Our Science

The re-definition of tumor stroma as an immune regulator rather than an inflexible immune barrier harbors profound untapped therapeutic opportunity.

In published work, we have demonstrated that regulated proteolysis of the matrix proteoglycan versican (VCAN) generates a bioactive fragment, versikine, that regulates the cross-talk between the APCs and effector CD8+ T cells. This bioactive fragment is a potent regulator of APC activity in the TME, and its presence is associated with both activation of APCs and expansion of the effector T cell population as well as penetration into the tumor site.

Strikingly, in vivo data now demonstrates that versikine sensitizes PD-1 pathway refractory tumors to anti-PD1 checkpoint inhibition, and the combination of versikine with PD1 checkpoint inhibitors leads to complete tumor regression in multiple animal tumor models.

Our Challenge

Many decades of research and development of drugs directly targeting the cancer cell have yielded great advances in therapy. However, the majority of cancers have remained poorly served with current therapies. More recently, a growing awareness of the importance of the tumor microenvironment (TME) has given rise to broad programs of novel agents that are complementing existing treatments. In particular, advances in immunotherapies, most notably the checkpoint inhibitors, have transformed treatment in multiple cancers. Despite these successes, targeting the TME remains an underdeveloped area in oncology. Moreover, multiple common cancers remain resolutely ‘immunologically cold’ in respect to their insensitivity to immunological modulation.

How to overcome the barriers of immune insensitivity

The TME is a complex and dynamic entity that interacts with the cancer cell in many ways, frequently being co-opted into a role that is supportive to further cancer growth and invasion. The range of interacting factors includes tumor-infiltrating immune cells, immune-suppressive cells, stromal cells, extracellular matrix and its breakdown products, soluble and chemical factors (such as chemokines, cytokines, pH and hypoxia), all of which influence and shape the process of antigen capture and presentation.

A key to overcoming the barrier of immune insensitivity lies in the better understanding of tumor antigen presentation and the complex and dynamic heterogeneity of tumor-infiltrating antigen presenting cells (APCs).

A Solution

The tumor stroma holds a prime role in this process by hosting specialised APC niches that support second antigenic touch encounters between primed T cells and tumor-resident APCs. It is this second round of co-stimulation of primed T cells that allows expression of full effector potential and tumor penetration, thereby preventing further tumor proliferation and growth. Conversely, the lack of second touch encounters will render the primed T cells deficient in their effector potential and allow continued tumor growth.

Enhancing T cell effect through directed stromal signalling

Our research indicates that recently identified stromal breakdown products provide instructive signals that mirror those of embryonic growth or wound healing. This contrasts with the conventional understanding of the TME as a physical and functional ‘immune barrier’. Indeed, the quantity and quality of second touch encounters between APCs and T cells produce distinct T cell infiltration patterns in human cancer, conferring predictable immune sensitivity or insensitivity.

We propose that APCs within second-touch niches become licensed for co-stimulation through these stromal-derived instructive signals. Stromal control of antigen presentation makes evolutionary sense as the host stroma-tumor interface constitutes the prime line of homeostatic ‘defense’ against the emerging tumor.

Our Plan

We intend to further characterize versikine, the bioactive proteolytic fragment of VCAN, and thereafter develop a platform of therapeutics that can deliver versikine to the tumor. These could be in the form of fusion proteins, antibody drug conjugates, bispecific antibodies, lipid nanoparticles, or other delivery vehicles such as therapeutic nanoparticles.

Step 1

Characterization of Versikine

Step 2

Therapeutic Platform Development

Step 3

Exploration of Delivery Mechanisms