In light of the numerous US FDA-approved humanized monoclonal antibodies (mAbs) for cancer immunotherapy, it is surprising that the advancement of B-cell epitope vaccines designed to elicit a natural humoral polyclonal antibody response has not gained traction in the immune-oncology landscape. Passive immunotherapy with humanized mAbs (Trastuzumab [Herceptin] Pertuzumab [Perjeta] has provided clinical benefit to breast cancer patients, albeit with significant shortcomings including toxicity problems and resistance, high costs, sophisticated therapeutic regimen and long half-life. The role of B-cell humoral immunity in cancer is under appreciated and under-developed. Thus, we have advanced the idea of active immunotherapy with specially designed chimeric B-cell epitope peptides incorporating a ‘promiscuous’ T-cell epitope that elicits a polyclonal antibody response, which provides safe, cost–effective therapeutic advantage over mAbs. We have developed two chimeric peptides comprising an herceptin-like and Perjeta-like conformational B-cell epitope vaccines and have translated our HER-2 vaccines in two Phase I/Ib clinical trials (NCT01376505; IND #14633) in breast and colon cancers overexpressing HER-2, and we have demonstrated excellent safety and anticancer immunity. This trial is being transferred from OSU to IUSCCC.

Cancer immunotherapy with checkpoint inhibitors has also resulted in impressive clinical results by restoring anti-tumor immunity and affording durable responses in several different cancer indications. Blockade of checkpoint receptors with monoclonal antibodies against cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4, ipilimumab) and program cell death protein 1 (anti PD-1, nivolumab) and its ligand (anti PD-L1, atezolizumab) has shown great clinical success in several cancer subtypes, yielding unprecedented responses. Despite this success, only a fraction of patients show a durable and complete response to monoclonal antibody drugs exhibiting a wide spectrum of immune-related adverse events, including the rapid development of resistance, poor tissue penetration, off-target effects, high treatment costs and high toxicity rates. Combinations of ICI have been advanced to resolve these problems, however with increased incidence of adverse events and autoimmunity.

We introduced the development of novel chimeric vaccines PD-1(PD1-Vaxx), PD-L1 (PDL1-Vaxx) and CTLA-4 (CTLA-4-Vaxx) B-cell peptide epitope vaccines and in preclinical studies in syngeneic BALB/c -CT26 and C57BL6/J-MC38 colon carcinoma mouse models. These studies support our effort to find a cure for colorectal cancers (CRC) which is set to take the most lives of people under 50 by 2030. In the USA, 5-year survival is only 12.5%, reflecting a clear unmet need for more effective treatments for patients with metastatic CRC (mCRC).

We have conducted in vivo efficacy combination studies: (i) PD1-Vaxx, (ii) PDL1-Vaxx and (iii) CTLA-4-Vaxx in syngeneic BALB/c 4T1 carcinoma mouse models to identify the best combination vaccine candidate as demonstrated by inhibition of tumor growth, prolonged survival rate and correlative in-vitro studies. Triple Negative Breast Cancer (TNBC) is an aggressive and deadly type of cancer that accounts for 15% of breast cancer cases diagnosed in the USA. It more frequently afflicts young women and those of African and Hispanic ancestry. In this presentation, I will review and discuss our approaches and strategies that focus on B-cell epitope cancer vaccines and combination onco-immuno strategies for CRC and TNBC.

Cell-based therapeutics show immense promise in treating a variety of currently incurable diseases due to their potent mechanisms. However, despite recent successes, challenges persist in manufacturing and commercializing these therapies. Notably, inconsistencies in reagent quality pose a significant hurdle, impacting the reproducibility, efficacy, and safety of cell therapy products. GenScript, a leading biopharmaceutical supplier, offers tailored solutions to overcome these obstacles. Our stringent quality control and robust supply chain management ensure reliable, high-quality reagents and services for both small and large-scale manufacturing. Furthermore, our innovative solutions accelerate the therapeutic pipeline from early-phase research to commercialization.

In our webinar, we address the manufacturing challenges of T cell therapies and demonstrate how our solutions effectively navigate each stage of the process. Whether you're in the discovery phase, moving to clinical trials, or advancing towards commercialization, GenScript provides customized support to meet your specific needs. From supplementary materials to automated tools, we're committed to expanding the accessibility of cell and gene therapies to benefit more patients.

The recognition of mRNA molecules as a transformative class of therapeutic drugs has soared, particularly with the development of COVID 19 mRNA vaccines. The cancer treatment landscape is similarly experiencing a dramatic shift through the introduction of mRNA-based immunotherapies. To enhance the stability and functionality of mRNA, more advanced solutions are required. In our upcoming presentation, we will illustrate the full spectrum of our one-stop circRNA service, sequence design, plasmid construction, mRNA synthesis, and LNP encapsulation. We will delve into our sequence optimization strategies, which include proprietary cyclization sequences, high-efficiency internal ribosome entry sites (IRES), codon optimization, and secondary structure refinement. We will also showcase our advanced in vitro transcription (IVT) production techniques and our novel circular RNA chromatography purification process, which consistently elevates circRNA purity levels >90%. Moreover, we will present our linear RNA processing platform as well as our comprehensive quality analysis platform. We aim to highlight our extensive expertise in the CMC development for both linear and circular RNA-based therapeutics.

Learning Objectives: 

1. Gain insights into the production process and optimization strategies of circRNA.

2. Summarize the strategic design for high efficiency cyclization of circRNA.

3. Review the comprehensive quality analysis platform for Circular and Linear RNA.

Chimeric antigen receptor (CAR) T-cell therapy shows significant potential in treating various human cancers. Unfortunately, researchers have faced difficulty in adapting this therapy to target solid tumors, where CAR T cells face unique challenges, such as antigen heterogeneity, an immuno-suppressive microenvironment, and T-cell exhaustion.

However, none of these challenges matter unless the CAR T cells can extravasate out of the blood stream and successfully migrate to the site of the tumor- an often-overlooked yet critical rate-limiting part of the process that cannot be modeled in conventional cell cultures.

To address this, Emulate has recently launched a validated Organ-Chip workflow enabling researchers to model the entire journey of solid tumor CAR T-cell therapy in a vascularized cancer cell line model.

Join Emulate Principal Scientist Anita Mehta, PhD, as she demonstrates the capabilities of this new CAR T Organ-Chip workflow in a data-driven webinar. Researchers will learn how to use Organ-Chips to model CAR T-cell therapy administration, vascular attachment, migration, and antigen-specific killing- all in a single model.

This presentation looks at the dynamic landscape of therapeutic antibody development, focusing on next-generation immuno-oncology therapeutics that target checkpoint inhibitors and incorporate the immune system’s defense strategies to modulate T-cell engagers. Through a comprehensive overview, attendees will gain insights into the history of antibody drugs, including key milestones and approved antibodies in immuno-oncology. The presentation will also highlight GenScript's technologies to advance therapeutic antibody development, offering innovative solutions tailored to each stage of the process. Discover how GenScript's expertise and state-of-the-art technologies can streamline workflow, optimize antibody leads, and facilitate the transition from preclinical studies to clinical trials.

Learning Objectives: 

1. Gain an understanding of the history and evolution of antibody drugs, including key milestones and therapeutic areas of focus.

2. Discuss GenScript's custom antibody generation and optimization services.

3. Review high-quality recombinant antibody and protein expression services.

Chimeric antigen receptor (CAR) T cell therapy has emerged as a novel therapeutic option for cancer patients in recent years. Despite its success, this approach faces acknowledged limitations and potential toxicities, such as antigen escape, on-target off-tumor effects, and an immunosuppressive microenvironment. To address the challenges associated with conventional CAR-T therapy, researchers are exploring innovative CAR strategies. These include the expression of dual or tandem CARs, the remodulation of CAR structure, and combination immunotherapies with checkpoint blockade. An alternative approach involves utilizing immune cell types such as natural killer (NK) cells in CAR-based therapies. CAR-NK cell therapies, created using the same receptor-antigen hybrid technology as CAR-T, express the CAR in NK cells. Compared to CAR-T therapy, CAR-NK cell therapy is considered safer with a reduced risk of negative immune side effects. Clinical trials have demonstrated promising results for CAR-NK cell therapies in both solid tumors and hematological malignancies. In this context, the session will emphasize how Sino Biological is at the forefront of facilitating the development of CAR-T and CAR-NK cell therapies through comprehensive solutions. These solutions encompass every stage, from CAR development to the preparation of CAR-T and CAR-NK cells, along with CAR-T/ CAR-NK cells quality control.

Learning Objectives: 

1. Summarize the different CAR-associated cellular immunotherapies in clinic.

2. Review current limitations and potential strategies of CAR-associated cellular immunotherapy.

3.Discuss Sino Biological solutions supporting CAR-T therapy, CAR-NK cell therapy development.

Despite the remarkable clinical efficacy of chimeric antigen receptor (CAR) T cells in hematological malignancies, only a subset of patients achieve a durable complete response. Furthermore, significant obstacles to CAR T cell therapy remain to treat solid tumors. Complex immunosuppressive tumor microenvironments (TME) and the exploitation of checkpoint pathways allow tumors to evade the immune system. We have developed novel methods to create CAR T cells enriched with T cells of memory phenotypes that have improved metabolic fitness for both hematological and solid tumors.

Learning Objectives:

1. Explain the challenges currently facing CAR T cell therapy.

2. Identify how CAR T cell can be engineered to address these challenges.

3. Describe how CAR T cells can be modified to overcome immune checkpoints in the tumor microenvironment.

Join this year's poster presenters in the Poster Hall during the Poster Discussion, Tuesday, April 30th, from 10:00 AM –11:00 AM PDT, to chat live about their posters and latest research and findings.

Nanovials are emerging as an accessible platform for performing single-cell functional screening leveraging standard instrumentation, such as flow cytometers and microfluidic single-cell sequencing platforms. Each cell and its secreted products are captured in nanovials where they can be analyzed and sorted using widely available fluorescence activated cell sorters. Nanovials also act as artificial antigen-presenting cells to capture T cells based on the binding of their T cell receptors (TCRs) to antigens on the nanovials, including peptide-loaded major histocompatibility complex I (pMHC) or MHC-like molecules that present metabolites. By binding to these antigens, T cells are activated to secrete cytokines and other effector molecules, which can be captured on the same nanovial. In this way, T cells can be selected based on binding AND functional characterization of secretion of cytokines and other effector molecules, and sorted for downstream single-cell sequencing of matched TCR alpha and beta chains. By adding an oligo-barcoded detection antibody specific to the secretions, each TCR sequence also can be functionally annotated based on the amount of secretion it induces. Because both binding and cellular function can be assayed for millions of cells with standard equipment, this new “lab on a particle” approach can accelerate the discovery of cancer-specific TCRs, and TCRs against metabolites presented by unconventional MHC-like molecules, with high accuracy, promising to transform the discovery of these critical recognition elements for improved engineered T cell therapies.

Learning Objectives: 

1. Discover how nanovial-based workflows can accelerate discovery of T cell receptors (TCRs).

2. Review how to associate secreted information from single cells to matched alpha and beta TCR sequences.

3. Discuss how TCRs from mucosal associated invariant T cells and invariant natural killer T cells can be recovered and functionally annotated.

Chimeric antigen receptor (CAR) T-cell therapy has been extremely successful in treating relapsed/refractory B-cell malignancies, with six CAR T-cell products now FDA approved. Unfortunately, very limited success has been seen in translating CAR T-cell therapy for T-cell malignancies, primarily due to the lack of a cancer-specific target antigen on malignant T cells. This has resulted in several challenges in translating this innovative immunotherapy for T-cell disease: (i) CAR T cells designed against a T-cell antigen undergo fratricide (self-killing) due to the shared antigen expression on normal and malignant T cells, leading to difficulty in CAR T-cell expansion; (ii) off-tumor on-target toxicity from T-cell antigen directed CAR T cells can result in life-threatening immunosuppression from T-cell aplasia and (iii) the inability to isolate healthy T cells from a patient with a T-cell malignancy can result in product contamination, wherein malignant T cells may be inadvertently genetically modified to express the CAR, thereby making them resistant to CAR therapy. To the best of our knowledge, no tumor-specific antigen has yet been identified with universal expression on cancerous T cells, thereby hindering the development CAR T-cell therapy for this disease. Numerous approaches have been tested to address each of these challenges, such as (i) disrupting target antigen expression on CAR-modified T cells, (ii) targeting antigens with limited expression on T cells, and (iii) using third party donor cells that are either non-alloreactive or have been genome edited at the T-cell receptor α constant (TRAC) locus. In this presentation, we will discuss CAR-based approaches that have been explored both in preclinical and clinical studies targeting T-cell antigens, as well as examine other potential strategies that can be used to successfully translate this therapy for T-cell disease.

Learning Objectives: 

1. Discuss the specific challenges involved in targeting T-cell malignancies with CAR T-cell therapy.

2. Review the different strategies utilized by investigators to overcome these barriers.

3. Discuss clinical trials testing CAR T-cell therapy for T-cell malignancies.

In the field of tumor immunotherapy, cancer vaccines are designed to help the immune system recognize and attack cancer cells. More efforts are needed to identify neoantigens, develop combination therapies, and optimize vaccination techniques before cancer vaccines become a viable treatment.

In this webinar, we will review the main types of vaccines and the pros and cons of each type. Key considerations for mRNA vaccine outsourcing and compare circular RNA and saRNA as alternative approaches. We will also discuss neoantigens and GenScript's solutions for advancing the development of cancer vaccines.

Learning Objectives: 

1. Review typical vaccine types and mechanism.

2. Discuss linear mRNA vaccine and circular RNA and saRNA as alternative approaches.

3. Summarize the importance of neoantigen peptide for personalized cancer vaccines.

Adoptive cell therapy (ACT) is an immunotherapy that employs living immune cells to target and destroy cancer cells. However, the inhibitory tumor microenvironment features several obstacles to antitumor immunity, including hypoxia, inhibitory ligands, and altered immune cell programming, supporting conversion of anti- to pro-tumorigenic cell types. We developed T cell engineering strategies to address multiple inhibitory mechanisms and enhance ACT efficacy. In the first approach, we developed Fas switch receptors that convert a death signal to a costimulatory signal for T cells. Here we show that this approach can “supercharge” T cells to overcome hypoxia barriers and significantly improve survival in murine models of cancer. Another obstacle to ACT efficacy is the induction of pro-tumor macrophages that promote resistance to therapy and exhibit reduced phagocytosis. Pro-tumor macrophages show significant plasticity and can be polarized to antitumor programming with costimulatory signals, increasing phagocytosis of tumor cells and recruitment of other antitumor immune cells. One such costimulatory signal, CD40, has been explored to induce antitumor myeloid immunity and agonist CD40 antibodies have been tested in clinical trials. However, enthusiasm for agonist antibody therapies has been dampened by dose-limiting toxicities, inadequate pharmacokinetics and tissue penetration, and the non-tumor targeted delivery of the antibody modality. We sought to develop a T cell engineering strategy to deliver CD40 costimulatory signals to the AML-BM and reprogram inhibitory macrophages. We engineered membrane-bound fusion proteins, CD40L Dual Costimulatory Receptors (DCR), that pair the CD40L ectodomain costimulatory endodomains. We advanced leading CD40L DCRs to proof-of-concept in vivo testing in murine tumor models and found that CD40L DCR-T cell therapy significantly enhanced therapeutic outcomes. We also observed a significant increase in antitumor macrophages as compared to control T cells, suggesting that CD40L DCR expression indeed induced macrophage conversion. Our long-term objective is to develop strategies and define mechanisms to employ both innate and adaptive immunity to provide a diverse and durable antitumor immune response against cancer, and support clinical translation.

Learning Objectives:

1. Summarize assays to evaluate T cell antitumor function.

2. Describe tumor microenvironment inhibitory mechanisms.

3. Explain how CD40 signaling alters immune cell programming.

Brain cancer research stands to benefit from the perspectives, tools, and methodologies of non-traditional fields, such as mechanical engineering. Here, I will discuss our engineering-based approaches to understanding “immunomechanics” (i.e., the generation of physical forces by immune cells) and “mechano-immunology” (i.e., the impact of physical forces on immune cell function) in the context of glioblastoma– a rare but universally fatal brain cancer. The heterogeneous and abnormal tumor microenvironment associated with glioblastoma is comprised up to 50% by immune cells, such as tumor-associated macrophages. These macrophages are reciprocally regulated with mechanics in the tumor microenvironment, which can drive cancer progression and treatment resistance. I will describe a novel in vitro model to study these interactions and reveal targetable mechanisms to improve therapeutic response, not only in the context of glioblastoma, but other cancers as well.  

Learning objectives:

1. Explain and distinguish immunomechanics and mechano-immunology.

2. Describe the mechanical forces generated by brain tumors as they grow.

3. Discuss the impact of mechanical forces on brain tumor immunity.

Understanding the spatial organization of the immune response within tumors is crucial for developing effective cancer immunotherapies. In this seminar, we delve into the interactions between the tumor microenvironment and immune cells, focusing on how these interactions influence tumor progression and rejection. We introduce the Skin Tumor Array by Microporation (STAMP) model as a novel preclinical tool for studying tumor immunotypes and dynamics in real time. Through a series of experiments, we explore the cellular and molecular determinants of different immunotypes and demonstrate their dynamic nature over time. By studying the complexities of the tumor-immune microenvironment, our research aims to contribute to the development of more effective cancer treatments and improve patient outcomes.

Learning Objectives: 

1. Explain the significance of the Cancer Immunity Cycle, outlining its 6 key steps and how they contribute to the body's ability to recognize and eliminate tumors.

2. Identify the three T cell immunotypes and understand their relation to tumor regression/progression.

3. Describe one of the key cellular determinants of different immunotypes and their roles in shaping tumor fate.

Throughout history, various approaches including surgery, radiation therapy, chemotherapy, and targeted therapy have been employed in the fight against cancer. In the 2010s, the emergence of immunotherapy marked a significant turning point in cancer treatment, leveraging our own immune system to combat cancer. Despite its breakthroughs, immunotherapy faces challenges such as resistance, both initially and over time. Our focus is on enhancing immunotherapy by targeting intrinsic pathways within cancer cells. Specifically, we examine two types of cancer cells: regular (differentiated) cancer cells and cancer stem cells (tumor-initiating cells). Join us as we delve into these research directions, illuminating our efforts to advance cancer treatment through innovative approaches.

Learning Objectives: 

1. Review targeting FBXO44/SUV39H1 pathway in cancer cells to enhance anti-PD1 immunotherapy. 

2. Summarize targeting novel regulators in glioblastoma stem cells for NK cell-based immunotherapy.

3. Explain viral mimicry strategy in cancer immunotherapy.

Cell-based therapies are advanced medical treatments for cancers and other diseases. Autologous and allogeneic cell therapies use immune cells from either a patient or from healthy donor sample blood, respectively, followed by the activation, expansion, and ex vivo genetic modification of those immune cells. The development and manufacturing of safe, high-efficacy cell therapy products involve complex and costly processes. Given the growing demand for these promising therapies, robust and well-characterized biomanufacturing processes must be established. 

Learning Objectives:

1. Describe current challenges in the cell therapy industry.

2. Summarize the importance of bioprocessing reagents manufactured with consistent, high-quality well-defined components.