Benefit of Dual Immunotherapy in GI Cancers

479 Background: Gastrointestinal (GI) cancers are a heterogeneous group of cancers with varying underlying pathophysiology and distinct treatment paradigms. Immunotherapy (IO) is unique in each of the subtypes and biomarkers utility varies. With the expansion of IO in each cancer subtypes, education remains essential to optimize patient outcomes through integration of the latest evidence-based data at point of care. Through the partnership between Medscape Oncology and the Society for Immunotherapy of Cancer, 2 educational activities were designed to increase the knowledge and competence of oncologists surrounding the role of IO in patients with advanced GI cancers. Methods: The 2 educational activities included a text based online activity with 3 chapters focused on gastroesophageal cancers, colorectal cancers, and hepatocellular carcinoma (HCC) and a 30-minute online, video discussion with 3 faculty and synchronized slides on HCC. Educational effectiveness was assessed with repeated paired pre/post assessment where learners served as their own controls. A chi-square test was used to identify statistical significance in proportion of correct responses. The first activity launched 11/27/2019 and the second activity launched on 5/8/20. Data were collected and reported through 8/25/2020. Results: A total of 8433 learners, including 1543 oncologists, participated from 11/2019 through 8/2020. Participation in education resulted in significant relative improvements among oncologist learners on IO in GI cancers in (n = 641): 110%: role or eligibility of immune checkpoint inhibitors (ICIs) (p < .001) 38%: clinical trial data of ICIs (p < .001) Subsequent education on unresectable HCC demonstrated a significant relative improvement in both knowledge and competence for oncologist learners (n = 902): 19%: regarding clinical trial data in unresectable HCC (p = .073) 19%; competence identifying role of ICIs in unresectable HCC (p < .05) 59%: competence managing irAEs in unresectable HCC (p < .001). Conclusions: These 2 online CME-certified educational activities resulted in statistically significant gains in oncologist knowledge surrounding the use of IO in advanced GI cancers Follow-up education on HCC demonstrated the value and benefit of multi-modal and sequential activities on improving competence among oncologists caring for patients with unresectable HCC There remains a need for continuous education as more oncologists utilize IO in their practice while the understanding and availability of clinical data continues to expand and evolve in the varying GI cancer subtypes. More than 50% of learners continued to demonstrate a need in understanding the clinical trial data or role of IO in metastatic GI cancers with more than 40% of the learners demonstrating continued need on clinical trial data or role of IO in HCC specifically.

Gastrointestinal (GI) cancers are highly aggressive and display genome instability, gene mutations, immune suppression, immune insensitivity, and desmoplasia. GI cancers represent as one among the most common cancer type with a burden of ~25% worldwide, with each year about 4.5 million global deaths. GI cancers are not preventive, the prognosis of patients with advanced tumors was difficult, and treating the GI cancers is the only option. For many years, the treatment of GI cancer patients involve surgery, radiotherapy, and chemotherapy in combination or alone. The successes oncologists achieved so far was great but not enough, since it is only recently, the very first promising clinical data comes into light in 2015. Hence novel therapeutic ways to treat GI cancer were much required. Presently, it appears that immunotherapy is the answer. Immunotherapy is advancing quickly and outlines, a conventional shift in the treatment of GI cancer through its promising benefits beyond conventional treatments. Currently, researchers are examining a variety of medicines and factors like immune checkpoint inhibitors, ACT, peptide vaccines, cytokines, and antibodies to treat GI cancers. In recent years, the FDA approved the utilization of anti-PD-1, anti-VEGFR2, and anti-CTLA-4, immunotherapy against a few GI cancers including gastric cancer, liver cancer, and colorectal cancers. Among all the GI cancers, biliary tract cancer and pancreatic cancer patients have limited/no immunotherapeutic options at the moment, nonetheless ongoing clinical investigation will provide some assuring therapeutic solutions. It is highly important to overcome the various factors contributing to varied effectiveness of immunotherapy in GI cancers. Researchers are currently investigating the potentiality of cancer stem cells and their specific markers as targets: outcomes from such studies may become new waves in immunotherapy treating GI cancers. Let us hope that oncologists will discover the “Magic bullet” to whitewash GI cancers in the near future and we believe it is just the beginning of the new era for immunotherapy and we have a long road ahead to succeed.

Tailoring immunotherapy in gastrointestinal cancer: the role of circulating factors Gastrointestinal (GI) cancer include malignant tumors affecting digestive organs such as esophagus, stomach, liver, pancreas, small intestine, colon and rectum. Its worldwide incidence and mortality are increasing in the last years, and the overall 5-years survival rate of patients remains less than 15%. In particular, with 1.9 million new cases and almost 0.9 million deaths in 2020, colorectal cancer (CRC) accounts for approximately 10% of all cancers and cancer-related deaths (1). Thus, prevention and treatment of GI cancer represent a major public health challenge. Moreover, the heterogeneous disease setting, challenges in early diagnosis, rapid-acting cancer development, and induction of resistance to therapy ascertain the need to identify diagnostic, prognostic and predictive biomarkers with innovative approaches for GI cancer (Figure 1 ). Tailoring Immunotherapy in Gastrointestinal Cancer: The Role of Circulating Factors is a Research Topic on the latest advances and future challenges in the field of GI tumors, with a particular focus on circulating factors as biomarker for immunotherapies. Overall, six articles provide interesting new insights regarding the use of immunotherapies in GI tumors, and the effectiveness of potential circulating biomarkers detection for predicting cancer progression or treatment response. The genetic, molecular and cellular complexity of cancer is now included in fourteen hallmarks of cancer (2). Among them, tumor-promoting inflammation plays a critical role in supporting cancer growth at different levels, by i) providing bioactive molecules to the tumor microenvironment (TME), including growth and survival factors; ii) supporting the development of new blood vessels; iii) activating extracellular matrix-modifying enzymes; iiii) altering the immune response. In particular, the normal hematopoiesis is altered in cancer patients and favors the expansion of pro-tumoral cell components, including Frontiers in Oncology frontiersin.org 01

Introduction: Circadian rhythms are evolutionarily conserved organismal processes that involve daily oscillations of biological machineries including those involved in cancer progression and immune response. Emerging research suggests that the efficacy of cancer immunotherapy may vary by time of treatment. Chronoimmunotherapy has not been studied in gastrointestinal (GI) cancers. Methods: This was a retrospective study of patients with GI cancers who received immunotherapy (nivolumab, pembrolizumab, or atezolizumab) from 2017 to 2022 at a single, academic cancer center, Rush University Medical Center (Chicago, IL). Patients were excluded if they received less than 2 infusions or if their disease burden was not assessed at a 2-3 month follow up. The primary outcome was tumor regression, defined as evidence of decreased tumor burden on radiographic imaging confirmed by the treating oncologist. Patients were divided into 2 groups; those that received 50% or more infusions after noon and those that did not. We used chi-square analysis to compare disease regression between groups. Results: Between 2017 and March 2022, we identified 63 GI cancer patients at Rush University Medical Center who were treated with immunotherapy, of which 43 patients had enough data for analysis and were included in this study. The median age was 66.7 years and 63% of patients were female. There was a trend towards a higher incidence of tumor regression in the morning vs afternoon group [(40% (9/21) vs 18% (4/22), respectively, P = 0.078]. Conclusion: Immunotherapy is becoming more widely used in multiple GI cancer types. We found a trend towards a higher incidence of tumor regression based on the timing of immunotherapy in GI cancers. The findings are consistent with results from previous studies in other tumor types (ie, melanoma, lung cancer), where administration of immunotherapy earlier in the day was associated with better outcomes. Larger studies will be needed to confirm these findings and to apply the concept of chronoimmunotherapy in GI cancers.

Role of cytokine-based immunotherapy approaches in gastrointestinal cancers.

The past few decades have witnessed the rise of immunotherapy for Gastrointestinal (GI) tract cancers. The role of immune checkpoint inhibitors (ICIs), particularly programmed death protein 1 (PD-1) and PD ligand-1 antibodies, has become increasingly pivotal in the treatment of advanced and perioperative GI tract cancers. Currently, anti-PD-1 plus chemotherapy is considered as first-line regimen for unselected advanced gastric/gastroesophageal junction adenocarcinoma (G/GEJC), mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC), and advanced esophageal cancer (EC). In addition, the encouraging performance of claudin18.2-redirected chimeric antigen receptor T-cell (CAR-T) therapy in later-line GI tract cancers brings new hope for cell therapy in solid tumour treatment. Nevertheless, immunotherapy for GI tumour remains yet precise, and researchers are dedicated to further maximising and optimising the efficacy. This review summarises the important research, latest progress, and future directions of immunotherapy for GI tract cancers including EC, G/GEJC, and CRC.

Tumor microenvironment, immunotherapy, and drug resistance in breast and gastrointestinal cancer Breast cancer (BC) and gastrointestinal (GI) cancers have historically been recognized for their significant heterogeneity and challenging nature, resulting in elevated rates of morbidity and mortality (1). Despite notable advancements and clinical achievements in cancer immunotherapies, particularly immune checkpoint blockade (ICB) therapy, which has demonstrated efficacy in various solid tumors such as melanoma (2), its effectiveness in patients with BC and GI cancers remains unsatisfactory (3, 4). The tumor microenvironment (TME), comprising non-malignant host cells and non-cellular constituents within the tumor, exerts a pivotal impact on tumorigenesis, progression, metastasis, and therapeutic resistance via dynamic interactions with neoplastic cells (5). The regulation of the tumor immune microenvironment, which is a notable tumorextrinsic factor, plays a pivotal role in the intricate mechanisms of drug resistance observed in breast and gastrointestinal cancers, particularly in the context of immunotherapy. Despite the significant advancements made in TME-targeted cancer therapy, such as ICB, the clinical efficacy of therapeutic approaches targeting the TME still falls short of expectations. Accordingly, there is a pressing need to ascertain novel targets and biomarkers that have the potential to enhance clinical effectiveness and precision in distinct patient populations. This Research Topic, titled "Tumor Microenvironment, Immunotherapy, and Drug Resistance in Breast and Gastrointestinal Cancer," was curated by 3 guest editors and comprises a collection of 9 articles, including 3 reviews and 6 original research studies. These articles offer a profound comprehension and novel Frontiers in Immunology frontiersin.org 01

P-0004 - The Evaluation of Cellular and Humoral Immunity Characteristics in Gastrointestinal and Hepatocellular Cancers

Despite the recent progress in cancer immunotherapies, most patients do not benefit from the currently available immune checkpoint blockers, and many develop severe immune-related adverse events. Therefore, it is urgent to develop alternative, effective immunotherapeutic approaches. An example of non-responsive cancers are gastrointestinal (GI) cancers, which account for 26% of the global cancer incidence and 35% of all cancer-related deaths. In many GI cancers, the failure of immunotherapies to yield clinical response is partially attributed to the inefficient antigen presentation by DC, which results in insufficient T cell stimulation despite their expression of tumor-associated antigens (TAA). To overcome these hurdles, we designed novel polymeric-based nanoparticles (NP) to deliver a combination of GI cancers antigens of CEACAM5 protein and toll-like receptor ligands to DC. We chose to encapsulate CEACAM5 antigens because it is overexpressed in GI cancers, such as gastric cancer, colorectal cancer, and pancreatic cancer. With this approach, we aim to modulate the tumor milieu-immune cell interactions to an anti-cancer phenotype in order to control tumor growth and improve overall survival. Our NP present an average diameter below 200 nm, narrow polydispersity index, slightly negative surface charge, spherical morphology, and high antigens and immune potentiators loading. Cy5-labeled NPs were found to be extensively internalized by DC, which triggered their activation in vivo, shown by the increasing expression of DC-related co-stimulatory molecules such as CD80, CD86, and CD40. Furthermore, we assessed the immunotherapeutic effect of our NP on mouse models and on a human 3D multi-cellular spheroid ex-vivo model, composing the patient’s tumor cells and peripheral blood mononuclear cells (PBMC). We found that the NP successfully induced a potent immune-mediated anti-tumor response against CEACAM5-positive GI tumors, sensitizing the tumor microenvironment to other therapies and decreasing tumor volume, ultimately leading to prolonged survival. Taken together, the developed NP induced a strong antigen-specific immune response and overall sensitized CEACAM5-expressing GI cancers to the clinically relevant treatments in vivo, that so far have shown limited clinical outcomes in addition to a specific T cell anti-tumor activity that was shown on our patient-derived ex vivo model. Citation Format: Daniella Vaskovich, Rita Acúrcio, Ron Kleiner, Barbara Carreira, Ana Matos, Helena Florindo, Ronit Satchi-Fainaro. A nano sized system for the treatment of gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3208.

Cancer immunotherapy has caused a paradigm shift from conventional therapies that directly target cancer cells to innovative therapies that utilize the host immune system. In particular, programmed cell death‐1 (PD‐1)/programmed death ligand‐1 (PD‐L1) inhibitors have achieved an impressive breakthrough and been approved for clinical use in several types of cancer including gastrointestinal (GI) cancer. To identify and develop predictive biomarkers for PD‐1 inhibitors is of great concern in clinical practice. Although PD‐L1 expression is considered a logical biomarker as PD‐L1 is a substantial target of the immune checkpoint inhibitors, its clinical significance in GI cancer remains unclear. In this review, we summarize the current evidence for PD‐L1 expression as a prognostic and predictive biomarker for PD‐1/PD‐L1 inhibitors in GI cancer from recent publications, and emerging evidence from recent key clinical trials on the efficacy of PD‐1/PD‐L1 inhibitors. Challenging clinical issues for PD‐L1 assessment are then discussed from the viewpoint of the methodology for PD‐L1 evaluation including the differences in PD‐L1 detection assays and evaluation criteria for PD‐L1 positivity. Moreover, we highlight the biological features of PD‐L1 expression in terms of tumor spatial and temporal heterogeneity, which suggests important implications for biomarker analysis. Finally, we describe future perspectives using liquid biopsy for better assessment of PD‐L1 status. This new information should improve our understanding of the clinical significance of PD‐L1 in GI cancer, leading to optimal patient selection and treatment strategy for the clinical use of PD‐1/PD‐L1 inhibitors in patients with GI cancer.

113 Background: Checkpoint inhibitor (CPI) therapies have shown prolonged survival in patients (pts) with microsatellite instability (MSI). Tumor mutation burden (TMB) has also been associated with benefit from CPIs, with pembrolizumab recently approved for solid tumors with a TMB of ≥10 muts/mb. However, the validity of a tissue-agnostic approach has been debated given the high degree of TMB variation across tumor types. We sought to evaluate the impact of TMB and MSI on CPI response in pts with advanced gastrointestinal (GI) cancers who received NGS profiling. Methods: Patients within the Sarah Cannon network with GI cancer and comprehensive next generation sequencing (NGS) data were identified through Genospace, Sarah Cannon’s clinico-genomic analytics platform. Microsatellite (MS) status [high (MSI-H) vs. stable (MSS)] was defined by NGS. TMB-high (TMB-H) was defined as ≥10 muts/mb. Kaplan-Meier estimates were used to examine time to treatment failure (TTF), defined as the time from therapy start to start of next therapy, death, or loss to follow-up. Results: We identified 5,788 pts with GI cancers who received NGS, of which 48% (N=3,603) had colorectal cancer (CRC). MS status was evaluated on 4,219 (66%) NGS reports, TMB on 2,922 (46%) reports, and both on 2,863 (45%) reports. MSI-H and TMB-H co-occurred on 127 reports (4%), MSS/TMB-H occurred on 312 reports (11%), and MSS/TMB-Low (TMB-L) occurred on 2,424 reports (85%). No reports were MSI-H/TMB-L. Overall, 580 pts (14%) received CPI therapy (N=52 MSI-H/TMB-H, N=41 MSS/TMB-H, N=215 MSS/TMB-L). Independent of line of therapy or tumor type, TTF was significantly shorter for CPI vs. non-CPI therapies [median TTF (mTTF)=151 vs. 238 days, respectively, p=3.4x10-9]. As expected, MSI-H was also associated with longer CPI TTF compared to MSS (mTTF=727 vs. 124 days, p=3.1x10-11). Due to small sample sizes, further analyses were focused on pts with CRC (Table). TMB-H was independently associated with longer CPI TTF compared to TMB-L (Table, p=9.2x10-10). Similarly, the co-occurrence of MSI-H/TMB-H was also associated with longer CPI TTF (Table). However, there was no difference in CPI TTF for MSS/TMB-H and MSS/TMB-L (Table, p=0.45). All pts who received non-CPI therapies, regardless of MS/TMB group, had longer TTF than MSS/TMB-H and MSS/TMB-L pts who received CPI (Table). mTTF [days (N)] for pts with CRC by biomarker. Conclusions: Despite recent tissue-agnostic approvals, TMB does not appear to be a good biomarker of CPI response in pts with CRC. Rather, time to CPI failure is associated with the co-occurrence of TMB-H with MSI-H. Continued research is needed to identify better biomarkers of response to immunotherapy in GI cancers. [Table: see text]

Immunotherapy is becoming an alternative method for gastrointestinal cancers, such as colorectal, gastric, and liver cancers. This field of research focuses on utilizing the immune system to recognize and eliminate cancer cells. One important method is immune checkpoint inhibitors, which enable T cells to recognize and attack tumor cells by releasing the immune system's brakes. Chimeric antigen receptor (CAR) T-cell therapy is another approach that modifies a patient's T cells to express receptors specific to tumor-associated antigens. Some cancer vaccines have demonstrated positive results in clinical trials, particularly colorectal and gastric cancers. Despite progress, challenges exist in immunotherapy for gastrointestinal cancers, such as treatment resistance, limited biomarkers for patient selection, and identifying new targets. In this review, different immunotherapy methods for all types of gastrointestinal cancers will be studied, and the limitations and benefits of each will be discussed in detail. By delving into the various immunotherapy methods, their limitations, and benefits, this review offers valuable insights that could potentially shape the future of gastrointestinal cancer treatment. It not only sheds light on the promising advancements in immune checkpoint inhibitors, CAR T-cell therapy, and cancer vaccines but also highlights the existing challenges that demand further research and innovation.

Because traditional treatment strategies for advanced gastrointestinal (GI) cancers often have a limited therapeutic effect, immunotherapy could be a viable approach for the therapy of advanced GI cancers, considering the recent success of immunotherapy in treating various refractory malignancies, including the DNA mismatch repair-deficient GI cancers. However, only a subset of cancer patients currently respond to immunotherapy. Thus, it is important to identify useful biomarkers for predicting cancer immunotherapy response. The tumor suppressor gene ARID1A has a high mutation rate in GI cancers and its deficiency is correlated with the microsatellite instability (MSI) genomic feature of cancer. We investigated the correlation between ARID1A mutations and tumor immunity using three GI cancer genomics datasets by the bioinformatic approach, and found that diverse antitumor immune signatures were more highly enriched in ARID1A-mutated GI cancers than in ARID1A-wildtype GI cancers. The elevated immune activity in ARID1A-mutated GI cancers was associated with the higher tumor mutation burden and lower tumor aneuploidy level, as well as a higher proportion of MSI cancers in this GI cancer subtype. Moreover, we found that ARID1A-mutated GI cancers more highly expressed PD-L1 than ARID1A-wildtype GI cancers. The elevated antitumor immune signatures and PD-L1 expression could contribute to the more active immunotherapeutic responsiveness and better survival prognosis in ARID1A-mutated GI cancers than in ARID1A-wildtype GI cancers in the immunotherapy setting, as evidenced in three cancer cohorts receiving immunotherapy. Thus, the ARID1A mutation could be a useful biomarker for identifying GI cancer patients responsive to immunotherapy.

Purpose:Randomized clinical trials describe the benefit of chemo-and immunotherapy for specific breast cancer patients with selected patient and disease characteristics. However, variability in practice occurs despite evidence-based guidelines [1]. The overall survival benefit for the whole population of breast cancer patients in Australia, if evidence-based guidelines for chemo-and immunotherapy were implemented, is unknown. Our study's purpose was to estimate the overall population survival benefit of routinely using evidence-based practice. Methods and Materials:Decision trees with evidence-based indications for chemotherapy have been previously defined [2]. Each branch corresponds to a specific cohort who have, or do not have, defined indications for chemotherapy and/or immunotherapy. Chemo -and immunotherapy benefit was defined as the absolute incremental benefit of either chemotherapy and/or immunotherapy over no chemo- and/or immunotherapy for radical and palliative indications. Multiple electronic citation databases were systematically queried, including Medline and the Cochrane Library. In cases where there were multiple sources of the same level of evidence, hierarchical meta-analysis was performed. The benefits of chemo- and immunotherapy were estimated for 1, 5, 10-year survival. To assess the robustness of our estimates, sensitivity analyses were performed. Results: The estimated 1-year, 5-year and 10-year absolute population-based overall survival benefits of optimally utilized chemo- and immunotherapy for breast cancer in Australia are 1.0% (95% CI, 0.9%-1.2%), 4.4% (95% CI, 4.3%-4.6%) and 5.2% (%-%), respectively. They are summarized in the Table 1. Estimation of Population Survival Benefit for First Line Chemo- and Immuno TherapyBreast CancerProportion of all cancer in Australia1 year survival benefit (Sensitivity range)5 year survival benefit (Sensitivity range)10 year survival benefit (Sensitivity range)Stage I-II10.0%0.6% (0.6%-0.7%)4.8% (4.6%-5.0%)6.9% (6.7%- 7.2%)Stage III1.6%3.0% (3.0%-3.1%)6.1% (5.8%-6.3%)0%Stage IV0.5%5.3% (5.1%-5.5%)4.9% (4.7%-5.1%)0%Whole Breast Cancer population12.1%1.0% (0.9%-1.2)4.4% (4.3%-4.6%)5.2% (5.0%-5.4%) Conclusion: Chemo- and immunotherapy agents improves overall survival in breast cancer at 1-, 5- and 10-years. Chemo-and immunotherapy provides a modest survival benefit to this patient population in Australia when it is used in accordance with guideline recommendations. These outcomes may allow comparison of treatment outcomes in a jurisdiction against what would be considered optimal based on evidence. 1. Fong, A., et al., A comparison of systemic breast cancer therapy utilization in Canada (British Columbia), Scotland (Dundee), and Australia (Western Australia) with models of "optimal" therapy. Breast, 2012. 21(4): p. 562-9. 2. Ng, W., Estimating the optimal chemotherapy utilisation rate as an evidence-based benchmark in cancers of the breast, upper gastrointestinal tract, gynaecological tract, head and neck, kidney, bladder, thyroid and unknown primary., in University of NSW, Faculty of Medicine. 2010, UNSW: Sydney. Citation Format: Delaney GP, Do V, Ng W, Barton MB. An estimation of the population survival benefit of first-line chemotherapy and immunotherapy for breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-14-11.

Immunotherapy in gastrointestinal cancer: Recent results, current studies and future perspectives