Since the publication of our March 30, 2011 article on melanoma on this blog, interest in melanoma has remained high. This is to be expected, with the March 2011 approval of ipilimumab (Medarex/Bristol-Myers Squibb’s Yervoy), and the expected approval of Daichi Sankyo/Plexxikon/Roche’s PLX4032/RG7204 in the near future.
The April 2011 issue of the Faculty of 1000′s The Scientist included two articles that focused on melanoma. The first article, entitled “Taking Aim at Melanoma”, was written by leading clinician and scientist Keith T. Flaherty, M.D., whose work (especially with respect to development of PLX4032) has been discussed in several articles on this blog. The second article, which we shall discuss further below, is entitled “Imagining a Cure”.
Then there was the American Association for Cancer Research (AACR) meeting (April 2-6, 2011, Orlando FL). This included numerous presentations on melanoma, including strategies for overcoming resistance to PLX4032 via development of combination therapies. There were parallel discussions on similar strategies in other cancers.
Haberman Associates will have a major new publication out shortly. This will (among other things) include discussions of combination therapies designed to overcome resistance to targeted therapies in several cancers, including melanoma.
The article entitled “Imagining a Cure” in The Scientist was written by National Cancer Institute (NCI) principal investigator Nicholas P. Restifo, M.D., and writer Megan Bachinski.
This article begins with what is the real desire of every cancer patient–a durable complete response, which is tantamount to a cure. In the case of patients with early-stage, localized melanoma, the disease is completely curable via surgery. However, metastatic melanoma is almost always fatal. Pre-March 2011 treatments, dacarbazine and interleukin-2 (IL-2), have reported complete response rates of 2.7 percent and 6.3 percent respectively. Even the newer treatments, ipilimumab and PLX4032, although they give improved survival over earlier treatments, only have reported rates of durable complete responses of 0.6 percent and 2.0 percent, respectively.
The authors then go on to discuss the only type of therapy that has resulted in high percentages of durable compete responses in metastatic melanoma patients–adoptive cell transfer (ACT), also known as adoptive immunotherapy. Dr. Restifo works in this area, as well as in other aspects of tumor immunology. Adoptive immunotherapy was pioneered by Steven A. Rosenberg, M.D. Ph.D., the Chief of Surgery and Head of the Tumor Immunology Section at the NCI, since the 1980s. Dr. Rosenberg remains a leader in the field, and Dr. Restifo works with him.
In ACT, a physician/researcher extracts a patient’s antigen-specific immune cells, which are usually found in tumor tissue. [Such cells are known as "tumor infiltrating lymphocytes" (TILs).] He or she then expands the numbers of the antitumor T lymphocytes in cell culture, using the T-cell growth factor, IL-2. The physician/researcher then infuses the cells, plus IL-2, intravenously into the patient. The infused T cells traffic to tumors and can mediate their destruction. Prior to TIL infusion, the patient may have his or her immune system temporarily ablated via “preparative lymphodepletion” with chemotherapy and sometimes also total-body irradiation. The preparative lymphodepletion treatment is associated with enhanced persistence of the transferred TILs.
In a recent clinical study of ACT, the treatment resulted in the disappearance of all tumors in 20/93 patients (21.5%) with advanced metastatic melanoma. For 19 of these 20 patients (95%), the complete responses have been durable and long-lasting, in some cases lasting for over 7 years. (See also the Faculty of 1000 evaluation.) Research on the mechanistic basis of adoptive immunotherapy, as well as on means to improve ACT technologies, is ongoing, so there is the potential to improve the durable complete response rate further.
Adoptive immunotherapy is not the only cancer immunotherapy that is in clinical studies or on the market. The newly-approved ipilimumab is a nonspecific T-cell modulator. Then there are the therapeutic cancer vaccines, including sipuleucel-T (Dendreon’s Provenge), which was approved for treatment of prostate cancer in 2010, as well as other cancer vaccines in clinical trials. Sipuleucel-T, which costs about $93,000, provides only a modest survival benefit (in one Phase 3 trial, 25.8 months compared to 21.7 months for placebo-treated patients) and is not associated with tumor regression. Overall, cancer vaccine clinical trials have resulted in an overall response rate of less than 4 percent. There have been no complete responses.
The authors of the article ask the following questions: If adoptive immunotherapy for metastatic melanoma has such a high durable complete response rate, why is it only available in a small number of cancer canters worldwide? Why is there little commercial interest in developing ACT? What can be done to facilitate the more widespread adoption of adoptive immunotherapies?
The authors give the following explanations: Adoptive immunotherapies are still considered experimental, are not FDA-approved, and are not paid for by third party payers. Thus only a handful of locations can bear the financial burden of administering adoptive immunotherapy. However, if a cancer center has a cell production facility with the required staff, the cost of producing a single dose of T-cells for adoptive transfer is approximately $20,000, much lower than a full course of Provenge or ipilimumab (approximately $120,000) treatment. ACT treatment also entails factoring in the cost of hospitalization. Most patients only require a single dose, however.
Adoptive immunotherapy is also comparable or less expensive than the cost of other, non-immunotherapy antitumor biologics, such as bevacizumab (Avastin) or cetuximab (Erbitux)—where the cost of the drug alone can exceed $80,000, and no patients are cured.
Moreover, according to the article, it would be difficult for a private company to pursue clinical trials for FDA approval and commercialization of ACT. To conduct such trials, a company would need to build a specialized cell processing and treatment facility, with a highly trained and competent staff. Adoptive immunotherapies also appear to lack a clearly defined claim to intellectual property (IP), since the patient’s own cells are not a “drug” to be patented. Nevertheless, Provenge also uses the patient’s own cells (in this case, antigen-presenting dendritic cells), and must be prepared specifically for each patient. In the case of Provenge, the cells are combined with a proprietary antigen/growth factor fusion protein (PA2024), however.
In the case of adoptive immunotherapies, various technologies for TIL isolation, selection, and expansion might be patentable, as might the use of genetically-engineered antitumor T cells.
The public sector might, according to the article’ authors, provide an alternative sponsor for adoptive immunotherapy. A network of cancer centers, institutes, and hospitals might form a consortium to refine ACT technology, and sponsor clinical trials aimed at FDA approval. Such FDA approval might provide substantial financial benefits for institutions in the consortium.
Moreover, research is underway to expand the types of cancers to be treated via adoptive immunotherapy. This research involves adoptive immunotherapy for synovial-cell sarcomas, B-cell lymphomas, and renal cancer. The expansion of adoptive immunotherapy beyond melanoma might, according to the authors, bring in new groups of stakeholders with an interest in making this type of treatment more widely available. Moreover, it might also encourage corporate and/or nonprofit organizations to envision the possibility of treating more common cancers, with the potential for larger financial rewards.
Given the superior results in terms of durable complete responses and comparable costs to other types of metastatic melanoma treatments, and the potential to treat other cancers, adoptive immunotherapy should not be ignored. However, it faces considerable hurdles to its widespread adoption.
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