An overall review of the immunobiology of TL1A and
TNFRSF25 can be found here: Schreiber Immunol Rev 2013
An accurate analogy for non-immunologists to understand the steps involved in immune activation (particularly for T cells) is to use the analogy of an automobile. In order to drive your car, you must first insert the key into the ignition, engage the appropriate gear in the transmission and then you are able to control the speed and direction of the vehicle using the accelerator, brake and steering. The steps required to activate human T cells follow a very similar hierarchy of signals. First, a T cell must engage an appropriate antigen via the T cell receptor, which is similar to inserting a key into the ignition. Second, an antigen-activated T cell must receive costimulatory signals through membrane bound receptors (B7-family receptors including CD28, CTLA-4 and PD-1 as well as tumor-necrosis factor family receptors), which is analogous to putting a car into gear. The sum action of engaging an antigen and a costimulatory receptor then sensitize T cells to a number of soluble cytokine receptors (including interleukin receptors and TNF family receptors), which provides an analogous signal to accelerating and steering your automobile. The hierarchy of these signals is organized such that costimulatory signals and cytokines are generally inactive unless the T cell receptor has first been engaged, similar to the ignition in your automobile.
There is considerable complexity within each of these signaling networks, particularly the costimulatory signals available to T cells. Generally speaking, costimulatory signals can be either activating (‘drive’ signals) or inhibitory (‘reverse’ signals). Activating signals are important for initiating an immune response and inhibitory signals are required to dampen an immune response when it is no longer needed. The FDA-approved monoclonal antibody, Yervoy, blocks the inhibitory activity of a receptor known as CTLA-4, resulting in de-inhibition of tumor-antigen specific T cells. This product has led to remarkable results in patients with very late-stage melanoma and soon in other tumor types. Similarly, there are two agents in development which block the inhibitory signal provided by a ligand known as PD-L1, to its receptor PD-1. These agents also lead to de-inhibition of immune responses and have shown promising results in stimulating immune responses in late-stage cancer patients.
There is a dynamic expression pattern of various costimulatory receptors among different types of T cells. Some, such as CTLA-4, are expressed by virtually all T cells in the human body. Others have a more restricted pattern of expression, which may be more specific to T cells that have developed ‘memory’ to a particular antigen; such as PD-1. Part of the excitement surrounding PD-1 blocking antibodies, is that they may be less toxic than CTLA-4 blocking antibodies. The reason for this is because PD-1 blocking antibodies act on a smaller population of T cells than Yervoy, and thus the likelihood of developing severe gastrointestinal inflammation or other toxicities is expected to be reduced.
A particularly exciting family of costimulatory receptors are related to tumor necrosis factor, and are grouped together as TNF-related superfamily members (TNFRSF). Generally speaking, this family of costimulatory receptors has an even more restricted pattern of expression than CTLA-4 or PD-1, and are thus believed to be responsible for fine-tuning of immune responses. Pelican Therapeutics is developing agents that stimulate one of these receptors, known as TNFRSF25.
TNFRSF25 interacts with a ligand known as TL1A, which has the highest similarity to TNF itself among all TNF family members. The core activity of TNFRSF25 stimulation is to amplify T cell sensitivity to endogenous IL-2 in a T cell receptor dependent manner.
TNFRSF25 is constitutively expressed by an immunosuppressive type of T cell known as regulatory T cells (Treg). In humans, Tregs are responsible for preventing autoimmunity throughout our lives, which is best exemplified by people who are born with a genetic deficiency in Tregs (known as IPEX syndrome), who suffer from multi-organ system inflammation and early death. Tregs are known to prevent virtually all forms of autoimmunity and are also known in experimental systems to be capable of providing durable tolerance to solid organ and cell based transplantation. Thus, there is considerable promise in developing Treg based therapies in humans. This progress has been limited to date however, to ex vivo based approaches (requiring similar manufacturing procedures to autologous cell vaccines) that face significant regulatory, safety, manufacturing and cost headwinds at commercial scale.
Pelican Therapeutics is developing PTX-25F to provide a first-in-class strategy to stimulate Treg proliferation in vivo. In pre-clinical studies, TNFRSF25 stimulating fusion proteins led to rapid and highly specific proliferation of Treg cells to 4-fold their resting frequency within 5 days. These expanded Treg were subsequently shown to prevent inflammation in animal models of acute asthma, chronic asthma, fully allogeneic solid organ transplants as well as prevent ocular immunopathology to herpes virus-1 infection.
In addition, Pelican is developing PTX-25A as a next-in-class agent to provide potent stimulation of CD8+ memory T cells for use in Immuno-Oncology. As compared to the known T cell costimulators (OX40, GITR, 4-1BB), TNFRSF25 provides several fold more potent stimulation of memory CD8+ T cells. This compound represents a highly promising target in the emerging Immuno-Oncology landscape that is now expanding beyond ‘checkpoint’ inhibitory compounds to include direct T cell costimulators as well.
A revolution in human immunotherapy is underway, heralded by the recent approval of Yervoy for late stage melanoma patients. The anticipated approval of PD-1 inhibitors will soon provide additional evidence that manipulation of costimulatory pathways is a valid therapeutic approach for human disease. These approvals will set the stage for the next generation of costimulatory receptor modulating agents; including TNFRSF25 targeting agents for the specific modulation of Treg cells and memory CD8+ T cells in vivo.