Phase 1 evaluation of intralesionally injected TLR9-agonist PF-3512676 in patients with basal cell carcinoma or metastatic melanoma

被引:120
作者
Hofmann, Maja A. [1 ]
Kors, Christian [1 ]
Audring, Heike [1 ]
Walden, Peter [1 ]
Sterry, Wolfram [1 ]
Trefzer, Uwe [1 ]
机构
[1] Charite, Dept Dermatol Venerol & Allergy, Skin Canc Ctr, D-10117 Berlin, Germany
关键词
basal cell carcinoma; metastatic melanoma; PF-3512676; Toll-like receptor agonists;
D O I
10.1097/CJI.0b013e318174a4df
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Synthetic oligodeoxynucleotides (ODNs), such as PF-3512676, that contain unmethylated cytosine-guanine motifs (CpG ODN) have been identified as highly potent immune activators by in vitro examinations and in murine models. CpG ODNs induce innate and adaptive immune responses by triggering Toll-like receptor 9 expressed by human B cells and plasmacytoid dendritic cells. A phase I study was initiated to investigate safety, tolerability, serum cytokine levels, cellular immune responses, and clinical activity of intralesional treatment with PF-3512676 in patients with basal cell carcinoma (BCC) or cutaneous or subcutaneous melanoma metastases. Intrapatient escalating doses of PF-3512676 (up to 10mg) were injected intralesionally every 14 days in 5 patients with BCC and in cutaneous or subcutaneous metastases of 5 patients with melanoma. PF-3512676 was well tolerated. Local swelling and erythema occurred at the injection site in 9/10 patients. There was only I incidence of a grade III hematologic adverse event (lymphocytopenia). Local tumor regressions were observed in patients with BCC (I complete regression, 4 partial regressions) and metastatic melanoma (I complete regression). After treatment with PF-3512676, interleukin-6 was increased in all patients, interferon-gamma induced protein-10 in 8/10 patients, interleukin-12p40 in 7/10 patients, and tumor necrosis factor-alpha levels in 6/10 patients. All patients had biopsies; moderate to abundant cellular infiltrates of lymphocytes were found post-treatment in most lesions of both histologic types. Intralesional treatment of skin tumors with PF-3512676 was safe and well tolerated. Despite the relatively low dosage, clinical activity was demonstrated both in patients with BCC and with cutaneous or subcutaneous metastatic melanoma lesions.
引用
收藏
页码:520 / 527
页数:8
相关论文
共 35 条
[1]  
Auf G, 2001, CLIN CANCER RES, V7, P3540
[2]  
Baines J, 2003, CLIN CANCER RES, V9, P2693
[3]   Metastatic melanoma: Chemotherapy [J].
Bajetta, E ;
Del Vecchio, M ;
Bernard-Marty, C ;
Vitali, M ;
Buzzoni, R ;
Rixe, O ;
Nova, P ;
Aglione, S ;
Taillibert, S ;
Khayat, D .
SEMINARS IN ONCOLOGY, 2002, 29 (05) :427-445
[4]   Divergent therapeutic and immunologic effects of oligodeoxynucleotides with distinct CpG motifs [J].
Ballas, ZK ;
Krieg, AM ;
Warren, T ;
Rasmussen, W ;
Davis, HL ;
Waldschmidt, M ;
Weiner, GJ .
JOURNAL OF IMMUNOLOGY, 2001, 167 (09) :4878-4886
[5]   Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition [J].
Bauer, S ;
Kirschning, CJ ;
Häcker, H ;
Redecke, V ;
Hausmann, S ;
Akira, S ;
Wagner, H ;
Lipford, GB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (16) :9237-9242
[6]   Macrophages are essential for antitumour effects against weakly immunogenic murine tumours induced by class B CpG-oligodeoxynucleotides [J].
Buhtoiarov, Ilia N. ;
Sondel, Paul M. ;
Eickhoff, Jens C. ;
Rakhmilevich, Alexander L. .
IMMUNOLOGY, 2007, 120 (03) :412-423
[7]  
Grimm EA, 2000, CLIN CANCER RES, V6, P3895
[8]  
Gursel M, 2002, EUR J IMMUNOL, V32, P2617, DOI 10.1002/1521-4141(200209)32:9<2617::AID-IMMU2617>3.0.CO
[9]  
2-F
[10]   Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway [J].
Hemmi, H ;
Kaisho, T ;
Takeuchi, O ;
Sato, S ;
Sanjo, H ;
Hoshino, K ;
Horiuchi, T ;
Tomizawa, H ;
Takeda, K ;
Akira, S .
NATURE IMMUNOLOGY, 2002, 3 (02) :196-200