The aim of immuno-oncology therapy is to revert the immune-suppressive environment created by the tumor cells into an immune-permissive environment. This will enable the immune cells to recognize and eliminate the tumor cells. As a result, the patient’s own body attacks the cancer cells leading to tumor control or tumor regression in responsive patients. The tumor immune-suppressive environment is characterized by the expression of immune checkpoints like PD1-PDL1, by the presence of immune-suppressive cells including regulatory T cells and by repulsive factors and the tumor vasculature that exclude immune cells from entering the tumor.
A major clinical breakthrough was achieved upon the development of checkpoint inhibitors targeting PD1-PDL1 that show clinical activity across a broad range of cancer types. Unfortunately, not all cancer patients respond well or in a durable manner. There is a need for additional immune oncology therapies that can be combined with the therapies currently in the clinic or in development.
"Conventional therapies like chemo and radiation often delay the disease instead of killing the tumor, which provides a long-term cure," notes Massimiliano Mazzone. "The latter possibility is achieved nowadays with immunotherapies. The main idea of immunotherapy is to use the body's own immune cells to fight cancer. Unfortunately, these soldiers often do not reach the tumors and treatment remains ineffective. Oncurious is engaged in studying the repulsive cues that exclude the immune cells out of the tumors and aims to break this barrier and increase the activity of the immune system against the tumor. The ultimate goal is to make the tumor unshielded."
Professor Massimiliano Mazzone (VIB-KU Leuven)
Oncurious is working on therapies that are focused on the elimination of CCR8-expressing immune-suppressive regulatory T cells, with the aim to boost the anti-tumor immune response. In addition, Oncurious is investigating different therapeutic concepts around T cell exclusion from the tumor. It is anticipated that increasing the influx of T cells and other immune cells into the tumor will stimulate the anti-tumor response.
These therapies will bring an enhanced therapeutic benefit to cancer patients on top of the existing clinical immune oncology treatments available.
Efector T cell activity in the tumor is strongly controlled by regulatory T cells. These regulatory T cells are a very immunosuppressive T cell subset that play an important role in the immune evasion by tumors (1). Inhibition of or removal of these regulatory T cells in the tumor microenvironment will lead to an enhanced immune response against the tumor cells. As regulatory T cells are crucial as well for the control of autoimmunity, modulating regulatory T cell activity is preferable limited to the tumor itself. This can be achieved through targeting markers that are specific for tumor infiltrating regulatory T cells.
Modulation of tumor T cell influx
Previous research made it clear that there is a strong link between high T cell levels inside the tumor and improved survival chances for patients (2). To dampen the body’s immune response the tumor excludes effector T cells. This is achieved through stromal and vascular inhibitory processes that reduce or completely block the influx of T cells into the tumor (3). Overcoming these factors is anticipated to result in higher T cell levels and a better anti-tumor immune response. In view of its novel targets around T cell migration Oncurious is developing an antagonistic molecule that blocks a T cell repulsive signal. In addition, Oncurious is also exploring whether modulation of the tumor vasculature to improve immune cell influx results in a better therapeutic outcome. Overall Oncurious believes that improving tumor T cell influx will improve the efficacy of the currently available immuno-oncology therapeutics to benefit the lives of cancer patients.
Medulloblastoma is a rapidly growing malignant primary brain tumor that originates in the cerebellum (the lower rear portion of the brain). It is the most common pediatric malignant brain tumor, accounting for 20% of all brain tumors in children. In the EU and US ~400 new patients are diagnosed annually, with boys being affected twice as much. The peak age of incidence is 3-5 years and ~80% of patients are diagnosed before 15 years old.
Current treatment consists of cancer surgery, followed by craniospinal (brain and spine) radiation and/or chemotherapy. Although treatment improves survival, these regimens are associated with significant morbidity and are highly toxic to the developing brains resulting in significant neurocognitive impairment in young children.
Treating medulloblastoma with anti-PlGF
In our search to improve the treatment of medulloblastoma, we are investigating the potential of anti-PlGF (placental growth factor) for the treatment of medulloblastoma.
This is based on the scientific research of Prof. Rakesh Jain (Massachusetts General Hospital, Harvard, Boston, US) and Peter Carmeliet (VIB-KU Leuven, Belgium). This research was published in 2013 in the scientific journal Cell (4). In this landmark paper, the authors illustrated that blocking PlGF signaling in medulloblastoma mouse models results in tumor regression, decreased metastasis and improved survival.
(1) Yano H, Andrews LP, Workman CJ, Vignali DAA. Intratumoral regulatory T cells: markers, subsets and their impact on anti-tumor immunity. Immunology. 2019 Jul;157(3):232-247.
(2) Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006 Sep 29;313(5795):1960-4.
(3) Sackstein R, Schatton T, Barthel SR. T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy. Lab Invest. 2017 Jun;97(6):669-697.
(4) Snuderl et al. Targeting Placental Growth Factor/Neuropilin 1 Pathway Inhibits Growth and Spread of Medulloblastoma. Cell. 28 Feb 2013.