Stepping Stones to Success with Drug Treatments for Melanoma

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04.25.2011

Recently, it was announced that the Food and Drug Administration has approved a breakthrough cancer medication from Bristol-Myers Squibb Co. that researchers have heralded as the first drug shown to prolong the lives of patients with advanced skin cancer.  The federal health agency approved an injectable drug called Yervoy for late-stage or metastatic melanoma. (http://www.dddmag.com/news-FDA-Approves-BMS-Melanoma-Drug-32511.aspx?et_cid=1328125&et_rid=45513765&linkid=http%3a%2f%2fwww.dddmag.com%2fnews-FDA-Approves-BMS-Melanoma-Drug-32511.aspx)

As Immunologists, we are encouraged by the fact that the FDA approved the biotech drug known chemically as ipilimumab, even though it only worked in a small segment of patients studied, and on average they lived just four months longer than patients given older medications. Ipilimumab is part of a group of targeted cancer medicines that harness the body’s immune system to fight off cancer, rather than attacking the disease with outside chemicals like chemotherapy. The drug works by blocking a molecule linked to immune cell response called CTLA-4, and maintaining activity of white blood cells. When the molecule is blocked, the cells maintain an “activated phenotype” and are able to fight off cancer.

The fact that Yervoy (ipilimumab) proved to prolong life for some patients is a good start in finding more effective ways to treat melanoma, which is often unresponsive to therapy.  While some will argue the value of the cost and time involved for this result, experts in immune monitoring and surveillance see promising research progress that may someday soon lead to more significant and meaningful treatments for those suffering from metastatic melanoma.

Two-tiered strategy may improve outcome for treating melanoma

Why is it an important milestone for treating melanoma? “If a single biologic, CTLA4, enhances the outcome, now researchers have the capability of adding in therapeutic strategies that are scientifically relevant to hopefully further improve the outcome”, says Sybil D’Costa, Ph.D., VP of R&D at ImmunoSite Technologies. Adding therapeutic strategies to improve the outcome.

For example, D’Costa suggests a two-tiered strategy that would be immunologically relevant and scientifically sound: possibly a “tickle” of melanoma specific T cells with DCs pulsed with melanoma peptides, and then the CTLA4 therapy to lengthen the timeline of the activation. This would also limit the immune-related side effects by targeting the immune response to the cancer.

In that instance the immune monitoring panels would be:

1. An evaluation of Dendritic cell function pre and post autologous cancer presenting Dendritic cell pulse

2. A determination of downstream effects of the DC pulse by evaluating surface activation and rafting of cancer specific CD4 and CD8 pre and post DC pulse and CTLA4 treatment

3. An evaluation of antigen specific functionality in helper and cytotoxic T cells pre and post CTLA4 treatment

4. An evaluation of shift in T regulatory cell activity

5. An evaluation of Tumor infiltrating lymphocytes in comparison to antigen (cancer) specific circulating lymphocytes

Such combinatorial strategies that are scientifically relevant are already being discussed and evaluated in the literature: 2011 Apr 5. CTLA-4 blockade increases antigen-specific CD8(+) T cells in prevaccinated patients with melanoma: three cases. http://www.ncbi.nlm.nih.gov/pubmed/21465316.

Contract Research Organizations (CROs) like ImmunoSite Technologies (IST) are very involved with pre-clinical and clinical research to assist drug and biologic companies in developing immune monitoring assays to assess the performance of drugs such as this.  While the initial results may be marginal, the progress towards a better drug treatment is clear.  It is significant that the FDA has approved the drug Yervoy for late-stage or metastatic melanoma. It should encourage more drug research approaches such as the two-tiered strategy outlined here.

Progress leads to more questions

Do you agree that the drug Yervoy (ipilimumab) has proven to be a “significant milestone” in treating melanoma?

What are your thoughts on the two-tiered strategy outlined in this post?  How would you amend it?

What are your thoughts on the potential for future cancer medicines that harness the body’s immune system to fight off cancer?  What research would you like to see conducted?

Update:  Two-tiered Strategy Proves Successful at Dana Farber Cancer Institute

In an April 27th announcement (http://www.dana-farber.org/abo/news/press/2011/new-technique-extends-cancer-fighting-cells-potency-in-melanoma-patients.html), the Dana Farber Cancer Institute talks about successful use of a two-tiered or combinational strategy for immune modulation in cancer.  This small study supports the two-tiered strategy suggested in this post.  In the Dana Farber Cancer Institute study, the positive results, five of five patients seemed to respond, indicate that such a combinational strategy would in fact help make a drug like Ipilimumab a scientifically relevant drug for immune modulation in cancer.

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