Therapy For Gastrointestinal Cancers Research Articles

Current State of Cell Therapies for Gastrointestinal Cancers.

Adoptive cell therapies include multiple cell-based therapies to harness the immune system's power to mount a robust anticancer effect. Early successes in solid tumors with checkpoint inhibition have increased the research and development of immunotherapy. The utilization of cell-based therapy for gastrointestinal malignancies is still in its infancy because of challenges of antigen specificity and access to the tumor microenvironment. In this review, we discuss the current state of adoptive cell therapies in terms of challenges and early successes in preclinical and clinical studies.

Nanotechnology in diagnosis and therapy of gastrointestinal cancer.

Advances in nanotechnology have opened new frontiers in the diagnosis and treatment of cancer. Nanoparticle-based technology improves the precision of tumor diagnosis when combined with imaging, as well as the accuracy of drug target delivery, with fewer side effects. Optimized nanosystems have demonstrated advantages in many fields, including enhanced specificity of detection, reduced toxicity of drugs, enhanced effect of contrast agents, and advanced diagnosis and therapy of gastrointestinal (GI) cancers. In this review, we summarize the current nanotechnologies in diagnosis and treatment of GI cancers. The development of nanotechnology will lead to personalized approaches for early diagnosis and treatment of GI cancers.

Proton Therapy in the Management of Pancreatic Cancer.

Simple SummaryRadiation treatment plays a pivotal a role in the management of pancreatic cancer, mainly in the neoadjuvant setting for borderline resectable tumors and in the definitive setting for unresectable localized disease. Most of the studies on pancreatic cancer use photon-based radiation therapy modalities. However, there is a growing interest in the application of protons therapy for gastrointestinal cancers. This review summarizes the literature on the use of proton therapy in the management of pancreatic cancer. Radiation therapy plays a central role in the treatment of pancreatic cancer. While generally shown to be feasible, proton irradiation, particularly when an ablative dose is planned, remains a challenge, especially due to tumor motion and the proximity to organs at risk, like the stomach, duodenum, and bowel. Clinically, standard doses of proton radiation treatment have not been shown to be statistically different from photon radiation treatment in terms of oncologic outcomes and toxicity rates as per non-randomized comparative studies. Fractionation schedules and concurrent chemotherapy combinations are yet to be optimized for proton therapy and are the subject of ongoing trials.

TACH101, a first-in-class pan-inhibitor of KDM4 for treatment of gastrointestinal cancers.

132 Background: TACH101 is a novel, potent small molecule inhibitor of KDM4, a novel epigenetic target for cancer therapy. KDM4 is a family of histone lysine demethylases that, when overexpressed, drives key processes linked to cancer. Validation of KDM4 as a driver gene was confirmed across gastrointestinal tumor types including esophageal, colon and gastric cancers, and is associated with formation of aggressive tumors. Methods: TACH101 was evaluated in in vitro and in vivo studies including cell inhibition assays, patient-derived xenograft (PDX) and organoid models, and bioinformatics analyses studies. Results: In vitro, TACH101 treatment potently inhibited cell proliferation in cell lines and organoid models representing esophageal, CRC, and gastric cancers. TACH101 induced apoptosis in human CRC (HT-29) and esophageal (KYSE-150) cancer cell lines (EC50s 0.033 - 0.092 µM). Further evaluation using a panel of > 300 cell lines from different tumor types showed potent activity of TACH101 against gastric cancer and CRC. In gastric cancer, 2D cell viability inhibition assays conducted on a panel of 11 gastric cancer cell lines showed 9/11 (82%) were sensitive to TACH101 treatment (IC50 0.004 - 0.072 µM); in PDX models, 4/5 (80%) were sensitive to TACH101 treatment (IC50 0.007 - 0.039 µM). In CRC, bioinformatics analysis indicated increased TACH101 sensitivity in cell lines with MSI-H status (IC50 1-150 nM). Sensitivity of MSI-H CRC to TACH101 was further confirmed in a panel of 14 CRC PDX models and 7 CRC organoid models in culture-based viability inhibition assays. In PDX models, 5/5 (100%) characterized as MSI were sensitive to TACH101 treatment (IC50 0.001 - 0.014 µM), whereas 4/8 (50%) characterized as MSS were sensitive to TACH101 (IC50 0.003 - 0.270 µM). In patient derived CRC organoid models, 3/3 (100%) characterized as MSI were sensitive to TACH101 treatment (IC50 0.022 - 0.149 µM) whereas 0/3 (0%) characterized as MSS were sensitive (IC50 > 10 µM). In vivo, TACH101 triggered effective tumor control (≥70%) in xenograft models of CRC (SU60), esophageal (KYSE-150) and gastric (GXA-3036) cancers. Pharmacologic studies showed TACH101 demonstrated favorable cell permeability, good oral bioavailability, and high metabolic stability. Conclusions: Preclinical work on TACH101 KDM4 inhibitor demonstrates compelling data and applicability as a potential therapy for gastrointestinal cancers. Preparations to advance TACH101 into clinical trials are underway.

CRISPR/Cas9 in Gastrointestinal Malignancies

Gastrointestinal (GI) cancers such as colorectal cancer (CRC), gastric cancer (GC), esophageal cancer (EG), pancreatic duct adenocarcinoma (PDAC) or hepatocellular cancer (HCC) belong to the most commonly diagnosed types of cancer and are among the most frequent causes of cancer related death worldwide. Most types of GI cancer develop in a stepwise fashion with the occurrence of various driver mutations during tumor progression. Understanding the precise function of mutations driving GI cancer development has been regarded as a prerequisite for an improved clinical management of GI malignancies. During recent years, CRISPR/Cas9 has developed into a powerful tool for genome editing in cancer research by knocking in and knocking out even multiple genes at the same time. Within this review, we discuss recent applications for CRISPR/Cas9-based genome editing in GI cancer research including CRC, GC, EG, PDAC and HCC. These applications include functional studies of candidate genes in cancer cell lines or organoids in vitro as well as in murine cancer models in vivo, library screening for the identification of previously unknown driver mutations and even gene therapy of GI cancers.

Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer

BackgroundThe human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer. However, the clinical relevance of germline HLA-mediated immunity in gastrointestinal (GI) cancer remains elusive.MethodsThis study retrospectively analyzed the genomic profiling data from 84 metastatic GI cancer patients treated with immune checkpoint blockade (ICB) recruited from Peking University Cancer Hospital (PUCH). A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was employed as the validation cohort. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood samples from all patients. Tumor tissues from 76 patients were subjected to WES analysis and immune oncology-related RNA profiling. We studied the associations of two parameters of germline HLA as heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) with the clinical outcomes of patients in both cohorts.ResultsOur data showed that neither HLA heterozygosity nor HED at the HLA-A/HLA-C locus correlated with the overall survival (OS) in the PUCH cohort. Interestingly, in both the PUCH and MSK GI cohorts, patients with high HLA-B HED showed a better OS compared with low HLA-B HED subgroup. Of note, a combinatorial biomarker of HLA-B HED and tumor mutational burden (TMB) may better stratify potential responders. Furthermore, patients with high HLA-B HED were characterized with a decreased prevalence of multiple driver gene mutations and an immune-inflamed phenotype.ConclusionsOur results unveil how HLA-B evolutionary divergence influences the ICB response in patients with GI cancers, supporting its potential utility as a combinatorial biomarker together with TMB for patient stratification in the future.

Proliferating cell nuclear antigen clamp associated factor, a potential proto-oncogene with increased expression in malignant gastrointestinal tumors.

Gastrointestinal (GI) cancers, including malignancies in the gastrointestinal tract and accessory organs of digestion, represent the leading cause of death worldwide due to the poor prognosis of most GI cancers. An investigation into the potential molecular targets of prediction, diagnosis, prognosis, and therapy in GI cancers is urgently required. Proliferating cell nuclear antigen (PCNA) clamp associated factor (PCLAF), which plays an essential role in cell proliferation, apoptosis, and cell cycle regulation by binding to PCNA, is a potential molecular target of GI cancers as it contributes to a series of malignant properties, including tumorigenesis, epithelial-mesenchymal transition, migration, and invasion. Furthermore, PCLAF is an underlying plasma prediction target in colorectal cancer and liver cancer. In addition to GI cancers, PCLAF is also involved in other types of cancers and autoimmune diseases. Several pivotal pathways, including the Rb/E2F pathway, NF-κB pathway, and p53-p21 cascade, are implicated in PCLAF-mediated diseases. PCLAF also contributes to some diseases through dysregulation of the p53 pathway, WNT signal pathway, MEK/ERK pathway, and PI3K/AKT/mTOR signal cascade. This review mainly describes in detail the role of PCLAF in physiological status and GI cancers. The signaling pathways involved in PCLAF are also summarized. Suppression of the interaction of PCLAF/PCNA or the expression of PCLAF might be potential biological therapeutic strategies for GI cancers.

Association between oral microflora and gastrointestinal tumors (Review).

The oral cavity contains the highest density and the most species of microorganisms compared with other parts of the body. Recent studies have determined that the species and abundance of oral microflora are closely associated with the development of upper gastrointestinal tumors, including oral, esophageal and gastric cancer. Additionally, differential abundant microbiota in patients with cancer and abnormal microorganisms inside the tumor tissue have been identified as critical markers of tumorigenesis. There is evidence to suggest that certain genera, including Firmicutes, along with various species, such as Porphyromonas, can increase the risk of oral cancer. Furthermore, Porphyromonasgingivalis is a risk factor for esophageal carcinoma, while Helicobacterpylori infections are a main cause of gastric cancer. Currently, as far as carcinogenic mechanisms of oral microorganisms are concerned, it has been hypothesized that the production of carcinogenic substances, chronic inflammation and altered cell metabolisms may be mechanisms by which oral microorganisms influence the development of upper gastrointestinal cancer. Certain phrases, including 'oral microbes', 'oral microorganism', 'oral microbiology', 'oral microflora', 'oral cancer', 'oral carcinoma', 'carcinoma of mouth', 'esophagus cancer', 'esophageal cancer', 'esophageal carcinoma', 'carcinoma of esophagus', 'gastric cancer', 'gastric carcinoma', 'stomach cancer', 'cancer of the stomach', 'carcinogenic mechanism' and 'carcinogenesis', were searched as key words in PubMed and Web of Science for articles published between 1975 to 2020. A total of 1,512 studies were obtained. After further searching the abstracts for key words, such as oral microorganisms, oral cancer, esophagus cancer, gastric cancer and carcinogenic mechanisms, 137 studies were selected. The current review systematically and comprehensively summarized the association between the oral microbiota and oral, esophageal and gastric cancer. Additionally, the current review described the carcinogenic mechanisms of oral microbes and attempted to identify common molecular mechanisms among different types of tumor. The association between upper gastrointestinal cancer therapy and oral microflora was also assessed. The present review may be used as a reference for future diagnosis and therapeutics for upper gastrointestinal tumors.

Future of targeted therapy for gastrointestinal cancer: Claudin 18.2

Abstract The treatment of gastrointestinal cancer has always been a crucial research area, and targeted therapy has been receiving increasing attention. At present, the effect of targeted therapy is unsatisfactory for gastric cancer. Thus, the discovery of new targets is crucial. Claudin 18.2 (CLDN18.2), a member of the claudin family, belongs to the tight junction protein family that controls the flow of molecules between cell layers. CLDN18.2 expression has been discussed in many studies. In recent years, there have been many studies on targeted therapy with CLDN18.2-ideal monoclonal antibody 362. Furthermore, CLDN18.2-specific chimeric antigen receptor T therapy has been used for CLDN18.2-positive tumors, such as gastric and pancreatic cancers. Considerable research has been focused on CLDN18.2. CLDN18.2, a newly discovered marker for precise targeted therapy of gastric cancer, could offer new hope for the treatment of gastric cancer.

Germline HLA-B evolutionary divergence to influence efficacy of immune checkpoint blockade therapy in gastrointestinal cancer.

e16101 Background: To date, although a number of biomarker-related investigations have focused on the intrinsic properties of tumor cells and immune microenvironment, how germline genetics influences efficacy of immune checkpoint inhibitors (ICIs) immunotherapy in gastrointestinal (GI) cancer is scarcely understood. Methods: Our investigation enrolled 94 metastatic GI cancer patients treated with ICIs recruited from Peking University Cancer Hospital (PUCH) between August 1, 2015, and May 24, 2019. A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was used for validation. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood mononuclear cell (PBMC) from all 94 patients. Tumor tissues from 86 patients were subjected to WES analysis and immune oncology-related RNA profiling. Results: We assessed the clinic relevance of germline HLA heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) to immunotherapy in patients with advanced GI cancers from the PUCH cohort. Our data showed that neither HLA heterozygosity nor mean HED correlated with the overall survival (OS) in the PUCH cohort. However, patients with high HLA-B HED showed a better OS and durable clinic benefit (DCB) rate compared with the lower subgroup (p < 0.05 for all comparison). The prognostic value of HLA-B HED was consistently validated in the MSK GI cohort (N = 84). Notably, a combinatorial biomarker based on HLA-B HED and tumor mutation burden (TMB) could better stratify potential responders (86 patients with tumor samples). Survival analysis performed on the PUCH and MSK GI cancer datasets further demonstrated the potential joint utility of HLA-B HED and TMB for prognosis stratification. Moreover, HLA-B HED high subgroup was characterized with a lower prevalence of TP53 mutation and enrichment of multiple immune related pathways, indicating an immune-inflamed phenotype of this subgroup. Conclusions: Taken together, our data create an intriguing argument for the germline HLA-B sequence divergence and TMB as complementary biomarkers in guiding patient selection for GI cancer immunotherapy. Further investigation revealed a potential HLA-B restricted mutational pattern of TP53, and can be indicative of tumor immune microenvironment in GI cancer.

Mesenchymal stem cells as professional actors in gastrointestinal cancer therapy: From Naïve to genetically modified.

Considering the high incidence and mortality rate of gastrointestinal cancers (GIs) worldwide and partial success of the current available GI cancer treatments, there is a necessity to discover more effective approaches in cancer therapy. The failure in conventional therapies seems to be related to the resistance of cancer cells to chemotherapy, inability to target tumor cells especially in metastatic cancers, deficient drug concentrations in tumor sites, and unfavorable effects on pivotal non-malignant bodily tissues following systemic administration. In this context, we need an appropriate carrier for the delivery of therapeutic agents specifically to the GI cancer site. Mesenchymal stem cells (MSCs), a prominent cell-based strategy for cancer treatment, overcome various cancer therapy limitations and could be used as vehicles to deliver many anticancer agents such as therapeutic genes (DNA or interference RNA), oncolytic viruses, and chemotherapeutic or nanoparticle drugs. Moreover, secreted molecules of unmodified MSCs lead to deregulation of several proteins and different signaling pathways eradicating cancer cells. In the present review, at first, we overview the characteristics and utility of MSCs in cancer therapy, secondly, we discuss the application of naïve MSCs and utilization of MSCs in the delivery of therapeutic agents in GI cancer therapy and, finally, more information about harnessing of genetically modified MSCs in GI cancer treatment will be presented.

Value of nutrition support therapy in patients with gastrointestinal malignancies: a narrative review and health economic analysis of impact on clinical outcomes in the United States.

Malnutrition, particularly under-nutrition, is highly prevalent among adult patients with a diagnosis of gastrointestinal (GI) cancer and negatively affects patient outcomes. Malnutrition is associated with clinical and surgical complications for patients undergoing therapy for GI cancers and the costs associated with those complications is a high burden for the US health system. Our objective was to identify high-quality evidence for nutrition support interventions associated with cost savings for patient care, followed by a complex economic value analysis to project cost savings for the US health system. A narrative literature search was conducted in which combined keywords in the areas of therapeutic nutrition (nutrition, malnutrition), a specific therapeutic area [GI cancer (esophageal, gastric, gallbladder, pancreatic, liver/hepatic, small and large intestine, colorectal)], and clinical outcomes and healthcare cost, to look for nutrition interventions that could significantly improve clinical outcomes. Medicare claims data were then analyzed using the findings of these identified studies and this modeling exercise supported identifying the cost and healthcare resource utilization implications of specific populations to determine the impact of nutrition support on reducing these costs as reflected in the summary of the evidence. Eight studies were found that provided clinical outcomes and health cost savings data, 2 of those had the strongest level of evidence and were used for Value Analysis calculations. Nutrition interventions such as oral diet modifications, enteral nutrition (EN) supplementation, and parenteral nutrition (PN) have been studied especially in the peri-operative setting. Specifically, peri-operative immunonutrition administration and utilization of enhanced recovery pathways after surgery have been associated with significant improvement in postoperative complications and decreased length of hospital stay (LOS). Utilizing economic modeling of Medicare claims data from GI cancer patients, potential annual cost savings of $242 million were projected by the widespread adoption of these interventions. Clinical outcomes can be improved with the use of nutrition interventions in patients with GI cancers. Healthcare costs can be reduced as a result of fewer in-hospital complications and shorter lengths of hospital stay. The application of nutrition intervention provides a positive clinical and economic value proposition to the healthcare system for patients with GI cancers.

Use of Molecular Assays and Circulating Tumor DNA in Early-Stage Colorectal Cancer: A Roundtable Discussion of the Gastrointestinal Cancer Therapy Expert Group.

The use of genomic testing is rapidly emerging as an important clinical tool both for cancer diagnosis and for guiding treatment decisions in a wide range of malignancies, including gastrointestinal (GI) cancers such as colorectal cancer (CRC). Advances in technologies such as polymerase chain reaction and next-generation sequencing methods have made it possible to noninvasively screen for CRC through, for example, the use of blood- or stool-based testing, with high specificity. Tests are also available that can provide prognostic information beyond traditional clinicopathologic factors such as tumor size, grade, and nodal status, which can enable clinicians to more accurately risk stratify patients for recurrence. Lastly, in the setting of resected CRC, tests are now available that can detect circulating tumor DNA as a means for noninvasive minimal/molecular residual disease monitoring, thereby potentially guiding the use of adjuvant chemotherapy and/or escalating or de-escalating therapy. The Gastrointestinal Cancer Therapy Expert Group (GICTEG) recently convened a virtual meeting to discuss current issues related to genomic testing in GI cancer, with the goal of providing guidance on the use of these tests for the practicing community oncologist, for whom GI cancer may be only one of many tumor types encountered. This article provides a summary of the discussion and highlights the key opinions of the GICTEG on this topic. IMPLICATIONS FOR PRACTICE: The Gastrointestinal Cancer Therapy Expert Group seeks to provide practical guidance and opinion on the treatment of gastrointestinal malignancies, including colorectal cancer (CRC), for the practicing community oncologist in situations for which guidelines from established bodies, such as the National Comprehensive Cancer Network and the American Society of Clinical Oncology, may be less clear. In the present report, clinical guidance on the use of molecular assays for a range of clinical indications in CRC is presented, including the use of circulating tumor DNA to detect minimal/molecular residual disease in patients with successfully resected early-stage CRC.

Peripheral blood T-cell receptor repertoire as a predictor of clinical outcomes in gastrointestinal cancer patients treated with PD-1 inhibitor.

Identifying valid biomarkers for patient selection impressively promotes the success of anti-PD-1 therapy. However, the unmet need for biomarkers in gastrointestinal (GI) cancers remains significant. We aimed to explore the predictive value of the circulating T-cell receptor (TCR) repertoire for clinical outcomes in GI cancers who received anti-PD-1 therapy. 137 pre- and 79 post-treated peripheral blood samples were included. The TCR repertoire was evaluated by sequencing of complementarity-determining region 3 (CDR3) in the TRB gene. The Shannon index was used to measure the diversity of the TCR repertoire, and Morisita's overlap index was used to determine TCR repertoire similarities between pre- and post-treated samples. Among all enrolled patients, 76 received anti-PD-1 monotherapy and 61 received anti-PD-1 combination therapy. In the anti-PD-1 monotherapy cohort, patients with higher baseline TCR diversity exhibited a significantly higher disease control rate (77.8% vs. 47.2%; hazard ratio [HR] 3.92; 95% confidence interval [CI] 1.14-13.48; P = 0.030) and a longer progression-free survival (PFS) (median: 6.47months vs. 2.77months; HR 2.10; 95% CI 1.16-3.79; P = 0.014) and overall survival (OS) (median: NA vs. 8.97months; HR 3.53; 95% CI 1.49-8.38; P = 0.004) than those with lower diversity. Moreover, patients with a higher TCR repertoire similarity still showed a superior PFS (4.43months vs. 1.84months; HR 13.98; 95% CI 4.37-44.68; P < 0.001) and OS (13.40months vs. 6.12months; HR 2.93; 95% CI 1.22-7.03; P = 0.016) even in the cohort with lower baseline diversity. However, neither biomarker showed predictive value in the anti-PD-1 combination therapy cohort. Interestingly, the combination of TCR diversity and PD-L1 expression can facilitate patient stratification in a pooled cohort. The circulating TCR repertoire can serve as a predictor of clinical outcomes in anti-PD-1 therapy in GI cancers.

M5C RNA Methylation Primarily Affects the ErbB and PI3K-Akt Signaling Pathways in Gastrointestinal Cancer.

5-Methylcytosine (m5C) is a kind of methylation modification that occurs in both DNA and RNA and is present in the highly abundant tRNA and rRNA. It has an important impact on various human diseases including cancer. The function of m5C is modulated by regulatory proteins, including methyltransferases (writers) and special binding proteins (readers). This study aims at comprehensive study of the m5C RNA methylation-related genes and the main pathways under m5C RNA methylation in gastrointestinal (GI) cancer. Our result showed that the expression of m5C writers and reader was mostly up-regulated in GI cancer. The NSUN2 gene has the highest proportion of mutations found in GI cancer. Importantly, in liver cancer, higher expression of almost all m5C regulators was significantly associated with lower patient survival rate. In addition, the expression level of m5C-related genes is significantly different at various pathological stages. Finally, we have found through bioinformatics analysis that m5C regulatory proteins are closely related to the ErbB/PI3K–Akt signaling pathway and GSK3B was an important target for m5C regulators. Besides, the compound termed streptozotocin may be a key candidate drug targeting on GSK3B for molecular targeted therapy in GI cancer.

Targeting Wnt Signaling for Gastrointestinal Cancer Therapy: Present and Evolving Views.

Simple SummaryTherapeutic targeting of Wnt has long been suggested for gastrointestinal (GI) cancer treatment because deregulation of Wnt signaling is associated with GI cancers. However, therapeutic targeting of Wnt is still challenging because of the pleiotropic roles of Wnt signaling in the human body. Thus, targeting strategies of Wnt signaling are continuously evolving. The current flows of targeting Wnt signaling for cancer treatment are focused on increasing the specificity of drugs and combinatory treatment with other cancer drugs that minimize side effects and increase efficacy. Additionally, increased knowledge about the β-catenin paradox has expanded the cases that can be treated with Wnt targeting therapy, not strictly considering Wnt upstream and downstream mutations. Here, we discuss these evolving views of targeting Wnt signaling and describe examples of current clinical trials.Wnt signaling governs tissue development, homeostasis, and regeneration. However, aberrant activation of Wnt promotes tumorigenesis. Despite the ongoing efforts to manipulate Wnt signaling, therapeutic targeting of Wnt signaling remains challenging. In this review, we provide an overview of current clinical trials to target Wnt signaling, with a major focus on gastrointestinal cancers. In addition, we discuss the caveats and alternative strategies for therapeutically targeting Wnt signaling for cancer treatment.

Adoptive Cell Therapy for Gastrointestinal Cancers

AbstractThe reinfusion of autologous or allogeneic immune cells that have been educated and/or engineered ex vivo to respond to tumor-specific antigens is termed “adoptive cell therapy.” While adoptive cell therapy has made tremendous strides in the treatment of hematologic malignancies, its utilization for solid tumors has lagged somewhat behind. The purpose of this article is to concisely review the clinical research that has been done to investigate adoptive cell therapy as a treatment for gastrointestinal malignancies.

Potential of Anti-MUC1 Antibodies as a Targeted Therapy for Gastrointestinal Cancers.

Gastrointestinal cancers (GI) account for 26% of cancer incidences globally and 35% of all cancer-related deaths. The main challenge is to target cancer specific antigens. Mucins are heavily O-glycosylated proteins overexpressed in different cancers. The transmembrane glycoprotein MUC1 is the most likeable target for antibodies, owing to its specific overexpression and aberrant glycosylation in many types of cancers. For the past 30 years, MUC1 has remained a possible diagnostic marker and therapeutic target. Despite initiation of numerous clinical trials, a comprehensively effective therapy with clinical benefit is yet to be achieved. However, the interest in MUC1 as a therapeutic target remains unaltered. For all translational studies, it is important to incorporate updated relevant research findings into therapeutic strategies. In this review we present an overview of the antibodies targeting MUC1 in GI cancers, their potential role in immunotherapy (i.e., antibody-drug and radioimmunoconjugates, CAR-T cells), and other novel therapeutic strategies. We also present our perspectives on how the mechanisms of action of different anti-MUC1 antibodies can target specific hallmarks of cancer and therefore be utilized as a combination therapy for better clinical outcomes.

A pilot trial of multiple-TSA-specific adoptive immune cell (MAIC) as adjuvant therapy in gastrointestinal cancer.

e15013 Background: Given the heterogeneity of tumors, more tumor antigens need to be covered for better efficacy in oncologic immunotherapy. We conducted a pilot clinical trial to evaluate the safety and efficacy of adoptive immune cell therapy targeting multiple tumor specific antigens in individual patients. Methods: A total of 10 patients bearing resectable gastrointestinal tumor are going to be recruited in the study. The tumor-specific antigens of each patient were identified by RNA sequencing of the surgical tumor tissue. And then the antigenic peptides were synthesized and adapted to produce the multiple-TSA-specific adoptive immune cells (MAIC), including dendritic cell (DC) and cytotoxic T lymphocyte (CTL). 1st dose of MAICs injected during the 2nd or 3rd week after surgery; three doses of MAICs administered at 3-week intervals. Results: Currently, 4 patients have been enrolled, as shown in Table. The first enrolled patient, P01, underwent adjuvant MAIC therapy and have no progression nearly 9 months. P02, P03 and P04 developed new lesions about 3 months after the 1st surgery. After the 2nd surgery, tumor antigens were modified and MAIC targeting new antigens were given for adjuvant therapy. Up to now, there were no death events with survival months from 6.57 to 9.10. Safety evaluation showed that no irAE occurred in 4 patients. Intriguingly, antigenic drift was observed in patient P02.The top 3 antigens were shift from GPC3, AFP and GAGE10 to MAGEA1, GPC3 and CTAG2. And the mutation profile of tumors revealed totally different tumor clones with no shared SNV mutation between two surgery lesions at all. Through TCR sequencing, we found new T cell clones introduced by MAICs persisted in peripheral blood (sum ratio variated from 6.47% to 9.68%). Among them, specific T cell clones were identified targeting four antigens, including GPC3, AFP, TERT and MAGEA1. Among them, TERT-specific T cell clones shew highest expansion ratio, from 0.63±0.17% in PBMC to 7.85±3.10% in CTL. Conclusions: Treatment with MAICs have be proved safety in resectable gastrointestinal cancer. And all together four-antigen-specific T cell clones elevated apparently in peripheral blood after the 1st infusion of MAIC, reflecting the advantage of MAIC at renewable antigenic targets. [Table: see text]

Overcoming Resistance to Targeted Therapies in Gastrointestinal Cancers: Progress to Date and Progress to Come.

Targeted therapies have transformed the treatment paradigm in diseases such as non-small cell lung cancer and melanoma but have shown relatively modest clinical benefit in gastrointestinal malignancies. Anti-EGFR therapy in RAS wild-type colorectal cancer, anti-HER2 therapy in HER2- amplified esophagogastric cancer, and FGFR and isocitrate dehydrogenase 1 (IDH1) inhibitors in FGFR2 fusion-positive and IDH1-mutant biliary tract cancers offer antitumor efficacy, but the clinical benefit and durability of response in each case are typically limited. We review targeted therapies in each of these therapeutic areas and discuss their clinical efficacy, mechanisms of primary and acquired resistance, and strategies to overcome this resistance. We discuss lessons learned that we hope will lead to an expanded role for molecularly targeted therapy options for patients with gastrointestinal cancers.