Combination Immunotherapy Research Articles

Digoxigenin activates autophagy in hepatocellular carcinoma cells by regulating the PI3K/AKT/mTOR pathway

Hepatocellular carcinoma (HCC) is recognized as a highly malignant tumor. Targeted combination immunotherapy, the initially approved regimen, is compromised by adverse side effects and low response rates during clinical treatment. Traditional Chinese medicine and its derived natural compounds, known for their anticancer effects, offer advantages of low toxicity and cost. In this study, we performed high-throughput phenotypic screening in vitro to identify promising anti-HCC drugs. Among 1,444 bioactive compounds, digoxigenin (DIG) was found to significantly impede HCC cell progression. We validated DIG’s therapeutic effects through assays such as cell counting by CCK8, lactate dehydrogenase, and colony formation. Analyses including transmission electron microscopy, western blotting, and immunofluorescence demonstrated that DIG inhibits HCC cell proliferation via autophagy. Network pharmacology and molecular docking studies suggest that DIG targets the PI3K/AKT/mTOR signaling pathway. Comparative treatments of Hep3B and Huh7 cells with DIG or mTOR inhibitors revealed similar inhibitory impacts, indicating that DIG induces autophagy by inhibiting the PI3K/AKT/mTOR pathway. In vivo studies confirmed that DIG halts the growth of subcutaneous xenograft tumors. In conclusion, DIG represents a potential HCC treatment by modulating the PI3K/AKT/mTOR pathway to induce autophagy. This research, via phenotypic screening, accelerates drug discovery and the development of novel therapies targeting the underlying mechanisms of liver cancer.

Radiomic and dosimetric parameter-based nomogram predicts radiation esophagitis in patients with non-small cell lung cancer undergoing combined immunotherapy and radiotherapy

BackgroundThe combination of immune checkpoint inhibitors (ICIs) and radiotherapy (RT) may increase the risk of radiation esophagitis (RE). This study aimed to establish and validate a new nomogram to predict RE in patients with non-small cell lung cancer (NSCLC) undergoing immunochemotherapy followed by RT (ICI-RT).MethodsThe 102 eligible patients with NSCLC treated with ICI-RT were divided into training (n = 71) and validation (n = 31) cohorts. Clinicopathologic features, dosimetric parameters, inflammatory markers, and radiomic score (Rad-score) were included in the univariate logistic regression analysis, and factors with p < 0.05 in the univariate analysis were included in the multivariate logistic regression analysis. Factors with significant predictive values were obtained and used for developing the nomogram. The area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve were used to validate the model.ResultsA total of 38 (37.3%) patients developed RE. Univariate and multivariate analyses identified the following independent predictors of RE: a maximum dose delivered to the esophagus >58.4 Gy, a mean esophagus dose >13.3 Gy, and the Rad-score. The AUCs of the nomogram in the training and validation cohorts were 0.918 (95% confidence interval [CI]: 0.824–1.000) and 0.833 (95% CI: 0.697–0.969), respectively, indicating good discrimination. The calibration curves showed good agreement between the predicted occurrence of RE and the actual observations. The decision curve showed a satisfactory positive net benefit at most threshold probabilities, suggesting a good clinical effect.ConclusionsWe developed and validated a nomogram based on imaging histological features and RT dosimetric parameters. This model can effectively predict the occurrence of RE in patients with NSCLC treated using ICI-RT.

Case report: Achieving significant tumor reduction in advanced pancreatic adenocarcinoma

Pancreatic cancer remains a highly malignant and challenging tumor with a dismal 5-year survival rate of only 13%. The majority of patients are diagnosed at advanced stages, where surgical options are limited, and prognosis is poor. Immunotherapy, particularly PD-1 inhibitors, has shown limited success in pancreatic cancer due to its unique tumor immune microenvironment. However, certain genetic profiles, such as BRCA1/2 mutations, high tumor mutational burden (TMB), or microsatellite instability-high (MSI-H), may enhance sensitivity to these therapies. This report presents two cases of advanced pancreatic cancer with BRCA1/2 mutations treated with a combination of chemotherapy and immune checkpoint inhibitors. The first patient, with TMB-H and stable microsatellites, achieved complete remission after conversion therapy and remains disease-free for over two years post-surgery. The second patient, with MSI-H and low TMB, experienced significant tumor regression and improved quality of life with a prolonged progression-free survival, although the patient ultimately declined surgery. These cases suggest that combined chemotherapy and immunotherapy may offer a promising treatment option for select pancreatic cancer patients, particularly those with specific genetic profiles, warranting further investigation into personalized approaches to immunotherapy in this malignancy.

Impact of time-of-day administration of immunotherapy on survival in metastatic renal cell carcinoma: the MOUSEION-09 meta-analysis.

Studies conducted in the last few years have suggested a connection between clinical outcomes and the time of immune checkpoint inhibitors (ICIs) infusion. However, few data are available regarding the differences between early and late time-of-day (ToD) administration in metastatic renal cell carcinoma (mRCC) patients receiving immunotherapy and immune-based combinations. In this meta-analysis, we aimed to fully investigate the influence of timing of administration on the efficacy of mRCC immunotherapy, by comparing early ToD versus late ToD dosing in this setting. The present systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Overall Survival (OS) was measured as Hazard Ratios (HRs) and 95% confidence intervals (CIs). Our search resulted in the identification of 1429 potentially relevant reports, which were subsequently restricted to four following independent evaluation of three authors. The pooled HR for OS in RCC patients receiving early ToD versus late ToD dosing was 0.62 (95% Confidence Interval, 0.50-0.72; p < 0.001). According to our findings, a statistically significant improvement in terms of OS for mRCC patients receiving early ToD administration compared with late ToD dosing was observed, with a reduction of death by 38%. Well-designed, randomized clinical and translational trials are required to clarify this issue and to establish recommendations for personalized treatments according to ToD.

Dysfunction and regulatory interplay of T and B cells in chronic hepatitis B: immunotherapy and emerging antiviral strategies

In the context of chronic hepatitis B virus (HBV) infection, the continuous replication of HBV within host hepatocytes is a characteristic feature. Rather than directly causing hepatocyte destruction, this replication leads to immune dysfunction and establishes a state of T-B immune tolerance. Successful clearance of the HBV virus is dependent on the close collaboration between humoral and cellular immunity. Humoral immunity, mediated by B-cell subpopulations, and cellular immunity, dominated by T-cell subpopulations show varying degrees of dysfunction during chronic hepatitis B (CHB). Notably, not all T- and B-cells produce positive immune responses. This review examine the most recent developments in the mutual regulation of T-B cells during chronic HBV infection. Our focus is on the prevailing immunotherapeutic strategies, such as T cell engineering, HBV-related vaccines, PD-1 inhibitors, and Toll-like receptor agonists. While nucleos(t)ide analogues (NUCs) and interferons have notable limitations, including inadequate viral suppression, drug resistance, and adverse reactions, several HBV entry inhibitors have shown promising clinical efficacy. To overcome the challenges posed by NUCs or monotherapy, the combination of immunotherapy and novel antiviral agents presents a promising avenue for future CHB treatment and potential cure.

Sonodynamic Nano-LYTACs Reverse Tumor Immunosuppressive Microenvironment for Cancer Immunotherapy.

Extracellular and transmembrane proteins, which account for the products of approximately 40% of all protein-encoding genes in tumors, play a crucial role in shaping the tumor immunosuppressive microenvironment (TIME). While protein degradation therapy has been applied to membrane proteins of cancer cells, it has rarely been extended to immune cells. We herein report a polymeric nanolysosome targeting chimera (nano-LYTAC) that undergoes membrane protein degradation on M2 macrophages and generates a sonodynamic effect for combinational cancer immunotherapy. Nano-LYTAC is found to have higher degradation efficacy to the interleukin 4 receptor (IL-4R) compared to traditional inhibitors. More importantly, it is revealed that the effect of nano-LYTAC on the function of the M2 macrophage is concentration-dependent: downregulating CD206 expression and interleukin 10 (IL-10) secretion from M2 macrophages at low concentration, while triggering their apoptosis at high concentration. Moreover, nano-LYTAC is found to possess long tumor retention (>48 h), allowing for multiple sonodynamic treatments with a single dose. Such a synergistic sonodynamic immunotherapy mediated by nano-LYTAC effectively reprograms the TIME via inhibiting the functions of M2 macrophages and regulatory T cells (Tregs), as well as promoting the maturation of dendritic cells (DCs) and tumor infiltration of T effector cells (Teffs), completely suppressing tumor growth, inhibiting pulmonary metastasis, and preventing recurrence under preclinical animal models.

Prospects for Treatment of Lung Cancer Using Activated Lymphocytes Combined with Other Anti-Cancer Modalities

This review explores the significance and prospects of using diverse T-cell variants in the context of combined therapy for lung cancer treatment. Recently, there has been an increase in research focused on understanding the critical role of tumor-specific T lymphocytes and the potential benefits of autologous T-cell-based treatments for individuals with lung cancer. One promising approach involves intravenous administration of ex vivo-activated autologous lymphocytes to improve the immune status of patients with cancer. Investigations are also exploring the factors that influence the success of T-cell therapy and the methods used to stimulate them. Achieving a comprehensive understanding of the characteristics of activated lymphocytes and deciphering the mechanisms underlying their activation of innate anti-tumor immunity will pave the way for numerous clinical trials and the development of innovative strategies for cancer therapy like combined immunotherapy and radiation therapy.

KDM1A epigenetically enhances RAD51 expression to suppress the STING-associated anti-tumor immunity in esophageal squamous cell carcinoma

Histone lysine demethylase LSD1, also known as KDM1A, has been found to regulate multiple cancer hallmarks since it was first identified in 2004. Recently, it has emerged as a promising target for stimulating anti-tumor immunity, specifically boosting T cell activity. However, it remains unclear whether and how it remodels the tumor microenvironment to drive oncogenic processes in esophageal squamous cell carcinoma (ESCC). In this study, protein levels in ESCC tissues were evaluated by immunostaining of tissue microarrays. Cell growth was assessed by colony formation assays in vitro and subcutaneous xenograft models in vivo. High-throughput transcriptomics and spatial immune proteomics were performed using bulk RNA sequencing and digital spatial profiling techniques, respectively. Epigenetic regulation of RAD51 by methylated histone proteins was analyzed using chromatin immunoprecipitated quantitative PCR assays. Finally, our clinical data indicate that KDM1A precisely predicts the overall survival of patients with early-stage ESCC. Inhibition of KDM1A blocked the growth of ESCC cells in vitro and in vivo. Mechanistically, our transcriptomics and spatial immune proteomics data, together with rescue assays, demonstrated that KDM1A specifically removes methyl residues from the histone protein H3K9me2, a transcription repressive marker, thus reducing its enrichment at the promoter of RAD51 to epigenetically reactivate its transcription. Additionally, it significantly inhibits the expression of NF-κB signaling-dependent proinflammatory genes IL-6 and IL-1B through RAD51, thus blocking the STING-associated anti-tumor immunity in stromal tumor-infiltrating lymphocytes (sTIL). Overall, our findings not only indicate that KDM1A is a promising target for ESCC patients at early stages but also provide novel mechanistic insights into its spatial regulation of STING-associated anti-tumor immunity in sTILs to drive the oncogenic processes in ESCC. The translation of these findings will ultimately guide more appropriate combinations of spatial immunotherapies with KDM1A inhibitors to improve the overall survival of specific subgroups in ESCC.

From tumor microenvironment to emerging biomarkers: the reshaping of the esophageal squamous cell carcinoma tumor microenvironment by neoadjuvant chemotherapy combined with immunotherapy

Esophageal squamous cell carcinoma is a cancer with high morbidity and mortality. The advent of immune checkpoint inhibitors has significantly increased complete response rates and postoperative R0 resection rates after neoadjuvant therapy. These drugs can largely reverse the suppression of the immune system caused by the tumor microenvironment, allowing the reactivation of anti-tumor immune infiltrating cells, significantly improving the patient’s tumor microenvironment, and thus preventing tumor development. However, there are still some patients who respond poorly to neoadjuvant combined immunotherapy and cannot achieve the expected results. It is now found that exploring changes in the tumor microenvironment not only elucidates patient responsiveness to immunotherapy and identifies more reliable biomarkers, but also addresses the limitations of prediction with imaging examination such as CT and the instability of existing biomarkers. In light of these considerations, this review aims to delve into the alterations within the tumor microenvironment and identify potential predictive biomarkers ensuing from neoadjuvant immunotherapy in the context of esophageal squamous cell carcinoma.

Hepatocellular carcinoma epi-immunotherapy with polyion complex micelles co-delivering HDAC8 inhibitor and PD-L1 siRNA

Hepatocellular carcinoma (HCC) lacking T cell infiltration is a malignancy with a poor prognosis and has an increasing incidence worldwide. Overexpression of histone deacetylase 8 (HDAC8) in HCC caused immune escape and promoted resistance to immune-checkpoint blockade therapy. Herein, we synthesized a polyion complex (PIC) to co-encapsulate the HDAC8 inhibitor PCI-34051 (PCI) and programmed death-ligand 1 small interfering RNA (siPDL1). The PIC micelles PCI-siPDL1@NPs efficiently delivered PCI and siPDL1 into Hepa1-6 cells and orthotopic Hepa1-6 tumors, inducing potent anti-tumor immune responses through a combination of epigenetic therapy and immunotherapy (epi-immunotherapy). PCI-siPDL1@NPs activated T cell-trafficking chemokine C-C motif ligand 4 (CCL4) production via HDAC8 inhibitor and decreased PD-L1 expression via siPDL1. The synergistic epi-immunotherapy significantly increased intratumoral CD8+ T cell infiltration, CD8+ T cell-mediated tumor cell killing, and the immunogenicity of HCC. Furthermore, PCI-siPDL1@NPs produced strong anti-tumor responses in the orthotopic Hepa1-6 HCC model and subcutaneous H22 model, which stimulated tumor regression and prolonged mice survival time. This study successfully constructed stable PIC micelles PCI-siPDL1, which synergistically activated antitumor immunity and reprogrammed the immunosuppressive tumor microenvironment for the treatment of HCC.

Manganese nanosheets loaded with selenium and gemcitabine activate the tumor microenvironment to enhance anti-tumor immunity

Breast cancer is among the most common malignant tumors globally. Despite advances in immunotherapy and targeted therapies, chemotherapy remains the primary clinical treatment. Gemcitabine, a cytosine nucleoside analog, is widely used for various solid tumors; however, its effectiveness is often limited by drug resistance and adverse side effects. In this study, we developed a novel drug delivery system, Mn/Se-Gem, designed to target tumor cells overexpressing CD44 and facilitate the controlled release of gemcitabine. This system exploits gemcitabine’s pH sensitivity and HA-mediated CD44 targeting to induce DNA damage. Simultaneously, it neutralizes the acidic tumor microenvironment and releases nano-selenium and manganese ions, which promote the excessive production of reactive oxygen species (ROS), leading to mitochondrial damage and enhanced apoptosis of cancer cells. Furthermore, Mn (II) activates the cGAS-STING pathway, increasing susceptibility to ROS-induced DNA double-strand breaks, promoting macrophage maturation, inhibiting M2 polarization, and enhancing the cytotoxic function of T lymphocytes against tumor cells. In summary, this combination of chemotherapy and immunotherapy presents a promising strategy for the treatment of breast cancer.

Self-delivered sonodynamic nanomedicine for enhanced tumor immunotherapy by simultaneously reversing the immunosuppression and immune resistance

Sonodynamic therapy (SDT) shows potential for noninvasive eradication of local solid tumors. However, its efficacy in suppressing metastatic tumors is limited by factors such as insufficient tumor accumulation, the immunosuppressive tumor microenvironment, and acquired immune tolerance. To address these challenges, we developed self-delivering sonodynamic nanomedicine incorporating Toll-like receptor (TLR) agonists R848 and programmed death-ligand 1 (PD-L1) inhibitors JQ1 for combined SDT and immunotherapy. These nanomedicines enhanced tumor accumulation of sonosensitizers, enabling potent SDT and induction of immunogenic cell death (ICD). Additionally, the co-encapsulated R848 and JQ1 alleviated tumor immunosuppression and immune tolerance, synergizing effectively with SDT to elicit a robust antitumor immune response. By integrating enhanced SDT with activated antitumor immunity, significant inhibition of primary, distant, and lung metastatic tumors was achieved. This study introduces a novel approach for combining SDT with immunotherapy using self-assembled active pharmaceutical ingredients.

Combinatorial immunotherapy of anti-MCAM chimeric antigen receptor modified expanded natural killer cells and NKTR-255 against neuroblastoma

Pediatric patients with recurrent metastatic neuroblastoma (NB) have a dismal 5-year survival. Novel therapeutic approaches are urgently needed. The melanoma cell adhesion molecule (MCAM/CD146/MUC18) is expressed in a variety of pediatric solid tumors, including NB, and constitutes anovel target for immunotherapy. Here, we developed a chimeric antigen receptor (CAR) expressing natural killer (NK) cell-targeting MCAM by non-viral electroporation of CAR mRNA into exvivo expanded NK cells. Expression of anti-MCAM CAR significantly enhanced NK cell cytotoxic activity compared to mock NK cells against MCAMhigh but not MCAMlow/knockout NB cells invitro. Anti-MCAM-CAR-NK cell treatment significantly decreased tumor growth and prolonged animal survival in an NB xenograft mouse model. NKTR-255, a polymer-conjugated recombinant human interleukin-15 agonist, significantly stimulated NK cell proliferation and expansion and further enhanced the in vitro cytotoxic activity and invivo anti-tumor efficacyofanti-MCAM-CAR-NK cells against NB. Our preclinical studies demonstrate that exvivo expanded andmodified anti-MCAM-CAR-NK cells alone and/or incombination with NKTR-255 are promising novel alternative therapeutic approaches to targeting MCAMhigh malignant NB.

METTL3-VISTA axis-based combination immunotherapy for APC truncation colorectal cancer

ObjectiveAlthough immune checkpoint blockade (ICB) therapy represents a bright spot in antitumor immunotherapy, its clinical benefits in colorectal cancer (CRC) are limited. Therefore, a new target for mediating CRC immunosuppression...

Chidamide and venetoclax synergistically regulate the Wnt/β-catenin pathway by MYCN/DKK3 in B-ALL.

B-cell acute lymphocytic leukemia (B-ALL) is a malignant proliferative B-lymphocyte disease. Although the outcome of B-ALL has greatly improved with combined chemotherapy, immunotherapy, and hematopoietic stem cell transplantation, some patients still experience drug resistance, relapse and a low long-term survival rate, therefore, finding novel approaches to improve the outcome of adult B-ALL patients is critical. Our previous studies revealed that the selective histone deacetylase inhibitor (HDACi) chidamide can inhibit the Wnt/β-catenin signaling pathway by inhibiting MYCN and increasing the expression of DKK3 in B-ALL cells. Some studies have indicated that histone deacetylase inhibitors (HDACis) can dysregulate the B-cell lymphoma-2 (BCL2) protein family, we speculate that chidamide and BCL2 inhibitor venetoclax synergistically inhibit the Wnt/β-catenin signaling pathway by inhibiting MYCN expression and increasing DKK3 expression. In our study, the in vitro and in vivo experiments confirmed that chidamide and venetoclax synergistically inhibited the expression of MYCN and increased the expression of DKK3 by inhibiting the activity of HDAC and BCL2, inhibiting the Wnt/β-catenin signaling pathway and B-ALL cell proliferation. These findings indicate that the HDACi chidamide and the BCL2 inhibitor venetoclax can be used in combination to treat B-ALL, providing a new method and strategy for treating B-ALL.

A case of delayed initial response to combination ipilimumab and nivolumab in malignant pleural mesothelioma

Malignant pleural mesothelioma has a poor prognosis with limited therapeutic options Although numerous trials have shown that combination immunotherapy with nivolumab and ipilimumab is one of the first line treatments for patients with unresectable MPM, there is limited data on delayed responses over a long follow up period. We report a case of a delayed response 7 months after the cessation of immunotherapy in a patient who initially had progressive malignant pleural mesothelioma with metastases.

Reversible Electroporation for Cancer Therapy.

Reversible electroporation refers to the use of high voltage electrical pulses on tissues to increase cell membrane permeability. It allows targeted delivery of high concentrations of chemotherapeutic agents including cisplatin and bleomycin, a process known as electrochemotherapy (ECT). It can also be used to deliver toxic concentrations of calcium and gene therapies that stimulate an anti-tumour immune response. ECT was validated for palliative treatment of cutaneous tumours. Evidence to date shows a mean objective response rate of ∼80% in these patients. Regression of non-treated lesions has also been demonstrated, theorised to be from an in-situ vaccination effect. Advances in electrode development have also allowed treatment of deep-seated metastatic lesions and primary tumours, with safety demonstrated in vivo. Calcium electroporation and combination immunotherapy or immunogene electrotransfer is also feasible, but research is limited. Adverse events of ECT are minimal; however, general anaesthesia is often necessary, and improvements in modelling capabilities and electrode design are required to enable sufficient electrical coverage. International collaboration between preclinical researchers, oncologists and interventionalists is required to identify the most effective combination therapies, to optimise procedural factors, and to expand use, indications and assessment of reversible electroporation. Registries with standardised data collection methods may facilitate this.

The application of immunotherapy combined with taxanes in second‑line treatment of advanced HER2 negative gastric cancer.

Human epidermal growth factor receptor-2 (HER2) negative advanced gastric cancer (GC) has a high global incidence and mortality rate with limited options for second-line treatment. Monotherapy is not effective and the combination of chemotherapy and immunotherapy has not yet been included in the guidelines. The present study aimed to explore a new treatment approach by conducting a single-center, retrospective, observational real-world study. A total of 21 patients with advanced HER2-negative GC, who had progressed after receiving standard first-line regimens [tegafur, gimeracil and oteracil potassium capsules (S-1) or capecitabine plus oxaliplatin], were selected. The application of programmed cell death-1 (PD-1) inhibitor combined with taxanes was selected as the second-line treatment. The primary outcomes measured were progression-free survival (PFS), pathological complete response, objective response rate (ORR), disease control rate (DCR) and adverse reactions in the present patient cohort. The median (m)PFS in the overall population was 7.1 months, with a 95% confidence interval (CI) of 6.0-8.2 months and the median overall survival (mOS) was 11.3 months, with a 95% CI of 4.5-18.2 months. The ORR was 9.5% and the DCR was 90.5%. Univariate and multivariate analyses indicated that Ki67 <70% and tumor marker-positive status [one or two increases among carcinoembryogenic antigen (CEA), cancer antigen (CA) 199 and CA125] were independent prognostic factors for PFS and overall survival (OS) in second-line treatment. Significant statistical differences were noted in PFS (mPFS=5.3 months, 95% CI: 3.1-7.5 months vs. mPFS=9.1 months, 95% CI: 6.2-12.0 months; P=0.002) and OS (mOS=8.8 months, 95% CI: 7.0-10.7 months vs. mOS=17.2 months, 95% CI: 16.0-18.5 months; P=0.013) between the Ki67-high group (Ki67 ≥70%) and the Ki67-low group (Ki67 <70%). Significant statistical differences were noted in OS between tumor marker-negative status (CEA, CA199 and CA125 within normal range) and tumor marker-positive status (one or two increases among CEA, CA199 and CA125; mOS=17.2 months, 95% CI: 16.0-18.4 months vs. mOS=8.8 months, 95% CI: 5.3-12.4 months; P=0.018); however, no significant differences were noted in PFS between these two groups. The present study retrospectively analyzed the new second-line approach of PD-1 inhibitor combined with taxanes for HER2 negative GC which effectively improved patient PFS and OS compared with single-agent chemotherapy. The expression levels of Ki67 and the tumor marker-negative status possess potential clinical value in monitoring prognosis and guiding future individualized use of chemotherapy combined with immunotherapy.

Efficacy of sintilimab combined with neoadjuvant chemotherapy and trastuzumab in conversional treatment of locally advanced HER2-positive gastric cancer: case analysis and literature review

BackgroundRegional lymph nodes that are fixed and fused into clusters or those exhibiting metastases outside the regional lymph nodes are generally classified as stage IV (M1) or unresectable. Patients with such nodes almost always need pre-operative treatment so that they can undergo surgical resection. Combining immunotherapy with trastuzumab and chemotherapy significantly improved the prognosis of HER-2 positive gastric/gastroesophageal junction (G/GEJ) cancer. However, very few reports are available on the role of immunotherapy in converting patients with unresectable cancer to resectable cancer.MethodsIn this study, we report on four patients with GC who were preoperatively treated with a combination of sintilimab, trastuzumab, and chemotherapy at Hubei Cancer Hospital, China, from January 2022 to October 2023. Both preoperative and postoperative clinical and pathological characteristics of each patient were analyzed. The preoperative tumor stage was cT4N3M1.ResultsPostoperative pathological results showed that two patients achieved pathological complete remission (pCR), while the pathological stage in the other two patients decreased to ypT1N0M0 and ypT2N0M0. None of them had nerve or vascular invasion. None of the patients had recurrences or metastases until the last follow-up (October 2024) after primary surgery. The present case report suggests that a combination of immunotherapy comprising trastuzumab and chemotherapy can improve the efficiency of conversion therapy for patients with HER-2 positive locally advanced G/GEJ cancer. This study also demonstrates the safety of immune checkpoint inhibitors in a conversional treatment approach.ConclusionWe showed that a pathological complete response (pCR) can be obtained even with unresectable advanced GC through treatment with sintilimab combined with neoadjuvant chemotherapy and trastuzumab.

Abstract IA025: Targeting the gut microbiome for cancer immunotherapy

Abstract Growing evidence suggests that the gut microbiota modulates the efficacy and toxicity of cancer therapy, most notably immunotherapy and its immune-related adverse effects. The impaired response to immunotherapy in patients treated with antibiotics supports this role of the microbiota. Until recently, results pertaining to the identification of the microbial species responsible for these effects were incongruent, and relatively few studies analyzed the underlying mechanisms. Gut microbial communities (microbiotypes) with non-uniform geographic distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts Now, a better understanding of the taxonomy of the species involved and of their mechanisms of action has been achieved. Defined bacterial species have been shown to promote a response to immune checkpoint inhibitors through the production of different products or metabolites, although a suppressive effect of Gram(-) bacteria may be dominant in some unresponsive patients. Machine learning approaches trained on patients’ microbiota composition can predict the ability of patients to respond to immunotherapy with some accuracy. Thus, the interest in modulating the microbiota composition to improve patients’ responsiveness to therapy has been mounting. Our data of a fecal microbiota transfer clinical trial in anti-PD1 refractory melanoma patients has provided clinical proof of concept of the possibility to target the gut microbiota composition in cancer therapy. Also, both in clinical studies and in experimental animals, diets rich in fibers improve the response to immunotherapy by modifying the gut microbiome suggesting the possibility of dietary approaches to target the microbiota composition in cancer therapy. However, while many early clinical studies have analyzed the association of the microbiota composition with the response to anti-PD-1 in cancer patients, emerging evidence suggests that the association may be context dependent and different types of mono or combination immunotherapies may be differentially regulated by the microbiota, Thus, a more personalized approach depending original gut microbiota composition of the patients and the type of immunotherapy protocol selected may be necessary for optimal clinical results. Citation Format: Giorgio Trinchieri. Targeting the gut microbiome for cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr IA025.