Tumors express tumor-associated antigens (TAA) that should make them objects of immune attack. However, recent evidence demonstrates that tumors actively defeat specific immunity. Cancer patients have increased numbers of circulating CD4+CD25+ regulatory T cells (Tregs). Treg depletion in mouse cancer models enhances immune-mediated tumor rejection and the efficacy of immune-boosting therapies. It has recently been demonstrated by the applicant in human ovarian cancer that CD4+CD25+ Tregs block tumor-specific immunity, foster tumor growth, and predict poor patient survival. The applicant hypothesizes that depleting Tregs in human cancer will enhance TAA-specific immunity and augment efficacy of immune-based therapies, helping them to fulfill their promise. Denileukin diftitox (Ontak) is a recombinant protein-fusing, full-length interleukin-2 to active diphtheria toxin. The prediction by the applicant that Ontak depletes Tregs and improves immunity in cancer patients has been tested. It has been demonstrated by the applicant that single, weekly Ontak injections significantly reduce mean blood CD4+CD25+ T cell prevalence and concentration while simultaneously increasing interferon-?+ T cells and expression of the Ki-67 proliferation antigen. The applicant has further demonstrated that CD4+CD25+ FOXP3+ cells were selectively reduced, and CD4+CD25+ T cells affected significantly reduced suppressive activity after Ontak. Together, these data are consistent with selective depletion of functional CD4+CD25+Tregs as predicted. In a patient with metastatic ovarian cancer, blood CA-125 (a tumor marker) dropped significantly form 94 to 16 units per milliliter (normal is less than 35 units per milliliter) following six Ontak doses. Positron emission tomography (PET)/computed axial tomography (CAT) fusion scans demonstrated resolution of most metastatic disease, although a left groin mass increased in size and was anaplastic ovarian carcinoma at biopsy. It recurred four months later, although the patient remains disease-free elsewhere. These data demonstrate clinical utility in this single patient, justifying a larger trial to confirm the result and elucidate underlying mechanisms.
The specific aims of this study are to perform detailed immune studies to understand Treg depletion and its consequences more fully and to test the hypothesis that Ontak treats refractory advanced-stage ovarian cancer.
|Thibodeaux, Suzanne R; Curiel, Tyler J (2011) Immune therapy for ovarian cancer: promise and pitfalls. Int Rev Immunol 30:102-19|
|Lin, Pei-Yi; Sun, Lishi; Thibodeaux, Suzanne R et al. (2010) B7-H1-dependent sex-related differences in tumor immunity and immunotherapy responses. J Immunol 185:2747-53|
|Curiel, Tyler J (2008) Regulatory T cells and treatment of cancer. Curr Opin Immunol 20:241-6|
|Barnett, Brian G; Ruter, Jens; Kryczek, Ilona et al. (2008) Regulatory T cells: a new frontier in cancer immunotherapy. Adv Exp Med Biol 622:255-60|
|Brumlik, Michael J; Daniel, Benjamin J; Waehler, Reinhard et al. (2008) Trends in immunoconjugate and ligand-receptor based targeting development for cancer therapy. Expert Opin Drug Deliv 5:87-103|
|Curiel, Tyler J (2007) Tregs and rethinking cancer immunotherapy. J Clin Invest 117:1167-74|