Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-trafficking CD4+ T-cells. Patients with advanced disease with extensive skin and blood involvement have a poor prognosis and exhibit marked defects in cell mediated immunity. Underlying these defects is an associated profound decline in the numbers of peripheral blood dendritic cells (DCs) along with marked deficiencies in the ability of these cells to produce cytokines, including IL-12 and IFN alpha, which are critical for antitumor immunity. Because host immune function appears to play an integral role in mediating disease- controlling responses in CTCL, we have been investigating a number of mechanisms for activating patients'DCs, including the use of synthetic imidazoquinolines (IMDs) which have been recognized as immune stimulatory by virtue of activation of DCs through Toll like receptors (TLR) 7 and 8 agonistic activity. Our preliminary data indicate that IMDs exhibit the capacity to induce in vitro the production of high levels of immune stimulatory cytokines from the peripheral blood cells of advanced CTCL patients which is associated with marked activation of NK cells and CD8+ T-cells and upregulation of CD80/CD86 on APCs. Such pre-clinical findings have typically been associated with significant clinical improvement when put into clinical practice for CTCL. Thus, this grant proposes an early phase II single-center, open-label trial of a novel IMD compound, 001/852A, which is a TLR 7 agonist with potent immune stimulatory properties. Patients with CTCL will be monitored longitudinally for 1) clinical responses, 2) adverse effects, and 3) in vivo immune stimulatory effects including NK and CD8 T-cell activation in the skin and blood, as well as antigen presenting cell activation. If immune stimulation and clinical efficacy are observed, the present investigators would be prepared to develop a more extensive late phase II or phase III trial using 001/852A. Cutaneous T-cell lymphoma (CTCL) is a skin invasive cancer of T-lymphocytes where disease progression appears to be controlled by the immune response. Our preliminary testing in the laboratory of a new compound 001/852A indicates that it can powerfully and broadly activate potential antitumor immune responses of patients with CTCL. In view of our test tube results suggesting that 001/852A could stimulate antitumor responses of CTCL patients, a phase II clinical trial of this promising agent with correlative immune monitoring has been planned.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Merritt, William D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Rook, Alain H; Gelfand, Joel M; Gelfand, Joel C et al. (2015) Topical resiquimod can induce disease regression and enhance T-cell effector functions in cutaneous T-cell lymphoma. Blood 126:1452-61
Cedeno-Laurent, Filiberto; Singer, Elisha M; Wysocka, Maria et al. (2015) Improved pruritus correlates with lower levels of IL-31 in CTCL patients under different therapeutic modalities. Clin Immunol 158:1-7
Huen, Auris O; Rook, Alain H (2014) Toll receptor agonist therapy of skin cancer and cutaneous T-cell lymphoma. Curr Opin Oncol 26:237-44
Guenova, Emmanuella; Watanabe, Rei; Teague, Jessica E et al. (2013) TH2 cytokines from malignant cells suppress TH1 responses and enforce a global TH2 bias in leukemic cutaneous T-cell lymphoma. Clin Cancer Res 19:3755-63
Stephen, Sasha; Morrissey, Kelly A; Benoit, Bernice M et al. (2012) Inhibition of cell-mediated immunity by the histone deacetylase inhibitor vorinostat: implications for therapy of cutaneous T-cell lymphoma. Am J Hematol 87:226-8
Kelly-Sell, Michael J; Kim, Youn H; Straus, Suzanne et al. (2012) The histone deacetylase inhibitor, romidepsin, suppresses cellular immune functions of cutaneous T-cell lymphoma patients. Am J Hematol 87:354-60
Wysocka, Maria; Dawany, Noor; Benoit, Bernice et al. (2011) Synergistic enhancement of cellular immune responses by the novel Toll receptor 7/8 agonist 3M-007 and interferon-?: implications for therapy of cutaneous T-cell lymphoma. Leuk Lymphoma 52:1970-9
Clark, Rachael A (2010) Skin-resident T cells: the ups and downs of on site immunity. J Invest Dermatol 130:362-70
Samimi, Sara; Benoit, Bernice; Evans, Katherine et al. (2010) Increased programmed death-1 expression on CD4+ T cells in cutaneous T-cell lymphoma: implications for immune suppression. Arch Dermatol 146:1382-8
Clark, Rachael A (2009) Regulation gone wrong: a subset of Sezary patients have malignant regulatory T cells. J Invest Dermatol 129:2747-50