Advances In Cancer Immunotherapy Research Articles

Progress in the treatment of advanced hepatocellular carcinoma with immune combination therapy.

Advanced hepatocellular carcinoma (HCC) is a severe malignancy that poses a serious threat to human health. Owing to challenges in early diagnosis, most patients lose the opportunity for radical treatment when diagnosed. Nonetheless, recent advancements in cancer immunotherapy provide new directions for the treatment of HCC. For instance, monoclonal antibodies against immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1/death ligand-1 inhibitors and cytotoxic t-lymphocyte associated antigen-4 significantly improved the prognosis of patients with HCC. However, tumor cells can evade the immune system through various mechanisms. With the rapid development of genetic engineering and molecular biology, various new immunotherapies have been used to treat HCC, including ICIs, chimeric antigen receptor T cells, engineered cytokines, and certain cancer vaccines. This review summarizes the current status, research progress, and future directions of different immunotherapy strategies in the treatment of HCC.

Immune microenvironment in hepatocellular carcinoma: current concepts and the role of blockade of immune checkpoints

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. The specificity of the immune microenvironment of an organ limits the possibilities of traditional therapeutic and surgical approaches to treatment, therefore one of the most important tasks of modern medicine is the search for new therapeutic targets targeting the tumor microenvironment. The introduction of checkpoint inhibitors into clinical practice expands immunotherapeutic options in the fight against liver cancer. The purpose of our review is to summarize the available data on the liver immune microenvironment in hepatocellular carcinoma and to present advances in cancer immunotherapy using immune checkpoint blockade. Material and methods. An analysis of the main foreign and domestic sources was carried out using the PubMed/Medline, ClinicalTrials.gov databases over the past 5 years. Results. In terms of morbidity and mortality, hepatocellular carcinoma is included in the list of the most common malignant neoplasms in the world and the forecasts for the coming decades are disappointing. Modern approaches to immunotherapy, taking into account the tumor microenvironment, are associated with better survival rates and safety profiles than standard therapy. Conclusion. The effectiveness of checkpoint inhibitors as monotherapy and combination strategies offers hope for improving the prognosis and quality of life of patients with unresectable HCC.

γδ T Cells: A Game Changer in the Future of Hepatocellular Carcinoma Immunotherapy.

Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment options and a poor prognosis for advanced-stage patients. Recent advancements in cancer immunotherapy have generated significant interest in exploring novel approaches to combat HCC. One such approach involves the unique and versatile subset of T cells known as γδ T cells. γδ T cells represent a distinct subset of T lymphocytes that differ from conventional αβ T cells in terms of antigen recognition and effector functions. They play a crucial role in immunosurveillance against various malignancies, including HCC. Recent studies have demonstrated that γδ T cells can directly recognize and target HCC cells, making them an attractive candidate for immunotherapy. In this article, we aimed to explore the role exerted by γδ T cells in the context of HCC. We investigate strategies designed to maximize the therapeutic effectiveness of these cells and examine the challenges and opportunities inherent in applying these research findings to clinical practice. The potential to bring about a revolutionary shift in HCC immunotherapy by capitalizing on the unique attributes of γδ T cells offers considerable promise for enhancing patient outcomes, warranting further investigation.

Interferons in Colorectal Cancer Pathogenesis and Therapy.

As key modulators of the immune response, interferons play critical roles following infection and during the pathogenesis of cancer. The idea that these cytokines might be developed as new therapies emerged soon after their discovery. While enthusiasm for this approach to cancer therapy has waxed and waned over the ensuing decades, recent advances in cancer immunotherapy and our improved understanding of the tumor immune environment have led to a resurgence of interest in this unique class of biologic drug. Here, we review how interferons influence the growth of colorectal cancers (CRCs) and highlight new insights into how interferons and drugs that modulate interferon expression might be most effectively deployed in the clinic.

Nanozymes in cancer immunotherapy: metabolic disruption and therapeutic synergy.

Over the past decade, there has been a growing emphasis on investigating the role of immunotherapy in cancer treatment. However, it faces challenges such as limited efficacy, a diminished response rate, and serious adverse effects. Nanozymes, a subset of nanomaterials, demonstrate boundless potential in cancer catalytic therapy for their tunable activity, enhanced stability, and cost-effectiveness. By selectively targeting the metabolic vulnerabilities of tumors, they can effectively intensify the destruction of tumor cells and promote the release of antigenic substances, thereby eliciting immune clearance responses and impeding tumor progression. Combined with other therapies, they synergistically enhance the efficacy of immunotherapy. Hence, a large number of metabolism-regulating nanozymes with synergistic immunotherapeutic effects have been developed. This review summarizes recent advancements in cancer immunotherapy facilitated by nanozymes, focusing on engineering nanozymes to potentiate antitumor immune responses by disturbing tumor metabolism and performing synergistic treatment. The challenges and prospects in this field are outlined. We aim to provide guidance for nanozyme-mediated immunotherapy and pave the way for achieving durable tumor eradication.

Strategies to Overcome Hurdles in Cancer Immunotherapy

Despite marked advancements in cancer immunotherapy over the past few decades, there remains an urgent need to develop more effective treatments in humans. This review explores strategies to overcome hurdles in cancer immunotherapy, leveraging innovative technologies including multi-specific antibodies, chimeric antigen receptor (CAR) T cells, myeloid cells, cancer-associated fibroblasts, artificial intelligence (AI)-predicted neoantigens, autologous vaccines, and mRNA vaccines. These approaches aim to address the diverse facets and interactions of tumors’ immune evasion mechanisms. Specifically, multi-specific antibodies and CAR T cells enhance interactions with tumor cells, bolstering immune responses to facilitate tumor infiltration and destruction. Modulation of myeloid cells and cancer-associated fibroblasts targets the tumor’s immunosuppressive microenvironment, enhancing immunotherapy efficacy. AI-predicted neoantigens swiftly and accurately identify antigen targets, which can facilitate the development of personalized anticancer vaccines. Additionally, autologous and mRNA vaccines activate individuals’ immune systems, fostering sustained immune responses against cancer neoantigens as therapeutic vaccines. Collectively, these strategies are expected to enhance efficacy of cancer immunotherapy, opening new horizons in anticancer treatment.

Interaction between Gut Microbiota and Dendritic Cells in Colorectal Cancer.

Colorectal cancer (CRC) is a malignancy that manifests in serial stages and has been observed to have an escalating incidence in modern societies, causing a significant global health problem. The development of CRC is influenced by various exogenous factors, including lifestyle, diet, nutrition, environment, and microbiota, that can affect host cells, including immune cells. Various immune dysfunctions have been recognized in patients with CRC at different stages of this disease. The signature of microbiota in the development of CRC-inflammation related to obesity, diet, and reactive host cells, such as dendritic cells (DCs)-has been highlighted by many studies. This study focuses on DCs, the primary cellular mediators linking innate and adaptive immune responses against cancer. In addition, this review focuses on the role of microbiota in dysbiosis and how it affects DCs and, in turn, the immune response and progression of CRC by stimulating different sets of T cells. Additionally, DCs' role in protecting this delicate balance is examined. This is to determine how gene yields of commensal microbiota may be critical in restoring this balance when disrupted. The stages of the disease and major checkpoints are discussed, as well as the role of the C-type lectin receptor of immature DCs pattern recognition receptor in CRC. Finally, based on a thorough examination of worldwide clinical studies and recent advancements in cancer immunotherapy, it is recommended that innovative approaches that integrate DC vaccination strategies with checkpoint inhibitors be considered. This approach holds great promise for improving CRC management.

Blockage of CacyBP inhibits macrophage recruitment and improves anti-PD-1 therapy in hepatocellular carcinoma

BackgroundDespite remarkable advancements in cancer immunotherapy, the overall response rate to anti-programmed cell death-1 (anti-PD-1) therapy in hepatocellular carcinoma (HCC) patients remains low. Our previous study has demonstrated the critical role of CacyBP/SIP (Calcyclin-Binding Protein and Siah-1 Interacting Protein) as a regulator of HCC development and progression. However, the possible impact of CacyBP on the tumor immune microenvironment has not yet been clarified.MethodsThe expressions of CacyBP and Myd88 in HCC cell lines and tissues was detected by bioinformatics analysis, real-time quantitative PCR, western blotting and immunohistochemistry. The interaction between CacyBP and Myd88 was measured using co-immunoprecipitation and immunofluorescence. In vitro and in vivo assays were used to investigate the regulation of CacyBP on tumor-associated macrophages (TAMs).ResultsWe identified that CacyBP was positively correlated with Myd88, a master regulator of innate immunity, and Myd88 was a novel binding substrate downstream of CacyBP in HCC. Additionally, CacyBP protected Myd88 from Siah-1-mediated proteasome-dependent degradation by competitively binding to its Toll/interleukin-1 receptor (TIR) domain. Inhibition of CacyBP-Myd88 signaling subsequently diminished HDAC1-mediated H3K9ac and H3K27ac modifications on the CX3CL1 promoter and reduced its transcription and secretion in HCC cells. Moreover, by using in vitro and in vivo strategies, we demonstrated that depletion of CacyBP impaired the infiltration of TAMs and the immunosuppressive state of the tumor microenvironment, further sensitizing HCC-bearing anti-PD-1 therapy.ConclusionsOur findings suggest that targeting CacyBP may be a novel treatment strategy for improving the efficacy of anti-PD-1 immunotherapy in HCC.

Recent Advances in Cancer Immunotherapy with a Focus on FDA-Approved Vaccines and Neoantigen-Based Vaccines.

Cancer immunotherapies refer to the concept of retraining the immune system to target malignant cells. Multiple immunotherapeutic options exist including immune modulating antibodies, immune stimulating cytokines, chimeric antigen receptor T cell therapy, and vaccines. Overall, this field has advanced rapidly as knowledge of the tumor microenvironment, immunological pathways, and biotechnology expands. Specifically, advancements in neoantigen identification, characterization, and formulation into a vaccine show promise. This review is focused on previously United States Food and Drug Administration-approved cancer therapeutic vaccines and neoantigen-based vaccine developments along with the associated relevant clinical trials.

Risk assessment of cancer patients based on HLA-I alleles, neobinders and expression of cytokines

Advancements in cancer immunotherapy have shown significant outcomes in treating cancers. To design effective immunotherapy, it's important to understand immune response of a patient based on its genomic profile. However, analyses to do that requires proficiency in the bioinformatic methods. Swiftly growing sequencing technologies and statistical methods create a blockage for the scientists who want to find the biomarkers for different cancers but don't have detailed knowledge of coding or tool. Here, we are providing a web-based resource that gives scientists with no bioinformatics expertise, the ability to obtain the prognostic biomarkers for different cancer types at different levels. We computed prognostic biomarkers from 8346 cancer patients for twenty cancer types. These biomarkers were computed based on i) presence of 352 Human leukocyte antigen class-I, ii) 660959 tumor-specific HLA1 neobinders, and iii) expression profile of 153 cytokines. It was observed that survival risk of cancer patients depends on presence of certain type of HLA-I alleles; for example, liver hepatocellular carcinoma patients with HLA-A*03:01 are at lower risk. Our analysis indicates that neobinders of HLA-I alleles have high correlation with overall survival of certain type of cancer patients. For example, HLA-B*07:02 binders have 0.49 correlation with survival of lung squamous cell carcinoma and −0.77 with kidney chromophobe patients. Additionally, we computed prognostic biomarkers based on cytokine expressions. Higher expression of few cytokines is survival favorable like IL-2 for bladder urothelial carcinoma, whereas IL-5R is survival unfavorable for kidney chromophobe patients. Freely accessible to public, CancerHLA-I maintains raw and analysed data (https://webs.iiitd.edu.in/raghava/cancerhla1/).

Peptide-Appended Nanosonosensitizers Targeting Tumor Glycolysis for Synergistic Sonodynamic-Immunometabolic Therapy of Spinal-Metastasized Tumors.

Despite recent advancements in cancer immunotherapy, challenges have yet to be surmounted to achieve two major goals of magnifying antitumor immunity and remodeling the immunosuppressive tumor microenvironment. Here, a nanosystem (ODM-R) that integrates oxygen-deficient molybdenum oxide (ODM) nanosonosensitizers and R7 peptides with tumor metabolism regulation effects is designed and fabricated for synergistic sonodynamic-immunometabolic therapy of spinal-metastasized tumors. The ODM generates reactive oxygen species upon ultrasound irradiation to implement sonodynamic therapy (SDT), inducing cancer cell apoptosis and immunogenic cell death. The R7 attached on ODM markedly inhibits the uptake of glucose and excretion of lactic acid in cancer cells by perturbing the glycolysis process. The combination of SDT and tumor glycolysis obstruction by ODM-R guarantees satisfactory efficacy in synergizing with PD-L1 antibody to eradicate spinal-metastasized tumors, achieving concurrent sonodynamic-triggered immune activation and immunosuppressive tumor microenvironment remodeling. This work provides a proof-of-concept of nanosonosensitizers for boosting cancer immunotherapy by SDT and tumor metabolic regulation.

Dendritic Cell-Derived Exosomes in Cancer Immunotherapy.

Exosomes are nanoscale vesicles released by diverse types of cells for complex intercellular communication. Numerous studies have shown that exosomes can regulate the body's immune response to tumor cells and interfere with the tumor microenvironment (TME). In clinical trials on dendritic cell (DC)-based antitumor vaccines, no satisfactory results have been achieved. However, recent studies suggested that DC-derived exosomes (DEXs) may be superior to DC-based antitumor vaccines in avoiding tumor cell-mediated immunosuppression. DEXs contain multiple DC-derived surface markers that capture tumor-associated antigens (TAAs) and promote immune cell-dependent tumor rejection. These findings indicate the necessity of the further development and improvement of DEX-based cell-free vaccines to complement chemotherapy, radiotherapy, and other immunotherapies. In this review, we highlighted the recent progress of DEXs in cancer immunotherapy, particularly by concentrating on landmark studies and the biological characterization of DEXs, and we summarized their important role in the tumor immune microenvironment (TIME) and clinical application in targeted cancer immunotherapy. This review could enhance comprehension of advances in cancer immunotherapy and contribute to the elucidation of how DEXs regulate the TIME, thereby providing a reference for utilizing DEX-based vaccines in clinical practice.

Monocyte subsets associated with the efficacy of anti‑PD‑1 antibody monotherapy.

Immune checkpoint inhibitors (ICIs) are among the most notable advances in cancer immunotherapy; however, reliable biomarkers for the efficacy of ICIs are yet to be reported. Programmed death (PD)-ligand 1 (L1)-expressing CD14+ monocytes are associated with shorter overall survival (OS) time in patients with cancer treated with anti-PD-1 antibodies. The present study focused on the classification of monocytes into three subsets: Classical, intermediate and non-classical. A total of 44 patients with different types of cancer treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) were enrolled in the present study. The percentage of each monocyte subset was investigated, and the percentage of cells expressing PD-L1 or PD-1 within each of the three subsets was further analyzed. Higher pretreatment classical monocyte percentages were correlated with shorter OS (r=-0.32; P=0.032), whereas higher non-classical monocyte percentages were correlated with a favorable OS (r=0.39; P=0.0083). PD-L1-expressing classical monocytes accounted for a higher percentage of the total monocytes than non-classical monocytes with PD-L1 expression. In patients with non-small cell lung cancer (NSCLC), a higher percentage of PD-L1-expressing classical monocytes was correlated with shorter OS (r=-0.60; P=0.012), which is similar to the observation for the whole patient cohort. Comparatively, higher percentages of non-classical monocytes expressing PD-L1 were significantly associated with better OS, especially in patients with NSCLC (r=0.60; P=0.010). Moreover, a higher percentage of non-classical monocytes contributed to prolonged progression-free survival in patients with NSCLC (r=0.50; P=0.042), with similar results for PD-L1-expressing non-classical monocytes. The results suggested that the percentage of monocyte subsets in patients with cancer before anti-PD-1 monotherapy may predict the treatment efficacy and prognosis. Furthermore, more classical monocytes and fewer non-classical monocytes, especially those expressing PD-L1, are involved in shortening OS time, which may indicate the poor efficiency of anti-PD-1 treatment approaches.

Potential of Personalized Dendritic Cell-Based Immunohybridoma Vaccines to Treat Prostate Cancer.

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second most common cause of death due to cancer. About 30% of patients with PCa who have been castrated develop a castration-resistant form of the disease (CRPC), which is incurable. In the last decade, new treatments that control the disease have emerged, slowing progression and spread and prolonging survival while maintaining the quality of life. These include immunotherapies; however, we do not yet know the optimal combination and sequence of these therapies with the standard ones. All therapies are not always suitable for every patient due to co-morbidities or adverse effects of therapies or both, so there is an urgent need for further work on new therapeutic options. Advances in cancer immunotherapy with an immune checkpoint inhibition mechanism (e.g., ipilimumab, an anti-CTLA-4 inhibitor) have not shown a survival benefit in patients with CRPC. Other immunological approaches have also not given clear results, which has indirectly prevented breakthrough for this type of therapeutic strategy into clinical use. Currently, the only approved form of immunotherapy for patients with CRPC is a cell-based medicine, but it is only available to patients in some parts of the world. Based on what was gained from recently completed clinical research on immunotherapy with dendritic cell-based immunohybridomas, the aHyC dendritic cell vaccine for patients with CRPC, we highlight the current status and possible alternatives that should be considered in the future.

Long noncoding RNA MIAT regulates TP53 ubiquitination and expedites prostate adenocarcinoma progression by recruiting TBL1X

Despite recent advances in cancer immunotherapy, their efficacy for treating patients with prostate adenocarcinoma (PRAD) is low due to complex immune evasion mechanisms. However, the function of long non-coding RNA (lncRNAs) in immune evasion has not been fully clarified. This study aimed to expound the role of myocardial infarction-associated transcript (MIAT), a lncRNA significantly upregulated in three PRAD-associated datasets, in immune evasion and try to reveal the potential mechanism. MIAT was highly expressed in PRAD tissues and predicted poor prognosis, and suppression of MIAT inhibited the malignant biological behavior of PRAD cells. Moreover, the depletion of MIAT promoted the immune response of CD8+ T cells and hampered the immune evasion of PRAD cells. In addition, MIAT downregulated TP53 protein expression by recruiting transducin beta-like protein 1X (TBL1X) for ubiquitination modification. Silencing of TP53 or overexpression of TBL1X was enough to abate the tumor suppressive effects of MIAT knockdown in vitro and in vivo. Our results provide evidence for a novel regulation mechanism of CD8+ T cells in PRAD and MIAT may serve as a potential therapeutic target in PRAD.

Light-responsive nanomedicine for cancer immunotherapy.

Immunotherapy emerged as a paradigm shift in cancer treatments, which can effectively inhibit cancer progression by activating the immune system. Remarkable clinical outcomes have been achieved through recent advances in cancer immunotherapy, including checkpoint blockades, adoptive cellular therapy, cancer vaccine, and tumor microenvironment modulation. However, extending the application of immunotherapy in cancer patients has been limited by the low response rate and side effects such as autoimmune toxicities. With great progress being made in nanotechnology, nanomedicine has been exploited to overcome biological barriers for drug delivery. Given the spatiotemporal control, light-responsive nanomedicine is of great interest in designing precise modality for cancer immunotherapy. Herein, we summarized current research utilizing light-responsive nanoplatforms to enhance checkpoint blockade immunotherapy, facilitate targeted delivery of cancer vaccines, activate immune cell functions, and modulate tumor microenvironment. The clinical translation potential of those designs is highlighted and challenges for the next breakthrough in cancer immunotherapy are discussed.

The Interplay between T Cells and Cancer: The Basis of Immunotherapy.

Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor (CAR)-engineered T cells has produced robust responses in blood cancers, and T cell receptor (TCR)-engineered T cells are showing promising results in the treatment of solid cancers. Despite these noteworthy advancements in cancer immunotherapy, numerous challenges remain. Some patient populations are unresponsive to immune checkpoint inhibitor therapy, and CAR T cell therapy has yet to show efficacy against solid cancers. In this review, we first discuss the significant role that T cells play in the body's defense against cancer. We then delve into the mechanisms behind the current challenges facing immunotherapy, starting with T cell exhaustion due to immune checkpoint upregulation and changes in the transcriptional and epigenetic landscapes of dysfunctional T cells. We then discuss cancer-cell-intrinsic characteristics, including molecular alterations in cancer cells and the immunosuppressive nature of the tumor microenvironment (TME), which collectively facilitate tumor cell proliferation, survival, metastasis, and immune evasion. Finally, we examine recent advancements in cancer immunotherapy, with a specific emphasis on T-cell-based treatments.

Dynamics and specificities of T cells in cancer immunotherapy.

Recent advances in cancer immunotherapy - ranging from immune-checkpoint blockade therapy to adoptive cellular therapy and vaccines - have revolutionized cancer treatment paradigms, yet the variability in clinical responses to these agents has motivated intense interest in understanding how the T cell landscape evolves with respect to response to immune intervention. Over the past decade, the advent of multidimensional single-cell technologies has provided the unprecedented ability to dissect the constellation of cell states of lymphocytes within a tumour microenvironment. In particular, the rapidly expanding capacity to definitively link intratumoural phenotypes with the antigen specificity of T cells provided by T cell receptors (TCRs) has now made it possible to focus on investigating the properties of T cells with tumour-specific reactivity. Moreover, the assessment of TCR clonality has enabled a molecular approach to track the trajectories, clonal dynamics and phenotypic changes of antitumour T cells over the course of immunotherapeutic intervention. Here, we review the current knowledge on the cellular states and antigen specificities of antitumour T cells and examine how fine characterization of T cell dynamics in patients has provided meaningful insights into the mechanisms underlying effective cancer immunotherapy. We highlight those T cell subsets associated with productive T cell responses and discuss how diverse immunotherapies might leverage the pre-existing tumour-reactive T cell pool or instruct de novo generation of antitumour specificities. Future studies aimed at elucidating the factors associated with the elicitation of productive antitumour T cell immunity are anticipated to instruct the design of more efficacious treatment strategies.

Abstract 188: Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development

Abstract Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients for a large range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. We developed an innovative alternative, built on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient specific organoids are generated from healthy and malignant tissues and stored as biobanks with high quality and reproducibility. HUB Organoids recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity, and morphological and functional traits. Since cancer progression and responses to immunotherapy are governed by immune cell interactions in the tumor microenvironment, we developed an assay in which colorectal (CRC) and non-small cell lung cancer (NSCLC) tumor organoids are co-cultured with simultaneously expanded paired tumor infiltrating lymphocytes (TIL) as a source of tumor reactive cells. Our system allows robust expansion of TIL with preserved T-cell receptor repertoires and has an establishment rate of 75%. Paired resources allow for screening of immune-modulatory therapies under physiologic conditions not depending on peptide-pulsing and allo-reactivity. For this purpose, we developed a organoid-TIL co-culture system which quantifies and characterizes tumor organoid apoptosis by combining image-based analysis with flow cytometry and cytokine release assays as measurements of T-cell cytotoxicity against tumor (and normal-matched) organoids. Our system offers a powerful tool for the development and validation of cancer immunotherapy and may help to stratify cancer patients for susceptibility of various types of immunotherapies. Citation Format: Soura Mardpour, Claudia Beaurivage, Jane Sun, Lorenz Jahn, Rene Overmeer, Lars-Eric Fielmich, Pleun Hombrink, Farzin Pourfarzad, Sylvia F. Boj. Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 188.

Abstract 908: Tumour organoid-t cell co-culture assay to evaluate CAR t cell cytotoxicity

Abstract Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients for a large range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. HUB developed an innovative alternative, build on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient specific organoids are generated from healthy and malignant tissues and stored as biobanks with high quality and reproducibility. HUB Organoids recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity, and morphological and functional traits. Since cancer progression and responses to immunotherapy are governed by immune cell interactions in the tumour microenvironment, we developed an assay in which various types of tumour organoids are co-cultured with T cells modified with chimeric antigen receptors (CAR T cells) to assess the cytotoxic potential. CAR-T cell therapy has been demonstrated to be efficacious against many hematological malignancies, however therapeutic application to treat solid cancers remains challenging. Our organoid-T cell co-culture assay offers a good platform to study the response of tumour organoids on the CAR T cells and will greatly contribute to our understanding of the critical factors that determine a successful CAR T cell therapy. In collaboration with GSK, HUB tested the cytotoxicity of GSK CAR T cells which target specific target antigen on human colorectal cancer (CRC) organoids. Six HUB CRC organoid models were selected based on differential expression levels of target antigen that was confirmed by FACS antibody staining. To evaluate GSK CAR T cell mediated organoid killing, caspase 3/7 expression was monitored at various timepoints and IFNγ secretion was measured by ELISA. For control, staurosporine and nonspecific-CAR T cells were included. Detected CRC-organoid killing demonstrated to be in line with antigen expression levels, indicating the specificity of the tested CAR T cells. Nevertheless, some CRC-organoid models demonstrated more resilient to CAR T cell mediated killing and further evaluation revealed upregulation of check point molecules such as PD-L1. This study reveals that tumour organoid-T cell co-culture assay hold value for preclinical development of CAR T-cell products and for evaluating tumour-evasion strategies. Moreover, this platform could potentially predict patient specific responses to CAR- T-cell therapy. Citation Format: Soura Mardpour, Mirella Georgouli, Ana Pereira Puri, Ravit Oren, Joshua Audu-Evans, Farzin Pourfarzad, Sara Brett, Pleun Hombrink, Sylvia F. Boj. Tumour organoid-t cell co-culture assay to evaluate CAR t cell cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 908.