this study was to examine the PI3K/AKT/mTOR pathway in myxomatous mitral valve disease (MMVD). Double-immunofluorescence examined expression of PI3K and TGF-ß1 in canine valves. Valve interstitial cells (VICs) from healthy or MMVD dogs were isolated and characterized. Healthy quiescent VICs (qVICs) were treated with TGF-ß1 and SC-79 to induce activated myofibroblast phenotypes (aVICs). Diseased valve-derived aVICs were treated with PI3K antagonists and expression of RPS6KB1 (encoding p70 S6K) was modulated using siRNA and gene overexpression. SA-ß-gal and TUNEL staining were used to identify cell senescence and apoptosis, and qPCR and ELISA to examine for senescence-associated secretory phenotype. Protein immunoblotting was used to examine expression of phosphorylated and total proteins. TGF-ß1 and PI3K are highly expressed in mitral valve tissues. Activation of PI3K/AKT/mTOR and increased expression of TGF-ß are found in aVICs. TGF-ß transitions qVICs to aVICs by upregulation of PI3K/AKT/mTOR. Antagonism of PI3K/AKT/mTOR reverses aVIC myofibroblast transition by inhibiting senescence and promoting autophagy. Upregulation of mTOR/S6K induces transformation of senescent aVICs, with reduced capacity for apoptosis and autophagy. Selective knockdown of p70 S6K reverses cell transition by attenuating cell senescence, inhibiting apoptosis and improving autophagy. TGF-ß-induced PI3K/AKT/mTOR signalling contributes to MMVD pathogenesis and plays crucial roles in the regulation of myofibroblast differentiation, apoptosis, autophagy and senescence in MMVD.

p53 Regulates Mitochondrial Dynamics in Vascular Smooth Muscle Cell Calcification.

Arterial calcification is an important characteristic of cardiovascular disease. It has key parallels with skeletal mineralization; however, the underlying cellular mechanisms responsible are not fully understood. Mitochondrial dynamics regulate both bone and vascular function. In this study, we therefore examined mitochondrial function in vascular smooth muscle cell (VSMC) calcification. Phosphate (Pi)-induced VSMC calcification was associated with elongated mitochondria (1.6-fold increase, p < 0.001), increased mitochondrial reactive oxygen species (ROS) production (1.83-fold increase, p < 0.001) and reduced mitophagy (9.6-fold decrease, p < 0.01). An increase in protein expression of optic atrophy protein 1 (OPA1; 2.1-fold increase, p < 0.05) and a converse decrease in expression of dynamin-related protein 1 (DRP1; 1.5-fold decrease, p < 0.05), two crucial proteins required for the mitochondrial fusion and fission process, respectively, were noted. Furthermore, the phosphorylation of DRP1 Ser637 was increased in the cytoplasm of calcified VSMCs (5.50-fold increase), suppressing mitochondrial translocation of DRP1. Additionally, calcified VSMCs showed enhanced expression of p53 (2.5-fold increase, p < 0.05) and ß-galactosidase activity (1.8-fold increase, p < 0.001), the cellular senescence markers. siRNA-mediated p53 knockdown reduced calcium deposition (8.1-fold decrease, p < 0.01), mitochondrial length (3.0-fold decrease, p < 0.001) and ß-galactosidase activity (2.6-fold decrease, p < 0.001), with concomitant mitophagy induction (3.1-fold increase, p < 0.05). Reduced OPA1 (4.1-fold decrease, p < 0.05) and increased DRP1 protein expression (2.6-fold increase, p < 0.05) with decreased phosphorylation of DRP1 Ser637 (3.20-fold decrease, p < 0.001) was also observed upon p53 knockdown in calcifying VSMCs. In summary, we demonstrate that VSMC calcification promotes notable mitochondrial elongation and cellular senescence via DRP1 phosphorylation. Furthermore, our work indicates that p53-induced mitochondrial fusion underpins cellular senescence by reducing mitochondrial function.

Targeting rare tumors: new focus for clinical research in China.

Rare tumor has a huge unmet medical need without standard regimens, calling for novel therapeutic interventions. The National Cancer Center of China identified a threshold of incidence for rare tumor as 2.5/100,000, based on the characteristics of Chinese population. Molecular profiles for rare tumor patients in China further provided prospects for precise and individualized targeted treatment. An ongoing phase II clinical trial, the PLATFORM study, is the first trial tailored for rare solid tumors in China, featured by molecule-guided therapeutics. With the promulgation of supportive policies to encourage the development of innovative drugs for rare tumors in China, opportunities will be provided for these patients and the gap will be filled in the treatment of rare tumors.

The reliability and integrity of overall survival data based on follow-up records only and potential solutions to the challenges.

Overall survival (OS) is considered the standard clinical endpoint to support effectiveness claims in new drug applications globally, particularly for lethal conditions such as cancer. However, the source and reliability of OS in the setting of clinical trials have seldom been doubted and discussed. This study first raised the common issue that data integrity and reliability are doubtful when we collect OS information or other time-to-event endpoints based solely on simple follow-up records by investigators without supporting material, especially since the 2019 COVID-19 pandemic. Then, two rounds of discussions with 30 Chinese experts were held and 12 potential source scenarios of three methods for obtaining the time of death of participants, including death certificate, death record and follow-up record, were sorted out and analysed. With a comprehensive assessment of the 12 scenarios by legitimacy, data reliability, data acquisition efficiency, difficulty of data acquisition, and coverage of participants, both short-term and long-term recommended sources, overall strategies and detailed measures for improving the integrity and reliability of death date are presented. In the short term, we suggest integrated sources such as public security systems made available to drug inspection centres appropriately as soon as possible to strengthen supervision. Death certificates provided by participants' family members and detailed standard follow-up records are recommended to investigators as the two channels of mutual compensation, and the acquisition of supporting materials is encouraged as long as it is not prohibited legally. Moreover, we expect that the sharing of electronic medical records and the legal disclosure of death records in established health registries can be realized with the joint efforts of the whole industry in the long-term. The above proposed solutions are mainly based on the context of China and can also provide reference for other countries in the world.

Drug conjugate-based anticancer therapy - Current status and perspectives.

Drug conjugates are conjugates comprising a tumor-homing carrier tethered to a cytotoxic agent via a linker that are designed to deliver an ultra-toxic payload directly to the target cancer cells. This strategy has been successfully used to increase the therapeutic efficacy of cytotoxic agents and reduce their toxic side effects. Drug conjugates are being developed worldwide, with the potential to revolutionize current cancer treatment strategies. Antibody-drug conjugates (ADCs) have developed rapidly, and 14 of them have received market approval since the first approval event by the Food and Drug Administration in 2000. However, there are some limitations in the use of antibodies as carriers. Other classes of drug conjugates are emerging, such as targeted drugs conjugated with peptides (peptide-drug conjugates, PDCs) and polymers (polymer-drug conjugates, PolyDCs) with the remaining constructs similar to those of ADCs. These novel drug conjugates are gaining attention because they overcome the limitations of ADCs. This review summarizes the current state and advancements in knowledge regarding the design, constructs, and clinical efficacy of different drug conjugates.

Breaking boundaries: Current progress of anticancer NK cell-based drug development.

Natural killer (NK) cell therapy is emerging as a cancer treatment. NK cells are innate cytotoxic lymphocytes that act as first-line responders to kill target cells without prior encounters. NK cells recognize cancer cells, virus-infected cells, and other types of stressed cell through a reservoir of germline-encoded receptors. NK cells are safe for allogeneic applications. Therefore, they are the ideal off-the-shelf cell, which overcome the low efficiency issue caused by the patient-by-patient nature of autologous cell therapy. Unlike T cells, NK cells cannot form a strong immune memory; therefore, they suffer from short in vivo persistence. However, different from T cells, NK cells have a reservoir of innate immune receptors targeting a variety of malignant cells. In addition, they can utilize antibody guidance in target recognition. With suitable engineering, NK cells can function as universal anticancer drugs that are not restricted to HLA and cancer types, which will benefit the large cohort of patients with rare cancer types and patients with no convenient drug targets for precision and personalized medicine. Here, we summarize and discuss the designs of current anticancer NK cell therapies.

Metformin protects against vascular calcification through the selective degradation of Runx2 by the p62 autophagy receptor.

Vascular calcification is associated with aging, type 2 diabetes, and atherosclerosis, and increases the risk of cardiovascular morbidity and mortality. It is an active, highly regulated process that resembles physiological bone formation. It has previously been established that pharmacological doses of metformin alleviate arterial calcification through adenosine monophosphate-activated protein kinase (AMPK)-activated autophagy, however the specific pathway remains elusive. In the present study we hypothesized that metformin protects against arterial calcification through the direct autophagic degradation of runt-related transcription factor 2 (Runx2). Calcification was blunted in vascular smooth muscle cells (VSMCs) by metformin in a dose-dependent manner (0.5-1.5 mM) compared to control cells (p < 0.01). VSMCs cultured under high-phosphate (Pi) conditions in the presence of metformin (1 mM) showed a significant increase in LC3 puncta following bafilomycin-A1 (Baf-A; 5 nM) treatment compared to control cells (p < 0.001). Furthermore, reduced expression of Runx2 was observed in the nuclei of metformin-treated calcifying VSMCs (p < 0.0001). Evaluation of the functional role of autophagy through Atg3 knockdown in VSMCs showed aggravated Pi-induced calcification (p < 0.0001), failure to induce autophagy (punctate LC3) (p < 0.001) and increased nuclear Runx2 expression (p < 0.0001) in VSMCs cultured under high Pi conditions in the presence of metformin (1 mM). Mechanistic studies employing three-way coimmunoprecipitation with Runx2, p62, and LC3 revealed that p62 binds to both LC3 and Runx2 upon metformin treatment in VSMCs. Furthermore, immunoblotting with LC3 revealed that Runx2 specifically binds with p62 and LC3-II in metformin-treated calcified VSMCs. Lastly, we investigated the importance of the autophagy pathway in vascular calcification in a clinical setting. Ex vivo clinical analyses of calcified diabetic lower limb artery tissues highlighted a negative association between Runx2 and LC3 in the vascular calcification process. These studies suggest that exploitation of metformin and its analogues may represent a novel therapeutic strategy for clinical intervention through the induction of AMPK/Autophagy Related 3 (Atg3)-dependent autophagy and the subsequent p62-mediated autophagic degradation of Runx2.

The Role of Transforming Growth Factor-ß Signaling in Myxomatous Mitral Valve Degeneration.

Mitral valve prolapse (MVP) due to myxomatous degeneration is one of the most important chronic degenerative cardiovascular diseases in people and dogs. It is a common cause of heart failure leading to significant morbidity and mortality in both species. Human MVP is usually classified into primary or non-syndromic, including Barlow's Disease (BD), fibro-elastic deficiency (FED) and Filamin-A mutation, and secondary or syndromic forms (typically familial), such as Marfan syndrome (MFS), Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Despite different etiologies the diseased valves share pathological features consistent with myxomatous degeneration. To reflect this common pathology the condition is often called myxomatous mitral valve degeneration (disease) (MMVD) and this term is universally used to describe the analogous condition in the dog. MMVD in both species is characterized by leaflet thickening and deformity, disorganized extracellular matrix, increased transformation of the quiescent valve interstitial cell (qVICs) to an activated state (aVICs), also known as activated myofibroblasts. Significant alterations in these cellular activities contribute to the initiation and progression of MMVD due to the increased expression of transforming growth factor-ß (TGF-ß) superfamily cytokines and the dysregulation of the TGF-ß signaling pathways. Further understanding the molecular mechanisms of MMVD is needed to identify pharmacological manipulation strategies of the signaling pathway that might regulate VIC differentiation and so control the disease onset and development. This review briefly summarizes current understanding of the histopathology, cellular activities, molecular mechanisms and pathogenesis of MMVD in dogs and humans, and in more detail reviews the evidence for the role of TGF-ß.

KRAS Mutation in Rare Tumors: A Landscape Analysis of 3453 Chinese Patients.

KRAS is the most commonly mutated oncogene in human cancers. Targeted therapy and immunotherapy for this gene have made remarkable progress in recent years. However, comprehensive molecular landscape analysis of KRAS in rare tumors is lacking. Retrospective analysis was performed on clinical samples from patients with rare tumors collected between September 2015 and September 2021, using hybrid-capture-based next-generation sequencing for genomic profiling and immunohistochemistry assay for PD-L1. Of the 3,453 patients included in analysis, KRAS mutations were identified in 8.7% patients in overall; mutation rate and mutation subtypes varied widely across tumor systems and subtypes. KRAS mutations included 21 missense mutations, of which G12D (29.2%), G12V (24.6%), and G13D (10.8%) were most common. Interestingly, KRAS G12C was observed in 0.6% patients overall, and in 5.7% of sarcomatoid carcinoma of the lung and 5.4% of clear cell ovarian cancer tumors, but none in small-bowel cancer tumors. 31.8% KRAS mutations and 36.4% KRAS G12C mutations co-occurred with other targetable alterations. No significant correlation was observed between TMB-H, MSI-H, PD-L1 status, and KRAS mutation status, which may be related to the high proportion of G12D. This study is the first KRAS mutation landscape study in rare tumors of large sample size in China and worldwide. Our results suggest that targeted therapy and immunotherapy are both feasible, albeit complex, in these patients. This information may have significant impact on the operation of clinical trials for rare tumor patients with KRAS mutations in China.

Landscape and perspectives of macrophage -targeted cancer therapy in clinical trials.

Tumor-associated macrophages (TAMs) exert integrated effects in all aspects of tumor progression, including tumor cell proliferation, angiogenesis, invasion, and metastasis. Recently, considerable preclinical and clinical trials have demonstrated that TAM-targeted therapy is an effective antitumor therapeutic approach, especially as a complementary strategy in combination with conventional chemotherapy, radiotherapy, or emerging immunotherapy. Here, we review all of the current clinical trials targeting TAMs worldwide up to May 2021 and highlight instances of the synergetic therapeutic efficacy of TAM-targeted combined therapeutic strategies. In total, 606 clinical trials were conducted, including 143 tested products. There has been explosive growth in macrophage-targeted therapy around the world during the past decade. Most trials were at early phase, and two-thirds used macrophage-targeting therapy as part of a combination approach. The most common combination is that of traditional chemotherapy with TAM-targeted therapy, followed by immune checkpoint inhibitors and targeted drugs. TAM-targeted therapeutic approaches are a newly emerging but rapidly developing area of anticancer therapy, especially as a combinatorial therapeutic approach. Further investigation of promising combination strategies will pave the way to more effective anticancer therapies.

CEA-regulated Oncolytic Virus Anticancer Therapy: A Promising Strategy for Rare Solid Tumors.

BACKGROUND: Rare solid tumors have attracted much more attention due to the great unmet clinical need, limited treatment options, and poor prognosis. As the most thoroughly studied tumor marker, carcinoembryonic antigen (CEA) can not only overexpress in various common solid tumors but also in several rare solid tumors. Oncolytic virus therapy has achieved excellent anticancer effects in the past decades. Due to the specific high expression of CEA in certain tumor tissues but not in normal tissues, CEA has been applied to improve the tumor specificity of gene expression. METHODS: The studies of CEA expression in rare solid tumors and CEA-regulated oncolytic virus therapy were reviewed. RESULTS: We showed the types of rare solid tumors with the overexpression of CEA. Elevated serum CEA levels can indicate the diagnosis, response of surgery or system therapy, distal metastasis, recurrence, and survival. Due to high tumor specificity, CEA-regulated OA therapy has demonstrated a surprising antitumor effect for common CEA-positive tumors in preclinical trials. CONCLUSION: These data suggested that CEA could be a diagnostic and prognostic biomarker for several rare solid tumors. We proposed the hypothesis that CEA-regulated oncolytic virus therapy could be a promising therapeutic strategy for CEA-positive rare solid tumors.