Abdullah Esmail

Gastrointestinal (GI) malignancies account for more than one-third of cancer-related deaths worldwide, and outcomes for advanced disease remain poor despite advances in systemic therapy and immunotherapy. Chimeric antigen receptor (CAR)-engineered cellular therapies have transformed the treatment of hematologic malignancies, but their application in solid tumors has been limited by antigen heterogeneity, immunosuppressive tumor microenvironments, on-target/off-tumor toxicity, and manufacturing challenges. This narrative review examines the clinical evidence supporting chimeric antigen receptor T-cell (CAR-T) and chimeric antigen receptor natural killer (CAR-NK) therapies directed against six major targets in GI oncology: claudin 18.2 (CLDN18.2), guanylyl cyclase C (GUCY2C), mesothelin (MSLN), glypican-3 (GPC3), carcinoembryonic antigen (CEA), and human epidermal growth factor receptor 2 (HER2). Among these, CLDN18.2 is the most advanced target; in the randomized phase II CT041-ST-01 trial, satricabtagene autoleucel significantly improved progression-free survival (PFS) compared with physician’s choice therapy in previously treated gastric or gastroesophageal junction cancer, providing the first randomized evidence of CAR-based therapy efficacy in a solid tumor. GUCY2C and GPC3 have shown promising early-phase activity in metastatic colorectal cancer and hepatocellular carcinoma, respectively, whereas mesothelin, CEA, and HER2 continue to face important biological and safety challenges. CAR-NK cells have emerged as a complementary platform with favorable safety characteristics and off-the-shelf manufacturing potential, although clinical experience in GI malignancies remains limited. We discuss the relative clinical maturity of these targets, key barriers to implementation, and emerging strategies that may advance the role of CAR-based cellular therapies in GI cancers.

Gastrointestinal (GI) malignancies account for approximately one-quarter of new cancer diagnoses and more than one-third of cancer-related deaths worldwide, yet as of August 2026, only one CAR-T therapy has received regulatory approval for a solid tumor indication anywhere in the world. The recent CT041-ST-01 phase II trial of satricabtagene autoleucel, the first randomized CAR-T trial conducted in a solid tumor, demonstrated a significant improvement in progression-free survival for patients with advanced gastric cancer (median 3.25 vs. 1.77 months; hazard ratio (HR) 0.37, p < 0.001). While this landmark study established the clinical feasibility of CAR-T therapy in solid tumors, it also underscored the biological barriers that continue to limit durable responses. GI tumors are characterized by heterogeneous antigen expression, dense desmoplastic stroma, inefficient immune-cell trafficking, profoundly immunosuppressive tumor microenvironments, and progressive T-cell dysfunction, all of which are further compounded by the logistical and economic challenges of autologous cell manufacturing. In this narrative review, we organize these obstacles within a unified four-barrier engineering framework and critically examine the strategies being developed to overcome each of them. We discuss advances in multi-antigen and logic-gated CAR architectures, stromal remodeling through fibroblast activation protein (FAP)-targeted approaches and extracellular matrix-degrading enzymes, chemokine receptor engineering, regional delivery, hypoxia-responsive CARs, cytokine-armored and persistence-enhanced constructs, dominant-negative and switch receptors, metabolic reprogramming, and intrinsic checkpoint disruption. We also review emerging manufacturing platforms, including allogeneic CAR-T and CAR-natural killer (CAR-NK) cells, induced pluripotent stem cell-derived products, CAR-macrophages, and in vivo CAR generation, together with engineering strategies designed to improve safety and scalability. Rather than relying on a single technological advance, the future of CAR-based therapy for GI malignancies will likely depend on integrating multiple engineering approaches to address the diverse biological barriers within the tumor microenvironment. By synthesizing current preclinical and early clinical evidence, this review provides a translational framework for the next generation of CAR-based cellular therapies in gastrointestinal oncology.

Immune checkpoint inhibitors (ICIs) have significantly changed the treatment landscape of several gastrointestinal (GI) malignancies, particularly microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) tumors. However, most GI cancers remain resistant to current PD-1/PD-L1-based immunotherapy because of complex and highly suppressive tumor microenvironments characterized by immune stromal exclusion, myeloid-driven immune suppression, defective antigen presentation, and adaptive immune resistance mechanisms. Emerging evidence suggests that alternative inhibitory pathways, including lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and V-domain Ig suppressor of T-cell activation (VISTA), contribute substantially to persistent T-cell dysfunction and resistance to checkpoint blockade. This review summarizes the immune landscape of GI malignancies and discusses the biological mechanisms underlying resistance to current ICIs. We highlight the evolving role of next-generation immune checkpoints, ongoing clinical development of novel inhibitors, and emerging combination strategies involving chemotherapy, anti-angiogenic therapy, radiation, bispecific antibodies, and tumor microenvironment modulation. In addition, we discuss current limitations in biomarker development and the growing role of circulating tumor DNA, spatial immune profiling, and multi-omics approaches in patient selection. Finally, we explore future directions aimed at improving precision immunotherapy and expanding durable responses across GI cancers.

Background: Pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, with a 5-year overall survival of only 11% across all stages. Serum CA 19-9, the standard clinical biomarker, is limited by inadequate sensitivity in early stage disease and poor specificity. Circulating tumor DNA (ctDNA), which reflects the real-time genomic landscape of the tumor and frequently detects KRAS alterations present in over 90% of PDAC cases, has emerged as a promising prognostic biomarker. However, prior meta-analyses have been limited by smaller cohort sizes and substantial heterogeneity. This systematic review and meta-analysis aimed to evaluate the prognostic impact of detectable baseline ctDNA status in PDAC, irrespective of disease stage. Methods: A systematic search of Scopus, PubMed, and Embase was conducted for studies published up to January 2026, following PRISMA guidelines. Studies were eligible if they enrolled adults with PDAC, assessed ctDNA status (positive vs. negative) at baseline, and reported overall survival (OS) or progression-free survival (PFS). Case reports, reviews, studies focusing on specific mutations, or studies without extractable survival data were excluded. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using a random-effects model (DerSimonian–Laird method). Heterogeneity was assessed using the I² statistic and Cochran’s Q test. Subgroup analyses were performed by disease stage (localized vs. advanced PDAC). Results: 14 studies encompassing 1032 patients were included; 487 (47.2%) had detectable baseline ctDNA. Overall, 482 patients (46.7%) had localized disease and 550 (53.3%) had advanced disease. Detectable baseline ctDNA was significantly associated with inferior OS across all 14 studies (pooled HR 2.33, 95% CI 1.98–2.75; p < 0.0001; I² = 7.9%) and with shorter PFS across eight studies (pooled HR 2.16, 95% CI 1.76–2.67; p < 0.0001; I² = 15.7%). In stage-stratified subgroup analyses, ctDNA positivity was independently associated with worse OS in both advanced PDAC (HR 2.21, 95% CI 1.77–2.75; I² = 5%) and localized PDAC (HR 2.54, 95% CI 1.97–3.28; I² = 14.6%), with no statistically significant difference between subgroups (p = 0.412). Similarly, ctDNA positivity predicted worse PFS in advanced (HR 2.19, 95% CI 1.69–2.82; I² = 35.4%) and localized disease (HR 2.15, 95% CI 1.40–3.31; I² = 0%), with no significant between-subgroup differences (p = 0.941). Heterogeneity was consistently low to moderate across analyses. Conclusions: Detectable baseline ctDNA is a potent, independent prognostic biomarker in PDAC, associated with more than a two-fold increased risk of death and disease progression irrespective of disease stage, with consistent findings across studies and ctDNA detection platforms. These findings support further prospective evaluation of baseline ctDNA for prognostic stratification, treatment personalization, and clinical trial enrichment before routine clinical implementation. Standardized assay methodologies and prospective validation are needed to facilitate its future integration into clinical practice.

Background: Metastatic colorectal cancer (mCRC) that progresses after standard first- and second-line therapies carries a poor prognosis, and multiple third-line treatment options are available without a clearly established optimal strategy. This study aimed to comprehensively compare the efficacy and safety of currently approved third-line treatments using reconstructed individual patient data (reconstructed IPD). Methods: A systematic review and reconstructed IPD meta-analysis of phase III randomized controlled trials was conducted in accordance with PRISMA-IPD guidelines. Kaplan–Meier survival curves were digitized and reconstructed using validated methodologies. The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS) and the incidence of grade ≥3 treatment-related adverse events (AEs). Results: A total of 3338 patients were included across five treatment groups: regorafenib (n = 650), fruquintinib (n = 739), trifluridine/tipiracil (TAS-102; n = 780), TAS-102 plus bevacizumab (n = 246), and pooled placebo (n = 923). TAS-102 plus bevacizumab demonstrated the greatest benefit (OS HR: 0.43, 95% CI: 0.35–0.50; median OS: 10.89 months; PFS HR: 0.20, median PFS: 5.51 months). Fruquintinib (OS HR: 0.67; median OS: 7.97 months; PFS HR: 0.32; median PFS: 3.70 months) and TAS-102 (OS HR: 0.70; median OS: 7.2 months; PFS HR: 0.41; median PFS: 2.09 months) showed comparable survival benefit to regorafenib (OS HR: 0.68; median OS: 7.04 months; PFS HR: 0.39; median PFS: 2.16 months), with fruquintinib demonstrating superior PFS versus regorafenib (HR: 0.71, p < 0.001). Grade ≥3 AEs were highest with TAS-102 plus bevacizumab (72.36%) and lowest with fruquintinib (34.02%), with hematologic toxicity predominating in TAS-102-based regimens and hypertension and hand–foot skin reactions more common with tyrosine kinase inhibitors. Conclusion: TAS-102 plus bevacizumab was associated with the greatest survival benefit in this indirect comparison and appears to be the most effective option for eligible patients. However, these findings should be interpreted cautiously given the absence of direct head-to-head trials. Among tyrosine kinase inhibitors, fruquintinib demonstrated superior PFS compared with regorafenib, while OS was comparable.

Background: Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and a significant cause of global cancer-related mortality, with the majority of patients diagnosed at advanced or unresectable stages. Historically, tyrosine kinase inhibitor (TKI) monotherapies such as sorafenib and lenvatinib served as the primary systemic standard of care. However, the emergence of immune checkpoint inhibitor (ICPI)-based combinations has significantly transformed the treatment landscape. We aim to perform a comparative analysis of ICPI-based combination treatment versus TKI monotherapy among advanced HCC patients. Methods: This study utilized a reconstructed individual patient data (IPD) pooled analysis derived from nine phase 3 randomized clinical trials, adhering to PRISMA-IPD reporting guidelines. A total of 6161 patients were included in the analysis, which categorized treatment into five primary strategies: ICPI monotherapy, ICPI plus bevacizumab, dual ICPI therapy (duplet), ICPI plus TKI, and TKI monotherapy as the control group. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and the incidence of grade 3 or higher adverse events (AEs). Results: The analysis demonstrated that ICPI-based combinations provided a significant survival advantage over TKI monotherapy. Key hazard ratios (HRs) for OS compared to TKIs were 0.76 (95% CI: 0.67–0.85, p < 0.001) for dual ICPI, 0.76 (95% CI: 0.68–0.85, p < 0.001) for ICPI plus TKI, and 0.70 (95% CI: 0.61–0.81, p < 0.001) for ICPI plus bevacizumab. Median OS was numerically highest for ICPI plus TKI at 19.68 months and dual ICPI at 19.58 months compared to 14.84 months for the TKI group. Among FDA-approved regimens, nivolumab plus ipilimumab (NivoIpi) achieved the longest median OS of 24.08 months. From a safety standpoint, the ICPI plus TKI group had the highest incidence of grade 3/4 AEs at 69.1%. Conversely, TKI monotherapy showed a 50.1% incidence, while dual ICPI therapy exhibited the most favorable safety profile at 32.7%. Conclusions: ICPI-containing combination therapies are superior to TKI monotherapy for the first-line treatment of advanced HCC, providing marked improvements in survival outcomes. Dual ICPI therapy represents the most balanced approach between efficacy and safety, achieving high survival with the lowest rates of severe toxicity. Among approved options, NivoIpi exhibited a numerically favorable survival signal, while DurvaTreme offered the highest tolerability, supporting a personalized treatment approach based on individual patient risk factors and hepatic reserve.

Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and remains a leading cause of cancer-related mortality worldwide due to frequent recurrence and early metastasis. While immune checkpoint inhibitor (ICPI)-based regimens have revolutionized the treatment landscape for advanced HCC, clinical evidence regarding the safety and efficacy of ICPI rechallenge following disease progression or severe immune-related adverse events (irAEs) remains sparse. This report describes a case of prolonged disease stability achieved through sequential immunotherapy using durvalumab and tremelimumab (Durva/Treme) after prior ICPI failure and high-grade toxicity. Case Description: A 65-year-old male with recurrent stage IV HCC and metastases to the adrenal glands and vertebral column was referred to our center after failing multiple lines of therapy, including atezolizumab/bevacizumab, sorafenib, and cabozantinib. Subsequent treatment with nivolumab plus ipilimumab was complicated by grade 3/4 immune-related hepatitis, necessitating a treatment hold and steroid intervention. Despite an initial response in hepatic lesions, imaging confirmed progression in the adrenal metastases. The patient was then transitioned to a rechallenge protocol with the STRIDE regimen (Durva/Treme). The patient completed 39 cycles of therapy over more than three years. Serial imaging demonstrated sustained stable disease (SD), and a significant reduction in alpha-fetoprotein (AFP) levels initially declined substantially during nivolumab/ipilimumab (Nivo/Ipi) therapy, rebounded prior to Durva/Treme initiation, and subsequently stabilized near baseline levels during ongoing Durva/Treme treatment. Notably, the rechallenge was well-tolerated with no recurrence of high-grade hepatotoxicity. Conclusions: This case demonstrates that ICPI rechallenge with Durva/Treme may provide durable disease control in selected patients with advanced HCC, even those with a history of severe immune-related toxicity. While the localized response was likely augmented by interval radiotherapy, the overall clinical course suggests that the STRIDE regimen may offer a feasible sequential immunotherapy option. These findings warrant further prospective investigation into the biological mechanisms of immune re-priming and the safety of immunotherapy sequencing in advanced oncology.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is frequently diagnosed at an advanced stage and remains associated with poor survival outcomes. Durable responses to systemic therapy in metastatic disease are uncommon. We report a case of metastatic PDAC with prolonged survival and sustained response following first-line treatment with NALIRIFOX. This report describes a patient with metastatic PDAC who achieved prolonged disease control and sustained response following first-line treatment with NALIRIFOX. Case Presentation: A 64-year-old woman presented with abdominal pain, early satiety, weight loss, and markedly elevated CA 19-9 levels. Imaging demonstrated a pancreatic head mass with multiple hepatic metastases, and biopsy confirmed metastatic poorly differentiated PDAC. The patient initiated first-line therapy with NALIRIFOX as part of the NAPOLI-3 protocol and completed 20 cycles over approximately 25 months. Following an early treatment delay secondary to grade 2 neutropenia, she achieved substantial biochemical and radiographic improvement. After eight cycles, imaging demonstrated marked radiographic response with disappearance of the pancreatic lesion and marked regression of hepatic metastases. Disease stability was maintained for more than two years before progression was identified in a dominant hepatic lesion after cycle 20. Conclusion: This case highlights the potential for prolonged disease control and extended survival with NALIRIFOX in metastatic PDAC, emphasizing the meaningful clinical benefit that may be achieved in selected patients despite historically poor outcomes.

Unresectable hepatocellular carcinoma (HCC) remains a global challenge, with limited effective treatment options for advanced-stage disease. The HIMALAYA trial (phase III randomized study that evaluated the STRIDE regimen) introduced the Single Tremelimumab Regular Interval Durvalumab (STRIDE) regimen, an immunotherapy-based approach that achieved a median overall survival (OS) of 16.43 months compared to 13.77 months with sorafenib. While statistically significant, this ~2.7 months OS gain warrants scrutiny in light of STRIDE’s increased immune-related toxicity and cost. This commentary evaluates STRIDE’s impact within the broader landscape of first-line systemic therapy for unresectable HCC, alongside other regimens such as atezolizumab plus bevacizumab and nivolumab plus ipilimumab. We explore STRIDE’s mechanism of action, safety profile, modest progression-free survival (PFS) improvement, and implementation challenges, incorporating insights from 2023–2025 research. In addition, we discussed its limitations in non-viral HCC and Child-Pugh B patients, the role of emerging biomarkers, and the potential of radiation to enhance immunotherapy efficacy. As a dual immune checkpoint inhibitor (ICI) strategy, STRIDE offers an important advance that may not only extend survival but also open the door to future curative approaches. However, optimizing its use will require refined patient selection and further investigation of synergistic combination therapies.