Research And Grants

(2023) Enhancing the recruitment of tumor infiltrating lymphocytes to improve responses to DMG therapies.

ABSTRACT

Diffuse midline glioma (DMG) including those within the pons (diffuse intrinsic pontine glioma [DIPG]) is the most lethal form of childhood cancer with a median overall survival of 9-11 months, and a 5-year survival <1%. DMG represents 20% of all pediatric cancer deaths, with no recognized treatments other than radiotherapy, highlighting the urgent need to progress innovative approaches. Immunotherapies have dramatically improved outcomes in other aggressive cancers, including melanoma patients with brain metastasis. However, immunotherapies such as immune checkpoint inhibitors (ICIs), have not shown clinical benefit in DMGs, likely due to a lack of immune cells in or near the tumor located in the central nervous system (CNS). Studies in other brain tumors that show untreated brain cancer patients experience immune suppression (T cell lymphopenia) as their T cells are sequestered within the bone marrow. We have powerful data showing that ONC201 promotes release of immune cells from the bone marrow, and makes DMGs more visible to the immune system, which, in combination with the drug paxalisib, recruits immune cells to the tumor. Furthermore, two patients receiving ONC201 and paxalisib over a 16-month period showed dramatic reductions in tumor volume and increased survival that we attribute to an immune response. This project will identify if untreated DMG patients experience lymphopenia. We will also determine whether ONC201 in combination with paxalisib promotes an immune response to help fight the tumor, and identify how we can further promote the function of the immune system to improve DMG outcomes.

LAY SUMMARY

DMGs harbor a ‘cold’ tumor microenvironment (TME), meaning few, if any, immune cells are in the immediate vicinity of the tumor. The absence of these immune features likely explains why antibody-based immunotherapies have not delivered a benefit for DMG patients, that has been seen in other cancers. We believe that the cold TME of DMG is promoted by DMG patients experiencing T cell lymphopenia (yet to be confirmed). In adults with glioblastoma (another aggressive/lethal brain cancer), T cells are confined within the bone marrow, unable to enter the bloodstream and hence the brain, and therefore the tumor is immunosuppressed even when treated with immunotherapies. This has been shown to be influenced by the protein ‘Beta-arrestin’ which becomes activated in T cells in the bone marrow, stopping their egress into the circulation. This phenomenon has also been shown in traumatic brain injury patients, where sepsis is the most frequent cause of death due to the body not being able to mount an immune response to infection. Although the mechanisms of immune suppression for glioblastoma patients and patients with brain injuries is not resolved, we believe the peripheral nervous system (PNS) is playing a role as it is implicitly linked with the immune system.

Our team have been studying the anti-DMG effects of the DRD2 antagonist ‘ONC201’ for four years. Our preclinical studies underpin the phase II, international, adaptive clinical trial ‘Combination Therapy for the Treatment of Diffuse Midline Glioma’, which is evaluating the effect of radiotherapy (RT) in combination with ONC201, or the PI3K/Akt inhibitor paxalisib, and, ONC201 + paxalisib as a maintenance therapy following the completion of RT.

Our studies show that:

i) ONC201 reduces beta-arrestin signaling, potentially aiding in the escape of T cells from the bone marrow.
ii) Treating DMG with ONC201, increases expression of immune recognition molecules on DMG cells, amplified when co-treating DMG cells with paxalisib.
iii) The combination of ONC201 with paxalisib promoted recruitment of immune cells to the tumor of mice engrafted with human DMGs, suggesting that the combination treatment illuminates the DMG to the immune system.
iv) ONC201 treatment of DMG mice with a functional immune system dramatically extended survival, compared DMG mice without a fully functioning immune system, suggesting a potential immune involvement in the response to ONC201 treatment.
v) Two DMG patients who are/have receiving/ed ONC201 in combination with paxalisib following compassionate access show a dramatic reduction in tumor burden, improved neurological functioning and increased progression free and overall survival.

We believe that ONC201, in combination with paxalisib, promotes the anti-cancer activity of T cells which is key to ONC201/paxalisib’s anti-DMG effects. We believe this only occurs in patients not receiving dexamethasone, a potent immunosuppressor prescribed to many/all DMG patients to reduce symptoms caused by brain swelling. This project seeks to understand/confirm whether DMG patients experience lymphopenia (reduced immune system function), and to enhance the immune-mediated, anti-DMG response to ONC201/paxalisib. In doing so, we will provide important new information on how we can enhance the benefit of therapies already in clinical trial (NCT05009992) and how we may bring the benefits of immune-based therapies (such as immune checkpoint inhibitors or CAR-Ts) that have been seen in other cancers, to the DMG community.