Identification of Immune Checkpoint-Based Strategies and Adoptive Immunotherapies with Radiation in Lung Cancer
CTLA-4 is an important molecule in our bodies that helps prevents the immune system from being over stimulated. When CTLA-4 is activated, it suppresses helper T-cells while increasing the concentration of T-regs or T regulatory cells, which promotes quiescence of the immune system. CTLA4 evolutionarily is necessary for inhibiting the development of autoimmune diseases. Tumors use this to their advantage and express signals to bind to CTLA-4 to avoid immune mediated destruction. This discovery has been instrumental for engendering the development of drugs, which act as an antibody to specifically target CTLA-4, such as Ipilimumab, and are now commonly used in immunotherapy for cancers. Interestingly enough, recent studies have show that the combination of radiation and Ipilimumab have led to not only complete responses, but also something known as the abscopal effect in which radiation, in addition to its local target, also produces a reduction of non-irradiated sites of disease. Dr. Welsh and his team are currently conducting trials utilizing specific doses of radiation with Ipilimumab on patients with liver or lung metastasis.
PD1 (Programmed Cell Death) is expressed on CD8+ and CD4+ T cells that bind to both ligands PDL1/PDL2. Like CTLA4, PD1 suppresses T cell activity, thus a specific therapeutics to prevent this interaction were developed (i.e. Pembrolizumab, Nivolumab). When blocked, studies have shown that the concentration of tumor infiltrating lymphocytes increases. Welsh and his team hypothesize that treating certain cancers with concurrent radiation and Nivolumab may yield even more complete responses. Thus, the Welsh lab has initiated a trial investigating the use of these antibody blocking drugs and radiation on patients with non-small cell lung cancer and small cell lung carcinoma.
OX40 is an antagonist molecule found on CD4+, CD8+, NK, NKT, and Treg cells. There are many benefits to the immune system that are associated with OX40 such as T cell proliferation and increase in T cell memory; however, there are negative aspects associated with the molecule the most predominant being that it aids in the expansion of Tregs. Research has shown that when OX40 is treated with agonist Treg function is impaired and Welsh and his team hypothesize that radiation and OX40 agonist may make an effective partnership in stimulating the immune system and promoting tumor regression. Welsh and his lab members hope to run future clinical trials that test these two therapies together.
Adoptive T-Cell Therapy
This method of immunotherapy takes advantage of the patient’s own immune cells, which have become activated to target the present tumor by expanding them (i.e. creates multiple copies of these anti-tumor specific immune cells) and then re-introducing them into the patient. Thus, this therapy creates an army of specific anti-tumor cells that can help the body combat the malignancy. Recent studies have shown that combining this powerful immunotherapy with radiation yields even more promising results, with more patients having complete responses to therapy and demonstrating an increase in 5-year overall survival.
Chimeric Antigen Receptors (CARs) is an approach to adoptive immune-cell therapy that bypasses the pathway normally conducted by the immune system to activate T cells and go straight to the tumor-specific antigen in question. Studies have shown its effectiveness in targeting tumor antigens and helping reduce the surrounding barrier that tumor stromas create to avoid T cell infiltration. Few studies have been conducted combining radiation and CARs for solid tumors. Welsh and his team hypothesize that radiation will help give CARs even more direct access to tumor infiltration because of radiation’s effect on tumor microenvironment.
Natural killer cells (NK) have the potential to be powerful therapeutic tools against solid tumors because not only can they immediately destroy malignant cells but they can also communicate with other T cells to recruit them towards infiltrating the solid tumors. The natural killer cells are first attracted to solid tumors because, in an effort to evade T-cell detection, tumors down regulate the expression of major histocompatability complex or (MHC1). This decrease in MHC1 signals to the NK cells that a foreign cell is present in the body that should eliminated. There have been few studies conducted that look at the combination of radiation and NK cell therapy. Welsh and his team will investigate the effects of such a combination in treating thoracic malignancies.