Meet HUB at booth #2367

SPOTLIGHT TALK

Patient-derived organoids: a revolutionary platform for faster, more efficient, and clinically relevant drug development

Speaker: Robert Vries, Ph.D., CEO, HUB Organoids
When: April 16th | 3:30-4:30 pm EST
Where: Spotlight Theater D 

Patient-derived organoids (PDOs) are a scalable and clinically-relevant platform preserving the original disease features in long-term cultures. PDOs are used in standard preclinical drug screening for target validation and lead selection as well as in co-clinical approaches where clinical trials in a dish are performed to stratify responders and non-responders and identify predictive biomarkers. In this talk, Dr. RObert Vries shows how PDOs have contributed to the successful development of oncology and immuno-oncology agents currently in clinical trials after significantly shortened developmental timelines, and proposes how they will take the center stage in drug development by replacing standard preclinical models for faster, cost-efficient, and successful pipelines

SPOTLIGHT TALK

Patient-derived organoids: an emerging platform to de-risk immunotherapy development

Speaker: Sylvia Boj, Ph.D., CSO, HUB Organoids
When: April 18th 10 AM-11 AM EST
Where: Spotlight Theater A

Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients with liquid cancers. 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 rapidly. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. Patient-derived organoids (PDOs) are generated from adult stem cells resident in healthy and malignant tissues which, when embedded in Matrigel^(R), form mini-organs that recapitulate complex characteristics of the parental tissue, including molecular heterogeneity, morphological and functional traits. Importantly they preserve tumor-specific antigens that are conventionally lost in standard in vitro models, therefore representing an excellent system to investigate target engagement, mechanisms of action and to stratify a patient population based on tumor molecular features. In this talk, Dr. Sylvia Boj, CSO at HUB Organoids will discuss the development of autologous patient-derived organoid biobanks relevant for testing immuno-oncological compounds (PDO and immune cells) and co-culture assays to evaluate different immuno-oncology products such as CAR T-cells, T cell engagers, and checkpoint inhibitors

POSTER PRESENTATION

#2924 Organoid co-cultures with autologous T cells to assess toxicity and efficacy of bispecific antibodies

Session Category: Immunology
Session Title: Therapeutic Antibodies 2
Session Date and Time: Monday, Apr 17, 2023, 1:30 PM - 5:00 PM
                                                 Location: Poster Section 23

The life expectancy of patients with various clinical indications has been positively affected by the recent advancements in cancer immunotherapy. The identification of new druggable targets and treatment strategies has led to an increasing number of patients being eligible for this form of therapy. Despite the promising therapeutic developments, there are obstacles in translating preclinical findings into practical applications due to the limited clinical predictive value of conventional 2D cancer models. HUB developed an innovative alternative, building on the discovery that adult stem cells proliferate and organize into three-dimensional organotypic structures when embedded into an extracellular matrix. Patient-specific organoids are generated from normal 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 non-small cell lung cancer (NSCLC) organoids are co-cultured with autologous T cells to evaluate the activity and assess the cytotoxic potential of a T cell-bispecific (TCB) antibody. Our organoid and T cell co-culture system quantifies and characterizes organoid apoptosis by image-based analysis of the Caspase 3/7 activity. Additionally, we assess cytokine secretion as a measure of T cell activation and function. Here, we measured the T cell cytotoxicity of autologous T cells against normal and tumor-derived PDOs to assess the sensitivity and specificity of a tumor antigen (TA)-targeting TCB. Immunohistochemistry confirmed higher TA expression on tumor-derived PDOs compared to normal-derived PDOs. In our co-culture assays tumor-derived PDO apoptosis exceeded in apoptosis of normal-derived PDOs. Similarly, IFN-γ secretion correlated with expression levels of targeted TA. In addition, PDO apoptosis and IFN-γ secretion increased in a dose-dependent fashion in the presence of the TA-targeting TCB. In summary, our organoid and T cell co-cultures offer an excellent platform to study the response of tumor organoids to T cell-bispecific antibodies and will significantly contribute to our understanding of the critical factors determining successful immunotherapies.

POSTER PRESENTATION

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

Session Category: Clinical Research Excluding Trials
Session Title: Adoptive Cell Therapy 1
Session Date and Time: Sunday Apr 16, 2023, 1:30 PM - 5:00 PM
Location: Poster Section 37

Since cancer progression and responses to immunotherapy are governed by immune cell interactions in the tumor microenvironment, we developed an assay in which various types of tumor 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 and T cell co-culture assay offers a good platform to study the response of tumor organoids on the CAR T-cells and will greatly contribute to our understanding of the critical factors that determine successful CAR T-cell therapy. In collaboration with GSK, HUB tested the cytotoxicity of GSK CAR T-cells which target specific target antigens on human colorectal cancer (CRC) organoids. Six HUB CRC organoid models were selected based on differential expression levels of target antigen that were confirmed by FACS antibody staining. To evaluate GSK CAR T cell-mediated organoid killing, caspase 3/7 expression was monitored at various time points and IFNγ secretion was measured by ELISA.  For control, staurosporine and nonspecific-CAR T cells were included.  Detected CRC-organoid killing was 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 resilience to CAR T cell-mediated killing, and further evaluation revealed the upregulation of checkpoint molecules such as PD-L1. This study reveals that tumor organoid and T cell co-culture assay holds value for the preclinical development of CAR T-cell products and for evaluating tumor-evasion strategies. Moreover, this platform could potentially predict patient-specific responses to CAR T-cell therapy.

POSTER PRESENTATION

#157: Patient in the lab: Down-scaling patient-derived organoid screening for diagnostic purposes

Session Category: Tumor Biology
Session Title: Tumor Organoids for Cancer Research
Session Date and Time: Sunday Apr 16, 2023, 1:30 PM - 5:00 PM
                                                 Location: Poster Section 6

Colorectal cancer (CRC) is the third leading cause of cancer and cancer-related death. A large fraction of CRC patients diagnosed with de novo metastatic disease do not benefit from standard medical care and experience substantial side effects. Therefore, there is an urgent need for preclinical models that help predict patient response in the clinic. Patient-derived organoids (PDOs or HUB Organoids) represent a significant breakthrough in preclinical models as they are directly established from patient tissue and accurately recapitulate patient disease. HUB Organoid Technology has previously demonstrated promising outcomes in preclinical drug screening. However, to provide direct patient benefit, the turnaround time between patient diagnosis and PDO-based results must be shortened. In collaboration with Yamaha Motor, the YAMAHA CELL HANDLER^TM has been optimized and validated to automatically pick and place with high accuracy a significantly reduced number of organoids per screening plate.

POSTER PRESENTATION

#189: Developing a patient-derived organoid biobank, suitable for large-scale drug screenings

Session Category: Tumor Biology
Session Title: Tumor Organoids for Therapeutic Testing
Session Date and Time: Sunday Apr 16, 2023, 1:30 PM - 5:00 PM
                                                 Location: Poster Section 7

Conventional models for preclinical drug screening offer poor predictive value for patient response, causing high attrition rates of new agents in the clinic. HUB’s proprietary Patient-Derived Organoid (PDO) Technology enables long-term expansion of primary patient material to generate ‘mini organs in a dish’ that can be used as patient avatars, thus bringing every “patient in the lab^®”. We present the world’s first NMIBC PDO biobank comprising 50 PDO models from transurethral resection of the bladder (TURB) biopsies collected at three hospitals. Clinical and pathological characterization of the PDOs confirmed the representation in the biobank of a range of tumor stages and differentiation grades, as well as patient treatment and follow-up. The genomic analyses of PDOs revealed mutations in known BC driver genes and genomic instability, a hallmark of cancer. Finally, transcriptomic analyses confirmed gene expression profiles familiar to BC and characterized gene fusions. Next, we successfully screened the biobank on a panel of two reference compounds for the treatment of bladder cancer and seven candidate drugs, indicating potential new leads for further development of some of the compounds. The work presented here shows the feasibility of building PDO biobanks representing a specific patient population, suitable for improving the drug development pipeline for the next generation of cancer drugs.

POSTER PRESENTATION

#151 Optimization of screening conditions using patient-derived organoids for diagnostic purposes

Session Category: Tumor Biology
Session Title: Tumor Organoids for Cancer Research
Session Date and Time: Sunday Apr 16, 2023, 1:30 PM - 5:00 PM
                                                  Location: Poster Section 6

Patient-derived organoids (PDOs) are increasingly adopted in preclinical research. PDOs, or HUB Organoids, are directly established from patient tissue, faithfully recapitulate patient disease, and effectively bridge the gap between the lab and the clinic, bringing a “patient in the lab®”. PDOs can also revolutionize clinical research because they can predict patient response to standard-of-care (SoC) compounds. However, there is an urgent need to refine the assay conditions to evaluate the activity of SoC drugs with different mechanisms of action (topoisomerase inhibitors, alkylating agents, targeted agents) and various types of molecules (small molecules, antibodies) and achieve optimal results from the PDO-based assay. Specifically, for metastatic colorectal cancer (mCRC), we have optimized the media composition required for drug screening assays to test response to SoC, such as oxaliplatin and panitumumab. Our results indicate that optimal media conditions are essential to observe an in vitro drug response in PDOs similar to the patient response in the clinic. In addition, an image-based readout was developed that enables precise quantification of organoid numbers ensuring high assay quality. Optimizing screening conditions to evaluate SoC compounds in PDOs is a required step to accelerate the implementation of the HUB Organoid Technology as a diagnostic platform to accurately predict treatment response and improve clinical outcomes for cancer patients.

POSTER PRESENTATION

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

Session Category: Tumor Biology
Session Title: Tumor Organoids for Therapeutic Testing
Session Date and Time: Sunday, Apr 16, 2023, 1:30 PM - 5:00 PM
                                                  Location: Poster Section 7

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, build on the discovery that adult stem cells proliferate and organize into three-dimensional organotypic structures when they are embedded into an 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 the screening of immune-modulatory therapies under physiologic conditions not depending on peptide-pulsing and alloreactivity. For this purpose, we developed an organoid-TIL co-culture system that 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 to various types of immunotherapies.