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Cyteph is a clinical-stage spin-out company of QIMR Berghofer, developing off-the-shelf T cell and CAR T cell therapies, harnessing the power of the immune system to target and destroy solid tumours. Cyteph CAR-T platform leverages virus-specific T cells to overcome the challenges with safety, efficacy and persistence that current CAR T therapies have faced in clinical development.

The virus-specific T cells underpinning the CAR-T platform have been significantly de-risked through three successful investigator-initiated phase 1 trials. Despite breakthroughs in the treatment of haematological malignancies with CAR T cells, their efficacy in treating solid cancers has been limited. We use highly potent virus-specific immune cells derived from healthy donors as the foundation of our therapies. This supports the development of off-the-shelf T cell therapy products that can be manufactured on a large scale, eliminating the need for costly and time-consuming T cell collection and engineering for each individual patient. These virus-specific T cells have been clinically validated for safety and potential durable response.

We have initiated a Phase I clinical trial based on HLA matched allogeneic virus-specific T cells in combination with pembrolizumab (in collaboration with MSD) in brain cancer patients. We are also using off-the-shelf allogeneic virus-specific T cells as a platform for delivery of chimeric antigen receptors (CAR). The first CAR to be developed using the platform targets EphA3, a receptor tyrosine kinase highly expressed on multiple solid cancers.

Immunotherapies are cancer treatments that activate the immune system to kill cancer cells. The development of immune checkpoint inhibitors (ICIs) provided revolutionary new treatment options for cancer patients. However, despite their clinical and commercial success, the majority of patients are refractory to current ICIs. As such, there is a high market interest for novel and differentiated immunotherapies. In particular, colorectal cancer (CRC) is the third most commonly diagnosed cancer and cause of cancer-related deaths worldwide. More than 1.9 million people were diagnosed with colorectal cancer worldwide in 2020, and the incidence in young patients has doubled. Approximately 85% of colorectal cancers are Microsatellite Stable positive (MSS+) and there is no long-term therapeutic options for late stage patients. Similarly, there is also a great unmet need for triple negative breast cancer and many other cancers with resistance to immune checkpoint inhibitors to improve prognosis and survival.

Fovero Therapeutic's proprietary Galectin-9 (GAL9) platform leverages cutting-edge research in the field of dysregulated immune function to overcome immuno-oncology (IO) resistance in solid tumours, addressing an unmet need in oncology and inflammatory indications.

Whilst PD-1/PD-L1 immunotherapy is only relevant to hot tumours with exhausted immune cells (e.g. melanoma) and CTLA-4 immunotherapy treats tumours which have an abundance of regulatory T cells (e.g. oesophageal cancer), the lead antibody for oncology, FT002, improves the efficiency of multiple immune cells to clear cold cancers with few immune cells (e.g. MSS+ CRC).

In pre-clinical models, anti-GAL9 treatment completely controls primary CT26 colon tumours and 4T1.2 triple-negative breast cancer (TNBS) and mice were then resistant to these tumours after 10 months.

About 10% of the global population suffers from autoimmune disorders, with 80-100 known conditions, including inflammatory arthritis, Systemic Lupus Erythromatous (SLE), Type 1 diabetes, Sjogren’s syndrome, and inflammatory Bowel Disease. While anti-TNF drugs show efficacy in inflammatory arthritis, they offer no significant benefit for diseases such as Sjogren’s syndrome or SLE. Additionally, single cytokine-blockade is typically short-lived, as these diseases are driven by multiple cytokines and no current immunotherapy targets multiple cytokines.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but there are no novel immunotherapies for inflammatory diseases like Sjogren’s syndrome and thus demand for new therapies.

Researchers at Fovero Therapeutics are addressing this need with a therapy that regulates multiple cytokines. Their proprietary Galectin-9 (GAL9) platform focuses on immune dysfunction, offering a solution for inflammatory diseases. FT024, a novel therapy, inhibits the cells responsible for secreting multiple cytokines, reducing their secretion by 28-73%, including granzyme B, which is linked to autoantigen modification in various autoimmune diseases. This partial blockade of multiple cytokines represents a new approach to managing disease while minimising side effects associated with complete cytokine blockade.

The effectiveness of CAR T cells in treating solid cancers faces significant challenges. Key issues include the varied expression of tumor-associated antigens (TAA) across tumors and their overlap with healthy tissues, complicating target identification. Additionally, obstacles in tumor trafficking and the immunosuppressive tumor microenvironment (TME) reduce CAR T cell efficacy.

CD226/DNAM-1 is vital for T and NK cell activation within the TME, countering inhibitory receptors like TIGIT. There are currently over 20 pharmaceutical programs targeting these receptors. CD226 is crucial for responses to anti-PD-(L)1 and anti-TIGIT treatments. CD155 (PVR), which is widely expressed in tumors, serves as a major immunosuppressive signal. Reduced CD226 on tumor-infiltrating lymphocytes (TILs) correlates with unresponsive T cells, highlighting challenges in enhancing CAR T cell therapy.

The down-regulation of CD226 on CD8+ TILs is driven by tumor-expressed CD155. A potential therapeutic solution is the human Y322F mutation, which improves T cell function in adoptive cell therapy (ACT). The armored CAR strategy involves engineering CD226 in CAR T cells to enhance their functionality, hypothesising that this will improve activation and resistance to the TME.

CD155 expression is elevated in 33 tumor types and is linked to poor responses to anti-PD-1 therapy. Enhancing CD226 could address limitations in current CAR T platforms, such as T cell exhaustion and maintaining effector functions in the TME.

Clinical trials involving CD226-axis therapies are mostly focused on TIGIT antibodies, with only one anti-CD226 agent, LY3435151, reaching clinical testing before being terminated. CD226's role in checkpoint immunotherapy is notable; high expression correlates with better outcomes in patients treated with anti-PD-L1 therapies. Engineered mutations could counteract CD155-induced down-regulation of CD226/DNAM-1, potentially improving treatment efficacy.

The histone methyltransferase enzyme G9a is overexpressed in many malignancies, including breast cancer and regulates expression of genes involved in tumour progression. QIMR Berghofer researchers, in partnership with drug discovery CRO Domainex, have developed a small molecule inhibitor of G9a (DMX8.1) which shows promising in vitro and in vivo efficacy against ER+ breast cancer and TNBC.

As a monotherapy, DMX8.1 significantly reduced cell viability in a range of breast cancer cell lines while having no effect on normal breast epithelial cells. In human tumour ER+ breast cancer and TNBC xenograft models, DMX8.1 demonstrated a marked reduction in cell viability in vitro and tumour growth in vivo. Additionally, we demonstrate that tumours derived from tamoxifen-resistant cell lines are resensitised to tamoxifen when combined with a G9a inhibitor, with the combination inducing tumour regression. Synergistic efficacy is also demonstrated when a G9a inhibitor is used in combination with chemotherapeutics such as doxorubicin. Mechanistically, DMX8.1 has been shown to specifically enhance expression of genes repressed by the MYC oncogene in cancer setting.

The molecular and physical properties of DMX8.1 are favourable for an orally administered drug, and the binding affinity is in the single digit nanomolar range. DMX8.1 displays good in vitro metabolic stability, further exemplified by good murine pharmacokinetic data. Further, we have developed a novel signature that could be used to select breast cancer patients who would benefit most from G9a inhibitor monotherapy treatment, and identified biomarkers for potential use as a target engagement early readout marker.

Cancer and infectious diseases account for a significant proportion of early morbidity and mortality worldwide. While the role of the immune system in controlling infectious diseases is well understood, ground-breaking research has shown that immune responses also control cancer. Revolutionary new treatments, called immunotherapies, work by stimulating the immune system to kill only cancer cells. Despite outstanding therapeutic benefits from the initial wave of immunotherapies, many patients and cancers are resistant to treatment and therefore new therapies are required.

Current poster child of immunotherapy is the blockade of signals to an immunosuppressive (checkpoint) receptor on T cells known as programmed cell death-1 (PD1). When PD1 on T cells binds programmed cell death-1 ligand 1 (PDL1) on DCs or tumour cells, T cells stop functioning. Antibodies directed against PD1 take the brakes off the immune system, and thereby allowing T cells to mount an effective attack against cancer. While blockade of the PD1 / PDL1 pathway has shown durable benefit for melanoma and other cancers, many patients do not respond or have transient responses to anti-PD1 therapy.

Recent studies have shown that PDL2, unlike PD-L1, is not a brake on the immune system. PD-L2 aggregates on the surface of antigen presenting cells like dendritic cells and out competes PD-L1 binding PD1, to prevent loss of T cell functions. Secondly, PDL2 improves T cell functions by binding a second receptor. A novel multimeric form of soluble PDL2 protein (sPDL2) has been developed at QIMR Berghofer. This protein can cure lethal malaria in mice and protect completely against reinfection after 150 days (Immunity, 2016). Similarly, sPDL2 can completely control advanced CT26 tumors and control B16.F10 tumors when combined with Treg depletion.