Imiquimod: Potential treatment for Skin Metastasis

Summary 

Safe, Effective and Accessible.

Used originally on genital warts, it has proven beneficial in the treatment of basal cell carcinoma and can be useful in the treatment of skin metastasis such as those from malignant melanoma, breast cancer and others.

Case reports 

Imiquimod in the Treatment of Breast Cancer Skin Metastasis: We report a case of breast cancer skin metastasis that was successfully treated with imiquimod when radiotherapy and several chemotherapy regimens were unsuccessful and excision was not a viable therapeutic option. In addition to regression of the lesion and an improvement in esthetic appearance, the patient also described a significant reduction in pain from the skin metastasis. http://jco.ascopubs.org/content/32/8/e22.full

Topical TLR7 Agonist Imiquimod Can Induce ImmuneMediated Rejection of Skin Metastases in Patients with Breast Cancer: Ten patients were enrolled and completed the study. Imiquimod treatment was well tolerated, with only grade 1 to 2 transient local and systemic side effects consistent with imiquimod’s immunomodulatory effects. Two patients achieved a partial response [20%; 95% confidence interval (CI), 3%–56%]. Responders showed histologic tumor regression with evidence of an immune-mediated response, showed by changes in the tumor lymphocytic infiltrate and locally produced cytokines. http://clincancerres.aacrjournals.org/content/early/2012/12/05/1078-0432.CCR-12-1149.full.pdf

Mechanism

The exact mechanism of action of imiquimod is not known, but it is an immune response modifier and it has been hypothesized to enhance an immune response against tumors by stimulating dendritic cells and macrophages and by activating inflammatory cytokines and chemokines through toll-like receptors.^3,4 There is also some evidence that it has antiangiogenic properties⁵ and that it can stimulate intrinsic apoptosis.^6–8  

More studies are required to better understand how this immune modifier acts on skin metastasis from breast cancer and other cancers, and a randomized clinical trial would be important to demonstrate efficacy. Imiquimod’s reported ability to treat a variety of different skin cancers and tumor metastases suggests that its immune-modifying properties result in a nonspecific antitumor response that may be intense and local. A recent study suggests that imiquimod’s stimulation of dermal mast cells through toll-like receptors leads to the expression of chemokine-2, which results in the migration of large numbers of plasmacytoid dendritic cells (pDCs) into the vicinity of the tumor.⁴ The activated pDCs then produce type I interferons that act in an autocrine manner to upregulate expression of granzyme B and tumor necrosis factor–related apoptosis-inducing ligand, transforming the pDCs into killer dendritic cells. Still, some reports have suggested that imiquimod may lead to an intrinsic apoptosis of tumor cells independent of its associated immune response, possibly by downregulating myeloid cell leukemia 1 and B-cell lymphoma/leukemia 2 proteins, among other antiapoptotic proteins, although the exact mechanism leading to tumor cell apoptosis is still not clear.^6–8

http://jco.ascopubs.org/content/32/8/e22.full

The TLR7/8 agonists have aroused interest because they not only activate antigen-presenting cells but also promote activation of T and natural killer (NK) cells. However, the exact mechanism by which stimulation of these TLRs promotes immune responses remains unclear, and different TLR7/8 agonists have been found to induce different responses. In this study, we demonstrate that both gardiquimod and imiquimod promote the proliferation of murine splenocytes, stimulate the activation of splenic T, NK and natural killer T (NKT) cells, increase the cytolytic activity of splenocytes against B16 and MCA-38 tumor cell lines, and enhance the expression of costimulatory molecules and IL-12 by macrophages and bone marrow-derived dendritic cells (DCs) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002679/

Safety

Safe:
http://clincancerres.aacrjournals.org/content/early/2012/12/05/1078-0432.CCR-12-1149.full.pdf
http://www.ncbi.nlm.nih.gov/pubmed/16103328

Preparation and administration

Topical:

Imiquimod 5% cream. The cream was self-applied by patients to all clinically apparent skin metastases for 5 d/wk for 8 weeks (1 cycle). Additional treatment cycles were left to the discretion of patient and treating physician. The cream was thinly spread onto the lesions, remained on the skin for approximately 8 hours overnight, and was washed off the following morning. One single use packet (containing 250 mg of the cream) was used to cover areas up to 100 cm2 ; another packet was used for each additional treatment area of 100 cm2 , up to a maximum of 6 packets per day. These dose determinations were based on extrapolation from clinical experience with dosing of up to 6 packets per application in patients with actinic keratoses (11, 12). http://clincancerres.aacrjournals.org/content/early/2012/12/05/1078-0432.CCR-12-1149.full.pdf

Source

It can be probably accessed at many pharmacies but here is a source that I know:

A pharmacy in Israel taking orders at the following email address (they also sell LDN, Noscapine, Interferon): orders (at) expertcompounding.com

Here is the price list I have seen in 2014:

IMIQUIMOD-10 Imiquimod 10mg 20 capsules $ 245.00 $
IMIQUIMOD-25 Imiquimod 25mg 20 capsules $ 580.00 $
IMIQUIMOD-50 Imiquimod 50mg 20 capsules $ 1,030.00 $
IMIQUIMOD CREAM Imiquimod Cream , 2.5mg per ml 20ml (total 50mg) $ 105.00

Synergy and Antagonism

Currently a clinical trial combining topical imiquimod and PD-1/PD-L1 blockade for treating breast cancer cutaneous metastasis is also being planned in the University of Washington. The idea behind this combination is based on the fact that TLR agonists such as imiquimod are believed to induce e.g. IL-10, Treg, and PD-L1. As a result, this combination would address the induced PD-L1 http://journal.frontiersin.org/article/10.3389/fimmu.2014.00083/full

Dendritic Cell therapy: The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002679/

References

Topical treatment of melanoma skin metastases with imiquimod The treatment of skin metastases of melanoma can be difficult in many cases because of the patients age, as well as the number, size and location of the lesions. We present the case of an 82-year-old male with melanoma skin metastases on the scalp, which responded satisfactorily to treatment with 5 % imiquimod cream. Imiquimod is a topical immunomodulator with antiviral and antineoplastic action. This case, along with others that have recently been published, supports the usefulness of this treatment in selected cases of melanoma skin metastases, at least for palliative purposes.

Topical treatment of melanoma skin metastases with imiquimod: a review 57 studies were identified. 46 did not meet inclusion criteria, leaving 11 case studies. Overall, 17 patients were treated in these 11 studies. Main treatment choice was 5% IMQ cream applied once daily (for 6-8 hours), five days per week under occlusive conditions, in 8/17 patients (47,1%). IMQ was applied 3 times weekly in 4/17 patients (23,53%), daily in 2/17 patients (11,76%) and twice daily in 2/17 patients (11,76%). Treatment length was variable, with a mean duration of 22 weeks (range from 8 weeks to 72 weeks). The majority of studies showed that IMQ is an effective and safe treatment for metastases of melanoma. Even if this treatment doesn’t stop the disease progression, it is mainly useful in clearing cutaneous metastases spreading from melanoma primary tumor.

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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