Use of immune suppression in ex vivo organ transplantation

Use of Immune Suppression in ex vivo Organ Transplantation

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While our main focus lies in cancer, our laboratory is also involved in the use of immune suppression to enhance the efficacy of organ transplantation. Currently, systemic immune suppression if critical to prevent rejection and ensuring the long-term viability of transplanted organs. Following transplantation, the recipient’s immune system recognizes the donor organ as foreign and mounts an immune response, leading to rejection. Immunosuppressive drugs are administered to suppress this response, thereby allowing the transplanted organ to integrate and function effectively within the recipient’s body. These drugs typically target various components of the immune system, including T cells, B cells, and cytokines, to inhibit immune activation and proliferation. While immune suppression is essential for preventing rejection, it also increases the risk of infections and other complications.

Our laboratory is working with other laboratories at Duke (such as the Bowles and Milano labs) to determine if ex vivo perfusion of organs using viral vectors can allow for the expression of immune suppressive genes that would allow for local immune suppression after organ transplant. In this way, gene therapy may be potently effective in enhancing transplantation and could allow for xeno-transplantation in the future.

Tumor dormancy and immune evasion

Tumor Dormancy and Immune Evasion

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Tumor dormancy and immune evasion represent two intertwined phenomena that contribute to cancer progression and therapeutic resistance. Tumor dormancy refers to a state in which cancer cells enter a quiescent phase, halting proliferation and evading detection by the immune system. During this period, cancer cells may reside in a dormant state within the primary tumor or disseminate to distant sites as micrometastases. Tumor dormancy can be induced by various factors, including the absence of pro-growth signals or the presence of inhibitory signals from the microenvironment. Importantly, dormant cancer cells often exhibit immune evasion mechanisms that allow them to escape immune surveillance and avoid immune-mediated destruction. This may involve downregulation of tumor antigens or major histocompatibility complex (MHC) molecules, upregulation of immune checkpoint molecules such as PD-L1, or recruitment of immunosuppressive cells like regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs). The interplay between tumor dormancy and immune evasion poses significant challenges in cancer therapy, as dormant cancer cells can later awaken, undergo metastatic outgrowth, and develop resistance to immune-based treatments.

We believe that understanding the mechanisms underlying tumor dormancy and immune evasion will be crucial for developing novel therapeutic strategies to prevent cancer recurrence and improve patient outcomes. Determining approaches that will allow for immune targeting and elimination of dormant tumor cells will be essential in achieving truly curative immunotherapies.

Mechanisms of metastasis

Mechanisms of Metastasis

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Almost all deaths in cancer are attributable to metastatic colonization of distant tissue and not to organ failure at from the primary tumor. The process of metastasis, or the spread of cancer cells from the primary tumor to distant sites in the body, involves a complex series of interconnected biological processes orchestrated by cancer cells. Initially, cancer cells acquire invasive properties through changes in gene expression and signaling pathways, allowing them to detach from the primary tumor and invade surrounding tissues. This process is facilitated by proteolytic enzymes that enable cancer cells to penetrate blood vessels or lymphatic vessels, with a strong selective pressure on these cells to evade immune surveillance and survive shear forces by adopting a dormant or quiescent state. Upon reaching a secondary sites, cancer cells can extravasate into the tissue parenchyma, aided by adhesion molecules and chemokines to adapt to the new microenvironment, proliferate, and establish metastatic colonies. The intricate mechanisms of metastasis involve a combination of genetic, epigenetic, and microenvironmental factors, making it a challenging aspect of cancer biology to understand and target therapeutically.

The ability of these cells to evade immunity and their ability to be targeted is a focus for work in our laboratory. Our studies have identified that many tumors are aided by inflammatory immune signaling axis to spread and can evade immunity in different manners, depending on the context of their metastatic site. While these sites vary, most cancers preferentially metastasize to specific organ sites, thus presenting an opportunity to specifically target immune suppressive mechanisms at an early stage of metastatic dissemination.

Local immune modulation of cancer

Local Immune Modulation of Cancer

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Tumors evolve to form highly immune-suppressive tissues that are often highly effective at suppressing immune cells. As such, it is imperative to manipulate the immune response within the tumor microenvironment to enhance anti-tumor activity and suppress these tumor-promoting signals. The local modulation of immunity aims to tip the balance towards immune-mediated tumor elimination through the local stimulation of immunity, which allows the education of systemic immune responses that are tailored to the cancer, which would allow for systemic responses against distant but related tumors. Local immune modulation represents a promising avenue in cancer therapy, offering a personally targeted immune response (in situ vaccine) and potentially less toxic alternatives to conventional treatments by stimulating immune responses to specifically combat cancer cell. However, the ability to stimulate local immune responses, neutralize immune suppression mechanisms, circumvent structural barriers within the tumor and administer these treatments within the tumor microenvironment remain significant challenges to this approach.

The focus of our research has been in exploiting gene delivery as a means to express innate and adaptive immune genes within the tumor microenvironment to stimulate immunity, as well as studies that determine the underlying immune suppressive mechanisms. The identification of these factors will allow our targeting of these factors, which could allow for new and more targeted methods to block immune-suppressive checkpoints.

Development of in vivo cancer models

Development of in vivo Cancer Models

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Mouse models of cancer serve as essential research tools in understanding the complexity of cancer biology and evaluating potential therapeutic interventions. While our laboratory uses many different cancer cell lines, de novo cancer require the use of genetically engineered mouse models (GEMMs). These GEMMs involve the manipulation of specific genes associated with cancer development, such as tumor suppressor genes or oncogenes, to mimic human cancer gene expression, mutations, and deletions. These models allow researchers to study the initiation and progression of cancer in a controlled environment. Critically, these models allow us to assess the development and metastases of cancers in an immune competent context, which is essential for our studies of tumor immunology. Additionally, cancers from these mice can be used to generate novel mouse-derived syngeneic cancer cells that cancer be used in immunocompetent mice, enabling researchers to investigate interactions between the immune system and cancer cells. These different models offer unique advantages and limitations, providing our lab with different platforms that can be used to address research questions.

Our laboratory is interested in the development of novel models of cancer that are reflective of human disease, with our current efforts focusing on the development of different models for breast, prostate, pancreatic, and lung cancers. Additionally, we are exploring the impact of immune tolerance against different antigens, developing models that allow for the use of xenoantigens and to assess different types of tissue-restrictive immune tolerance.

Antibody and antibody-drug conjugate therapeutics in cancer

Antibody and Antibody-Drug Conjugate Therapeutics in Cancer

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While immunotherapy has been dominated by studies of T cells, antibodies (the product of B cells) have been proven agents against cancer for decades and are the mainstay of treatment for several different types of cancer. More recently, Antibody-Drug Conjugates (ADCs) have emerged as powerful strategies in cancer treatment, leveraging the specificity of antibodies to target cancer cells while minimizing damage to healthy tissues. Treatments using monoclonal antibodies (mAbs) are still the standard-of-care for many cancers, which bind to specific antigens on cancer cells and trigger immune-mediated destruction of cancer cells. Additionally, ADCs combine the targeting ability of antibodies with the cytotoxic potency of chemotherapeutic drugs. In ADCs, a cytotoxic drug is conjugated to the antibody, allowing for selective delivery of the drug to cancer cells expressing the target antigen. While these therapies are emerging as the new frontline of cancer treatment, it remains surprisingly unknown how they clinically function and are regulated. It also remains unclear why some fail and what role antibodies play in the tumor immune microenvironment.

Our lab is interested in understanding the role of B cells and different types of antibodies in the tumor microenvironment and in dissecting the mechanisms of action for the agents. Furthermore, we are invested in identifying novel antibodies that could be used in cancer treatment, as well as exploring strategies that might enhance the clinical efficacy of anti-tumor antibodies and ADCs.

Cancer vaccines

Cancer Vaccines

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Cancer vaccines are a promising approach in immune oncology, aiming to both stimulate immunity against cancer, while targeting adaptive immunity at critical oncologic targets. Unlike traditional vaccines that prevent infectious diseases, cancer vaccines are generally utilized to treat existing cancers or prevent cancer recurrence/resistance. Cancer vaccines stimulate innate immune response, thereby triggering adaptive immunity to recognize specific antigen expressed by cancer cells, as a means to target these cells. While some cancer vaccines use a patient’s own cells or proteins to train the immune system, our group has used a variety of genetically engineered viruses as cancer vaccines. In our clinical trials and those of others, cancer vaccines have shown remarkable potential, offering a more targeted and potentially less toxic alternative to conventional treatments like chemotherapy or radiation therapy. However, significant challenges remain, including the impact of immune tolerance, the highly immune suppressive nature of advanced cancers, as well as the variability of individual immune responses, necessitating additional ongoing research and development to optimize their effectiveness.

In our laboratory, we are currently exploring the potential of different kinds of vaccine platforms in isolation or combination with immune checkpoint inhibitor and agonist agents to enhance their therapeutic efficacy against a variety of cancers.