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Immunological Strategies to Fight Skin Cancer

B. Berman, MD, PhD; O. A. Perez, MD; D. Zell, MD
Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, USA

ABSTRACT

Skin cancer is the most common human cancer, and is currently considered a global epidemic. Recently, there has been a growing interest in immunomodulators, or upregulators of the immune response, for the treatment and cure of various forms of skin cancer, including melanoma and nonmelanoma skin cancers, cutaneous T-cell lymphoma, Kaposi’s sarcoma, cutaneous extramammary Paget’s disease, and vulvar intraepithelial carcinoma neoplasia. Strategies to augment the host’s immune response against cancer cells and/or cancer cell antigenicity have been investigated, including recombinant cytokines, immunomodulators, dendritic cell immunization, tumor antigen vaccination, T-cell-based immunotherapy, and gene therapy. Although the current standard of care for most of these cancers includes Mohs micrographic surgery, curettage, and cryo-, laser-, or radiotherapy, immunomodulators are becoming essential in the treatment of patients who are poor surgical candidates and/or require noninvasive therapy.

Key Words: skin cancer, melanoma, squamous cell carcinoma, immunomodulators, interferon, imiquimod

Recently, there has been a growing interest in immunomodulators for the treatment and cure of skin cancers. The therapeutic effect of immunomodulators on melanoma and nonmelanoma skin cancers, cutaneous T-cell lymphoma (CTCL), Kaposi’s sarcoma (KS), cutaneous extramammary Paget’s disease, and vulvar intraepithelial carcinoma neoplasia (VIN) is currently being investigated. Today, immunomodulators are essential in the treatment of patients who are poor surgical candidates and/or require noninvasive therapy, and there is a growing interest in understanding the safety, mechanisms, and therapeutic effect of immunomodulators on skin cancers.

Interferon

Cutaneous Melanoma

In the United States, adjuvant high-dose interferon (IFN) therapy has become the standard of care for melanomas with a high risk of recurrence, and the FDA has approved the use of IFN-á-2b for the treatment of patients with melanomas thicker than 4mm and patients with lymph node metastasis. An early randomized prospective trial by Creagan, et al. did not find a significant difference between IFN-á-2b treated melanoma Stage I and II subjects vs. untreated controls. Although the experimental group had a longer disease-free survival (median, 17 months for the IFN-á-2b group vs. 10 months for the control group), the difference was notsignificant (p=0.09).1 However, when Rusciani, et al. evaluated Stage II melanoma IFN-á-2b treated subjects vs. Stage II untreated controls, they found a metastasis rate of 19.6% (10 of 51 treated subjects) vs. 60% (18 of 30 untreated controls) at 3 years followup (p<0.0001), and a metastasis rate of 25% (4 of 16 treated subjects) vs. 63% (12 of 19 untreated controls) at 5 years follow-up (p<0.005). The Stage I melanoma IFN-á-2b treated subjects did not have a significantly different disease progression than the untreated Stage I controls at 3 and 5 years follow-up.2

IFN-á-2b therapy appears to be more effective in patients with lesions that have a poor prognosis. A recent study examined the combination of IFN-á-2b and surgery in high-risk melanoma patients. In this retrospective study of 150 patients, adjuvant high-dose IFN was an effective treatment option for patients with high-risk melanoma (Stage IIC, III) after definitive surgery. The 2-year and 5-year relapse-free survival rates were estimated at 48% and 36%, respectively.3

Basal Cell Carcinoma

The antiproliferative property of IFNs has also been employed in the treatment of patients with low-risk nodular basal cell carcinoma (nBCC) or superficial basal cell carcinoma (sBCC). Basal cell carcinoma (BCC) cells have been shown to express the CD95 ligand (FasL) and CD95 receptor (FasR), whereas the surrounding CD4+ T cells predominantly express FasR. Thus, in IFN treated patients, BCC may regress by FasR–FasL mediated apoptosis.4 Intralesional IFN-á-2b at a concentration of 1.5 million international units (IU) used over a 3 to 4-week period has been shown to have an overall success rate of up to 100%.5,6 However, when used for aggressive forms of BCC, this protocol has resulted in a cure rate of only 27% of treated patients.7 Therefore, IFN treatment of BCC remains an alternative only for patients with low-risk nodular or superficial BCC.

Squamous Cell Carcinoma/ Actinic Keratosis

Intralesional recombinant IFN-á-2b has been shown to be effective in the treatment of squamous cell carcinoma (SCC) and actinic keratosis (AK). When IFN-á-2b was administered at a dose of 1.5 million IU three times/ week for 3 weeks to SCC lesions, 33 of 34 (97.1%) lesions showed an absence of SCC histologically.8 However, when compared to other treatments for AK, the use of IFN is limited by the pain of injections and the multiple follow-up visits necessary.

Cutaneous T-cell Lymphoma

IFN-a is one of the most effective single-therapy agents for the treatment of CTCL.9 Low-grade, nonHodgkin, T-cell lymphomas are always associated with cutaneous involvement and include mycosis fungoides (MF) and the Sézary syndrome (SS).10 A literature review by Bunn, et al. of 207 MF and SS cases treated with IFN- a-2a revealed an overall response rate of 55%, with 17% of cases being complete responders to IFN-a-2a therapy. These authors concluded that recombinant IFN-á-2a monotherapy has greater benefit in patients with early-stage disease, with 3 million IU of IFN-á-2a given subcutaneously three times/week being the optimal treatment regimen. In this study, no therapeutic differences were observed between IFN-á-2a and -2b.11 A study by Vonderheid, et al. has revealed that intralesional injections of MF plaques with IFN-á-2b at a dose of 1 million IU given three times/week for 4 weeks produces substantial localized clinical and histological improvement with 10 of 12 plaques demonstrating complete regression localized to the IFN-á-2b injected sites.12


Interferon-a-
2b/ Study

Melanome

Design

Number of Treated Patients

Dose/ Route

Frequency/ Duration

Length of Treatment

Partial Clearance Rate

Complete
Clearance
Rate

Creagan et al.1 Stages I, II Ra, Pr 131 20 MU/m2/ IM t.i.w. x 12 wk 6.1 yrs 41 (Stage I)
12 (Stage II)
72
Fluck et al.3 Stages IIC, III Ra, Re 150 20 MU/m2/ IM
10 MU/m2/ SC
5 d/wk x 4 wks
t.i.w. x 48 wks
2.9 yrs 17 (Stage IIC)
N/R (Stage IIIA)
40 (Stage IIIB)
9 (Stage IIIC)
73
Kirkwood et al.42 1.8 Stages IIB, III Ra, Pr 146 20 MU/m2/ IM
10 MU/m2/ SC
5 d/wk x 4 wks
t.i.w. x 48 wks
6.9 yrs 17 38
Kirkwood et al.43 Stages IIB, III Ra, Pr 215 20 MU/m2/ IM
10 MU/m2/ SC
5 d/wk x 4 wks
t.i.w. x 48 wks
4.3 yrs 28 84
Kirkwood et al.44 Stages IIB, III Ra, Pr 438 20 MU/m2/ IM
10 MU/m2/ SC
5 d/wk x 4 wks
t.i.w. x 48 wks
1.3 yrs 37 46

Table 1: Summary of key published studies assessing the efficacy of interferon-a-2b for skin cancer treatment Abbreviations: CTCL–cutaneous T-cell lymphoma; d–day; IM–intramuscular; MU–million international units; N/R–Not Reported; Pr–prospective; Ra–randomized; Re–retrospective; SC–subcutaneous; t.i.w.–three times/week; wk–week; yrs–years.


Kaposi’s Sarcoma

The use of IFN-a-2a and -2b in the treatment of KS in patients with acquired immune deficiency syndrome due to the human immunodeficiency virus has been approved by the US FDA. The recommended dosages for IFN-a-2a and -2b are 36 and 30 million IU subcutaneously three times/week, respectively. The average response rate of KS to high-dose IFN-á therapy has been approximately 30%. In many cases, tumor recurrence has been observed within 6 months after discontinuation of treatment, and response to subsequent treatments has not been reliable. This has led to indefinite treatment regimens until side-effects become intolerable.13

Imiquimod

As an immune response modifier, imiquimod induces IFN-á, tumor necrosis factor (TNF)-a, IL-1, IL-6, IL-8, and IL-12 production by monocytes, macrophages and toll-like receptor (TLR)-7-bearing plasmacytoid dendritic cells. TLR-7 is an essential receptor for imiquimodinduced immune responses.14 Imiquimod also generates production of IFN-a after CD4 cells are stimulated by IL-12. IFN-a stimulates cytotoxic T lymphocytes responsible for killing virus-infected and tumor cells.

Topical imiquimod 5% cream has been found to be effective in the treatment of lentigo maligna (LM, in situ melanoma). In a pilot, open-label, nonrandomized study evaluating the effectiveness of imiquimod 5% cream once daily for a maximum of 13 weeks on five patients with LM, a 100% response rate was observed without reoccurrence during a 3–18 month follow-up interval.15 Case reports describing multiple metastatic melanoma skin lesions clearing after topical imiquimod 5% cream application have also been published. The two patients studied applied imiquimod 5% cream three times/week to the metastatic skin lesions with a 1cm surrounding margin.16

Basal Cell Carcinoma

Imiquimod 5% cream has been shown to induce the expression of FasR on BCC cells, and FasR mediated apoptosis may contribute to the effectiveness of imiquimod in BCC treatment.17 An initial 16-week, dose-ranging, vehicle-controlled trial examining the effect of 5% imiquimod cream on nBCC and sBCC found an overall histological response rate of 83% (20/24) in the 5% imiquimod cream treatment group vs. 9% (1/11) in the vehicle treatment group.18 Subsequent sBCC randomized, multicenter studies have reported 100% efficacy with twice daily application vs. 73–88% efficacy with once daily application of 5% imiquimod cream.19–21

Squamous Cell Carcinoma/ Actinic Keratosis

Imiquimod studies in SCC patients are restricted to AK and in situ SCC clinical presentations. A 16- week, twice weekly, imiquimod 5% cream treatment regimen has been approved by the FDA for patients with AK lesions on the face or scalp. This treatment regimen has achieved a 45.1% (97/215) complete clearance and a 59.1% (127/215) partial clearance rate. These clearance rates are significantly higher than the complete and partial clearance rates found in the vehicle group (p< 0.001).22

Bowen’s Disease

Current therapies for Bowen’s disease, or intraepidermal SCC, include 5-Fluorouracil, surgical excision, curettage, electrocautery, cryo-, laser-, photo-, and radiotherapy.23 In a Phase II open-label study, 16 biopsyproven plaques of Bowen’s disease, with diameters ranging between 1–5.4 cm, were treated once daily for 16 weeks with imiquimod 5% cream. Of the 16 lesions treated, 15 were on the lower extremities and 1 was on the shoulder. Fourteen of 15 patients (93%) had no residual tumor present in the 6-week post-treatment follow-up biopsy. Thirteen patients were followed to 6 months without disease recurrence.24

Extramammary Paget’s Disease

Extramammary Paget’s disease (EMPD) is an infrequent epidermal malignancy most commonly occurring in the anogenital and vulvar regions. Therapeutic modalities include wide local excision and Mohs micrographic surgery. A case report of two patients with primary limited cutaneous perineal and genital EMPD describes successful treatment of EMPD with imiquimod 5% cream, with confirmation of cure after 7.5–12 weeks of monotherapy. The treatment-associated morbidity was minimal when compared with other more invasive therapies.25 Another case study has documented the eradication of EMPD of the scrotum in a 68-year-old male with nightly application of imiquimod 5% cream for 6 weeks, with no signs of reoccurrence at 6 months after discontinuation of therapy.26

Imiquimod/ Study

Skin Cancer

Design

Number of Treated Patients

Dose/ Route

Frequency/ Duration

Length of Treatment

Partial Clearance Rate %

Complete
Clearance
Rate

Wolf, et al.15 Melanoma - Lentigo Maligna Pi, OL, NR 5 5% cream /Top q.h.s. x 5–13 wks 10 wks (median) 100 (5/5) 0 (0/5) (at median follow-up of 13 months)
Marks, et al.19 BCC - Superficial Ra, OL, DR 3, 33, 30, 33 5% cream/ Top b.i.d. x 7 d/wk q.d. x 7 d/wk b.i.d. x t.i.w q.d. x t.i.w. 6 wks 100 (3/3) 87.9 (29/33) 73.3 (22/30) 69.7 (23/33) N/R
Geisse, et al.20 BCC - Superficial Ra, DB, VC 185, 179, 179, 181, 5% cream/ Top 5% cream/ Top Vehicle/ Top Vehicle/ Top 5 d/wk q.d. x 7 d/wk q.d. x 5 d/wk q.d. x 7 d/wk 6 wks 82 (152/185) 79 142/179) *3 (11/360)* N/R
Schulze, et al.21 BCC - Superficial Ra, DB, VC 84, 82 5% cream/ Top Vehicle/ Top q.d. x 7 d/wk q.d. x 7 d/wk 6 wks 80 (67/84) 6 (5/82) N/R
Mackenzie- Wood24 Bowen’s Disease - Leg/Shoulder Pr, OL 16 5% cream/ Top q.d. x 7 d/wk 16 wks 93 (14/15) 0 (0/13) (at 6 month follow-up)
Lebwohl, et al.22 Actinic Keratosis - Face/Scalp Ra, DB, VC 2 phase 3 trials 215 221 5% cream/ Top Vehicle/ Top q.d. x 2 d/wk q.d. x 2 d/wk 16 wks 45.1 (97/215) 3.2 (7/221) 83.3% 0% (at 8 wk follow-up)
Korman, et al.45 Actinic Keratosis - Face/Scalp Ra, DB, VC 2 phase 3 trials 242 250 5% cream/ Top Vehicle/ Top q.d. x 3 d/wk q.d. x 3 d/wk 16 wks 48.3 (117/242) 7.2 (7.2/250) 86.6% 14.3% (at 8 wk follow-up)

Table 2: Summary of key published studies assessing the efficacy of imiquimod for skin cancer treatment Abbreviations: BCC–basal cell carcinoma; b.i.d.–twice/day; d–day; DB–double blind; DR–dose response; N/R–not reported; NR–non-randomized; OL–open label; Pi–pilot study; Pr–prospective; Ra–randomized; Top–topically; VC–vehicle controlled; wk–week; q.d.–once/day; q.h.s.–every night; t.i.w.–three times/week; *–combined.

VIN

Imiquimod was preconceived as possibly beneficial in the treatment of VIN of human papilloma virus etiology, due to its antiviral and antineoplastic properties; however, the literature shows mixed results. In a prospective, observational study examining the effects of imiquimod 5% cream three times/week for 16 weeks in 15 patients with high-grade VIN, 3 demonstrated local side-effects, including soreness, burning, erythema, ulceration, and blistering. One patient required hospitalization, catheterization, and analgesia. Of the 13 patients who completed the study, four demonstrated clinical improvement. Of these four patients, only one had a negative VIN biopsy. All four patients who responded clinically relapsed 4 months after treatment.27However, in a recent study examining the effect of imiquimod 5% cream applied three times/week for a maximum of 16 weeks in eight patients with biopsy-proven bowenoid and basaloid, VIN 2/3 had better results. Total clearance and partial clearance was observed in six patients and two patients, respectively, and the post-treatment biopsy showed an absence of precancerous lesions in seven of eight patients (87.5%).28

Dendritic Cell-based Therapy

The use of autologous dendritic cells (DCs) loaded with tumor-associated antigens as a natural adjuvant to actively prime an effective immune response against tumor cells is also being investigated.29–35 A Phase I clinical trial by Escobar, et al. designed to address the safety and efficacy of immunizations with tumor lysateloaded DCs in Stage III–IV metastatic melanoma patients found a significantly longer post-vaccination survival in patients with a delayed type IV hypersensitivity reaction against the melanoma cell lysate (17.25 months) than in nonresponders (8.625 months), (p=0.0261).36 This study demonstrated that the vaccination procedure used was safe and could induce a clinical and immunologic response in patients with advanced melanoma, like other studies with comparable protocols.35,37 However, a recent randomized Phase III clinical trial studying the effect of dacarbazine monochemotherapy vs. vaccination with autologous peptide-pulsed DCs in patients with metastatic melanoma found Grade 3/4 toxicities in seven patients in each treatment arm, and a total of 75 deaths at median follow up of 22.2 months. No significant differences were found in overall or progression-free survival between the two treatment arms.29

IL-12 Study

Skin Cancer CTCL

Design

Number of Treated Patients

Dose/ Route

Frequency/ Duration

Length of Treatment

Partial Clearance Rate

Complete
Clearance
Rate

Rook et al.41 T1/2 T3 T4 Pr, OL 5, 2, 3 50–300ng/kg/SC q.d. x 2 d/wk q.d. x 2 d/wk q.d. x 2 d/wk up to 24 wks 40% (2/5) 0% (0/2)* 50% (1/2) *Observed regression of injected tumor 40% (2/5) 0% (0/2)* 50% (1/2) *Observed regression of injected tumor

Table 3: Summary of key published studies assessing the efficacy of IL-2 for skin cancer treatment Abbreviations: CTCL: cutaneous T-cell lymphoma; d: day; IL: Interleukin; OL: open label; Pr: prospective; q.d.: once per day; SC: subcutaneous; wk: week.

Interleukin-2

Cutaneous Melanoma

Dose-related serious toxicities have limited IL-2 studies in melanoma patients, and low-dose IL-2 therapy has produced disappointing clinical response rates.38 When high-dose, 100,000 units/kg, intravenous, recombinant IL-2 was examined in 47 patients with metastatic malignant melanoma, up to 20% achieved objective responses; however, three patients developed myocardial infarction and one patient died during therapy.39 IL- 2-based biochemotherapy (IL-2, IFN-á-2b, cisplatin, dacarbazine, and vinblastine) has shown a response rate of 48%. It appears that this combination is statistically superior to either IL-2 or chemotherapy alone.40 Results of ongoing trials may clarify the true value of IL-2 in combination chemotherapy.

IL-12

Cutaneous T-cell Lymphoma

CTCL presents with marked defects in IL-12 production, and progression of CTCL has been associated with profound defects in cell-mediated immunity and cytokine production. A Phase I dose-escalation trial examined the effect of recombinant human IL-12 (rhIL- 12) at a concentration of 50ng/kg, 100ng/kg, or 300ng/ kg, given two times/week subcutaneously for up to 24 weeks in 10 patients with CTCL. A complete clinical response (CR) was defined as complete disappearance of all measurable CTCL lesions for at least 1 month. A partial response (PR) was defined as at least 50% disappearance of all CTCL skin lesions for at least 1 month. Only patients with plaque stage disease (n=2) presented a CR. Two plaque stage patients and one Sézary syndrome patient had a PR. None of the T3 stage patients responded to the rhIL-12 treatment. The authors announced the development of future Phase II/III clinical trials based on the high response rate of plaque stage CTCL patients to rhIL-12.41

Future clinical trials on immunomodulators will continue to change the approach, management, and follow-up of skin cancer patients. These skin cancer therapies will continue to be based on principles governing the immune system. As our knowledge of the immune system continues to grow, the application of safe and efficacious immunomodulators to treat skin cancer will continue to change the practice of dermatology.

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