Immunotherapies are ones that mobilize the body’s own immune system defense against disease processes. This blog entry is about immunotherapies for skin cancers, focusing on an effective older one known as imiquimod or by its trade name aldara, and a partially effective newer one still in the approval process called ipilimumab.
About skin cancer immunotherapies
The concept of cancer immunotherapy goes back many years and has been of particular interest for treating deadly cancers for which no good conventional treatment exists. “Cancer immunotherapy is the use of the immune system to reject cancer. The main premise is stimulating the patient’s immune system to attack the malignant tumor cells that are responsible for the disease. This can be either through immunization of the patient (e.g. by administering a cancer vaccine, such as Dendreon’s Provenge), in which case the patient’s own immune system is trained to recognize tumor cells as targets to be destroyed, or through the administration of therapeutic antibodies as drugs, in which case the patient’s immune system is recruited to destroy tumor cells by the therapeutic antibodies(ref).”
Basal cell carcinoma immunotherapy
Imiquimod is a topical cream immunotherapy agent originally approved in the 1990s for the treatment of genital warts()()(). It was later found to be effective in clearing up actinic keratoses (a possibly pre-cancerous condition of damaged skin) and superficial (non-penetrating) basal cell carcinomas. As outlined in the 2010 publication New perspective in immunotherapy: local imiquimod treatment, imiquimod, known by its trade name Aldara, is largely a success story. “Imiquimod belongs to the family of synthetic small nucleotid-like molecules of imidazoquinolinamines. It is an immune response modifier with potent antiviral and antitumor effects, which are mediated by Toll-like receptors (TLR7 and TLR8). Imiquimod targets predominantly TLR7 expressing plasmacytoid dendritic cells and Langerhans cells, with secondary recruitment and activation of other inflammatory cells. Activation of TLR7 results in the stimulation of the innate and acquired immune responses, in particular cell mediated immune pathways. Topical imiquimod cream 5% (Aldara, MEDA Pharma) has been found to be effective for the treatment of actinic keratoses, superficial basal cell carcinoma and anogenital warts. Topical imiquimod is especially recommended for the treatment of large clinically asymptomatic fields containing tumor cells (“field cancerization”). Treatment with imiquimod applied at home by patient gives excellent cosmetic results. There are some data on its efficacy in nodular basal cell carcinoma and in some other skin cancers. The drug appears to be well tolerated with mild to moderate to local inflammation at the site of application. This paper provides a review about current experience and possible future development of imiquimod.”
Imiquimod was approved in 2004 by the FDA for use with patients having a normal immune system and who have superficial basal cell carcinoma – one of the four types of basal cell carcinoma. It is approved for application to tumors with a maximum diameter of 2.0 centimeters, and use is limited to certain areas of the body. For tumors in areas like the face or for larger areas where multiple small tumor sites may be involved(ref), use of imiquimod can be an attractive alternative to surgery. The 2006 paper Use of 5% imiquimod cream in the treatment of facial basal cell carcinoma: a 3-year retrospective follow-up study reports “We found that 5% imiquimod cream is an effective treatment option for superficial and nodular basal cell carcinomas, giving a clearance rate of 89.5% at an average of 39 months of follow up.”
I need to disclose that I was treated for a superficial basal cell carcinoma on my face using 5% imiquimod cream about 4 years ago and after a few months of treatment the cancer was permanently gone. Also, a biopsy four weeks ago showed that another small sore on my face was a basal cell carcinoma. I doubled up on my morning curcumin and other anti-inflammatory supplements and a second biopsy on the same spot 12 days later showed actinic keratoses but no signs of basal cell carcinoma. Nonetheless, with the help of my understanding dermatologists, I have just-in-case commenced a new round of treatment on the spot using imiquimod. This is personal anecdotal data that may or may not be relevant to others. Please see the medical disclaimer for this blog.
The story of immunotherapies for melanoma is much more of a mixed one. The 1992 publication Immunotherapy with monoclonal antibodies in metastatic melanoma opens with statements that could be still written today: “Therapy for metastatic melanoma has been disappointing to date. Treatment with chemotherapy only uncommonly results in complete responses and rarely results in long-term survivors.” The abstract of the publication goes on to say “The identification of human melanoma cell surface antigens has led to the development of an array of mouse monoclonal antibodies (MAb) for use in the diagnosis and therapy of patients with metastatic melanoma. Strategies utilizing MAbs based on immunologic approaches have been developed. Naked MAbs directed against glycoprotein surface antigens or conjugated to toxins or radionuclides have shown little biologic or clinical activity. However, phase I studies of MAb directed against glycolipid antigens have yielded objective tumor shrinkage with occasional complete responses. Severe toxicity has been seen infrequently. Possible anti-tumor mechanisms include complement activation and antibody-dependent cellular cytotoxicity utilizing natural killer cells or monocytes as effector cells. Strategies to enhance the anti-tumor effects of MAb, including combinations with cytotoxic agents and cytokines, have been introduced with limited success thus far. The development of a human IgG anti-mouse antibody has been seen in nearly all treated patients. A new generation of MAb engineered to overcome the immunogenicity of mouse MAb and to enhance immune effector function will soon enter clinical trials.” Yet, despite the sounded note of optimism, progress now 18 years later has been tortuously slow.
The May 2010 blog entry Melanoma Research Update discusses the long and mostly-dismal history of clinical trials for melanoma and an April 2010 publication on a PhaseI/Phase2 trial of using autogolous denditric cells as a melanoma immunotherapy, Vaccination with autologous dendritic cells pulsed with multiple tumor antigens for treatment of patients with malignant melanoma: results from a phase I/II trial. I said “I decode this (the results) to mean that about a quarter of the treated patients extended their mean survival time from 9 months to 18.4 months. While this is only a Phase I/II study, it casts doubt on whether dendritic cell cancer immunotherapy, a major focus of current cancer research, will provide a magic bullet against aggressive cancers.” This still seems to be the case.
A little more than a month ago, a new report appeared on a Phase III clinical trial of a monoclonal antibody treatment against melanoma. The June 2010 publication in the New England Journal of Medicine Improved Survival with Ipilimumab in Patients with Metastatic Melanoma describes Phase III clinical trial results for ipilimumab, an immunomodulatory monoclonal antibody that targets cytotoxic T-lymphocyte antigen 4 (CTLA4). “A total of 676 HLA-A*0201–positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136).” (gp100 is a glycoprotein peptide vaccine) — “The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76)(ref).”The good news is that, for patients with advanced melanoma who were virtually certain to die soon, the ipilimumab treatment increased survival by an average of 3.7 months. Also, ipilimumab alone or in combination with a glycoprotein peptide vaccine improved the statistical probability for prolonged survival. “In study, ipilimumab provided durable disease control in 20-30 percent of patients and improved two-year survival. – “These study results finally provide good news to the many researchers and clinicians who have faced disappointment for decades in treating a disease for which average survival is just six to nine months,” he (Dr. O’Day, who reported on the work) says. “The improvement in median survival associated with ipilimumab is impressive, but it is equally impressive that its benefit for improving survival appears to be persisting, with the longest available follow-up now out to 4.5 years(ref).”
Ipilimumab is still awaiting FDA approval which may take a year. In the interim the drug is being offered to eligible recipients in a “compassionate use” trial at St. Luke’s Hospital cancer center(ref).
The bad news, of course, is that ipilimumab falls far short from being a cure for melanoma.
Besides monoclonal antibody treatments like ipilimumab, two other kinds of immunotherapy are being used to treat melanoma: Cytokine therapy (interferon, interleukin) and Monoclonal antibody therapy. From the SkinCancerNet article Immunotherapy: What It is and How It Can Help Fight Cancer: “Cytokine Therapy: “Cytokines” are proteins released by cells in the immune system that help boost immunity. Two cytokines have been approved by the FDA for the treatment of metastatic melanoma: Interferon-alpha and Interleukin-2 (IL-2. — In clinical trials, these two cytokines have helped shrink tumors in about 10% to 20% of patients with stage III and stage IV melanoma. It is believed that cytokines hold enormous potential for cancer therapy, and many cytokines are being studied in clinical trials because of their ability to enhance the body’s immune response to cancer cells. – Interferon. Interferons are substances within the immune system that are produced in response to infection. They are classified as alpha, beta, or gamma forms — depending on the chemical structure, biologic activities, and other criteria. Interferon-alpha is FDA-approved for treating melanoma in stage IIB (primary tumor is 4 millimeters or more) and stage III (spread to the lymph nodes) when used along with another therapy, such as surgery. In these stages, interferon-alpha helps prevent recurrence and increases the likelihood that all cancer is eliminated.”
Up to this point, after some 20 years of research and development, melanoma immunotherapies only work in some patients and produce only partial results. Meanwhile, the quest for better immunotherapy or combination immunotherapy treatments for melanoma goes on.
Much additional information relating to melanomas and emerging melanoma treatments are in the earlier blog post Melanoma Research Update.