Recent clinical trials have demonstrated the potential of immunotherapy-based treatments for cancer therapy, including tumor-specific vaccines and immune-modulating agents. One of the benefits of immunotherapy is the generation of tumor-specific responses that may have fewer side effects than standard treatments. Additionally, tumor immunotherapy has the potential to generate potent long-term immune “memory”, which can protect against tumor recurrence at local and distant sites. One of the goals of immunotherapy is to stimulate cytotoxic CD8 T cells that are capable of destroying tumors. Generating optimal CD8 T cell responses requires T cell receptor (TCR) stimulation along with the provision of co-stimulatory signals. Recent studies have demonstrated that ligation of tumor necrosis factor receptor (TNFR) family co-stimulatory receptors such as OX40 (CD134), 4-1BB (CD137), or CD27 can significantly augment T cell responses. Led by William L. Redmond, Ph.D., the Cancer Immunotherapy Laboratory investigates the cellular and molecular mechanisms by which OX40 agonists boost the function of CD8 T cells to enhance tumor immunotherapy.
OX40 Agonists Enhance CD8 T Cell Effector Function
Our interest in OX40 stemmed, in part, from numerous pre-clinical studies demonstrating that OX40 stimulation significantly boosts anti-tumor immunity against a variety of cancers including melanoma, breast, and prostate tumors. We showed that therapy with a drug that stimulates OX40 (agonist anti-OX40 monoclonal antibody, or anti-OX40 mAb) enhanced CD8 T cell activation, restored the function of non-responsive T cells, and helped promote tumor regression. Importantly, this therapy has been translated from the laboratory into the clinic through multiple clinical trials that are testing OX40 agonists for the treatment of patients with cancer. Currently, we are investigating the transcriptional mechanisms by which OX40 agonists augment CD8 T cell effector function including the role of the transcription factor Eomesodermin (Eomes), which is a master regulator of CD8 T cell differentiation and memory.
We are also investigating the cellular and molecular mechanisms by which tumors suppress CD8 T cell-mediated immunity and exploring how combination immunotherapy can overcome these obstacles to augment anti-tumor immunity. For example, molecules such as CTLA-4, PD-1, and PD-L1 are negative regulatory proteins called immune checkpoints that serve to down-regulate immune function. Under normal conditions, this is a critical regulatory process that prevents the onset of autoimmune disease. However, these same inhibitory proteins also limit the generation of potent tumor-specific immunity. Drugs that block these immune checkpoints release the brakes on tumor-reactive T cells allowing them to seek out and destroy tumor cells. Given that OX40 and CTLA-4 regulate distinct aspects of tumor immunity – OX40 ligation augments T cell function, while blockade of CTLA-4 relieves the brakes on immune activation, we are investigating the mechanisms by which combination therapy synergizes to relieve tumor-induced immune suppression and augment tumor immunotherapy. Specifically, we are exploring the cellular and molecular mechanisms by which OX40 agonists synergize with checkpoint blockade, common gamma chain cytokines, tumor-specific vaccines, and targeted radiation therapy to promote tumor regression. We expect that these studies will lead to new avenues of investigation and the identification of additional therapeutic targets. Ultimately, our goal is to translate the results obtained from our laboratory into the clinic for the benefit of cancer patients.
Model: Overcoming immune suppression and CD8 T cell anergy to generate potent tumor-specific immunity.
Ligation of co-stimulatory molecules with T cell agonists such as anti-OX40 mAb plus checkpoint blockade (e.g., anti-CTLA-4, anti-PD-1 mAb) enhances anti-tumor immunity leading to tumor regression. However, these combinations are often not sufficient to rescue the cytolytic function of tumor-specific CD8 T cells. The provision of tumor-specific vaccines or in situ vaccination (e.g., chemotherapy, radiation therapy) plus combination immunotherapy (anti-OX40/anti-CTLA-4 mAb) can restore the function of anergic CD8 T cells leading to tumor regression. Adapted from: Redmond WL, Linch SN. Commentary: Combinatorial immunotherapeutic approaches to restore the function of anergic tumor-reactive cytotoxic CD8+ T cells. Human Vaccines and Immunotherapeutics, Jul 26:1-4, (2016). doi:10.1080/21645515.2016.1193277.