This issue of JDD is dedicated to skin cancer and is a harbinger of major contributions of skin research to the exploding knowledge of targeted therapy and immunotherapy of cancers. As scientific knowledge on signal transduction pathways of cancer stem cells and the immune system emerge at an unprecedented rate, new targeted therapies and immunotherapies are emerging in oncology including vismodegib (Genetech), Yervoy, and topical therapies such as imiquimod, resiquimod, and Picato (ingenol mebutate).1,2 The intense study of dendritic cell and T-cell subsets in inflammatory and neoplastic skin diseases makes this the most exciting arena for product development in dermatology and medicine.3,4 Emerging stars in dermatology have been given awards by the Skin Cancer Foundation.
A previous issue of the JDD was dedicated to Dendreonâ€™s Provenge (Sipuleucel-T), the first therapeutic DC vaccine proven effective and FDA approved for advanced cancer.5
The JDD looks forward to second and third generation DC products, including ones with direct delivery to the skin like CpG. Since this 2010 Provenge editorial was published, Yervoy (Ipilumab) has been approved by the FDA and currently PD-1 drugs are anticipated to be approved as early as this year. Thus, cancer immunotherapy is no longer limited to patients with a low tumor load. As we lean more about the skin as an immune organ, molecular skin research will play as increasingly important role in oncology. A recent report from the Australian Institute for Bioengineering and Nanotechnology used a densely packed microinjection array (Nanopatch) and greatly enhanced CD-8 killer T-cell responses.6 Skin delivery, as opposed to intramuscular delivery, needs to be developed both for preventive and therapeutic cancer immunotherapy.
The 2011 Nobel Prize was awarded for the innate immune regulation of the acquired innate immune system.7 Traditionally, the skin has been considered the largest immune system of the body, although Clark et al are changing this concept to include computations that suggest there are more acquired immune cells in the skin than in the peripheral circulation.8 As our knowledge of molecular events in the skin grows and we begin to understand the mechanisms behind exciting products like Picato,9 the ability of topical therapy is likely to extend beyond treatment of skin cancer to systemic cancers including lung, prostate, breast, colon, ovarian, and others.
The development of CpG agonists in cancer has a long history including the development of Coley Pharmaceutical acquired by Pfizer Pharmaceutical. Pfizer invested in a failed phase III clinical trial with a CpG agonist for lung cancer and discontinued the program. The reasons for the failure need further study. Had the product been delivered via the skin DC network rather than SQ, a different outcome may have evolved. A study by Ng et al shows direct delivery of a protein antigen to skin antigen-presenting cells with CpG as an adjuvant results in potent CD-8 killer cells. Study of CpG via skin DC delivery is clearly warranted.10,11
Further development of topical immunomodulators such as imiquimod, resiquimod, ingenol mebutate, and CpG will improve the cutaneous microenvironment for present and future targeted and immunotherapeutic systemic agents.
William Levis MD and Frank Martiniuk PhD
New York University School of Medicine,
Departments of Medicine and Dermatology, New York, NY
- Doan HQ, Gulati N, Levis WR. Ingenol mebutate: potential for further development of cancer immunotherapy. J Drugs Dermatol. 2012;11:1156-7.
- Stahlhut M, Bertelsen M, Hoyer-Hansen M, Svendsen N, Eriksson AH, Lord JM, Scheel-Toellner D, Young SP, Zibert JR. Ingenol mebutate: induced cell death patterns in normal and cancer epithelial cells. J Drugs Dermatol. 2012;11:1181-92.
- Lowes MA, Russell CB, Martin DA, Towne JE, Krueger JG. The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses. Trends Immunol. 2013;34:174-8.
- Hijnen D, Knol EF, Gent YY, Giovannone B, J P Beijn S, Kupper TS, Bruijnzeel-Koomen CA, Clark RA. CD8(+) T Cells in the Lesional Skin of atopic dermatitis and psoriasis patients are an important source of IFN-γ, IL-13, IL-17, and IL-22. J Invest Dermatol. 2013; 133:973-9.
- Levis WR, Martiniuk F. The role of complement in dendritic cell (DC) control of T-cell subsets. J Drugs Dermatol. 2010;9:1364-6.
- Fernando GJ, Chen X, Primiero CA, Yukiko SR, Fairmaid EJ, Corbett HJ, Frazer IH, Brown LE, Kendall MA. Nanopatch targeted delivery of both antigen and adjuvant to skin synergistically drives enhanced ntibody responses. J Control Release. 2012;159:215-21.
- Wagner H. Innate immunity's path to the Nobel Prize 2011 and beyond. Eur J Immunol. 2012;42:1089-92.
- Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, Dowgiert RK, Kupper TS. The vast majority of CLA+ T cells are resident in normal skin. J Immunol. 2006;176:4431-9.
- Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012; 366:1010-9.
- Ng HI, Fernando GJ, Kendall MA. Induction of potent CD8+ T cell responses through the delivery of subunit protein vaccines to skin antigen-presenting cells using densely packed microprojection arrays. J Control Release. 2012;162:477-84.
- Krieg AM. CpG still rocks! Update on an accidental drug. Nucleic Acid Ther. 2012;22:77-89.