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. The generation of 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. investigate the mechanisms by which OX40 ligation with an agonist (activating) anti-OX40 antibody boosts the function of T cells to enhance tumor immunotherapy.
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 (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 in a pre-clinical model. Importantly, this therapy has been translated from the laboratory into the clinic through multiple clinical trials with an anti-human OX40 mAb for the treatment of patients with cancer. Currently, we are investigating the transcriptional mechanisms regulating OX40 expression, including the role of common gamma chain (gc) cytokines in regulating this process and the mechanisms by which anti-OX40/gc cytokines synergize to boost tumor immunotherapy.
Additional projects are focused on understanding the cellular and molecular mechanisms by which tumors suppress the immune response. Understanding the mechanisms that promote immune suppression is of particular importance given their role in inhibiting the generation of potent anti-tumor immunity. For example, in contrast to the activating effects of OX40 ligation, CTLA-4 is a negative regulatory protein expressed on T cells that serves to down-regulate immune function. Under normal conditions, this is a critical regulatory process that prevents the onset of autoimmune disease. However, CTLA-4 also limits the generation of potent tumor-specific immunity and studies have shown that blocking CTLA-4 function significantly enhanced tumor immunotherapy, forming the rationale for the development and recent FDA approval of an anti-CTLA-4 mAb (Ipilimumab) for cancer therapy. 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 combined anti-OX40/anti-CTLA-4 therapy synergizes to relieve tumor-induced immune suppression and augment tumor immunotherapy.
We are also investigating the mechanisms by which combination immunotherapy augments tumor-specific immunity, including the role of regulatory RNAs, known as microRNAs, in regulating this process. Our specific research goals include: 1) To determine the mechanisms by which anti-OX40 therapy in the presence of CTLA-4 blockade augments tumor immunotherapy; 2) Examine the extent to which the efficacy of combined therapy is regulated by T cell-specific microRNAs; and 3) Determine the genomic targets and function of T cell-specific microRNAs following dual anti-OX40/anti-CTLA-4 therapy. Together, these studies will provide unique insight into the cellular and molecular mechanisms by which combined anti-OX40/anti-CTLA-4 therapy augments tumor immunotherapy and the role of microRNAs in regulating T cell function. 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 this pre-clinical study into the clinic for the benefit of cancer patients.
Current Projects
Regulation of OX40 by common gamma chain (gc) cytokines
1) Determine the molecular mechanisms by which STAT3 and STAT5 differentially regulate OX40 receptor expression on murine and human T cells.
2) Investigate the mechanisms regulating the induction of tumor-specific CD8 T cell anergy and test whether combined anti-OX40/gc cytokine therapy restores the function of anergic CTL in tumor-bearing hosts
3) Examine whether OX40 ligation augments the differentiation of endogenous CD8 T cells in tumor-bearing hosts.
Combination Immunotherapy
1) Determine the mechanisms by which anti-OX40 therapy in the presence of CTLA-4 blockade augments tumor immunotherapy.
2) Examine the extent to which the efficacy of combined therapy is regulated by T cell-specific microRNAs.
3) Determine the genomic targets and function of CD8 T cell-specific microRNAs following dual anti-OX40/anti-CTLA-4 therapy.
4) Investigate the extent to which dual anti-OX40/anti-CTLA-4 therapy plus tumor-specific vaccination boosts tumor immunotherapy.
Full List of Publications
Links:
Federation of Clinical Immunology Societies
American Association for Cancer Research
Society for Immunotherapy of Cancer
American Association of Immunologists
American Cancer Society
Prostate Cancer Foundation
National Institutes of Health
Laboratory Team
William L. Redmond, PhD.
Stefanie N. Linch, PhD.
Michael J. McNamara, PhD.
Melissa J. Kasiewicz, B.S.