CTOS Op Ed |
The Difficulty and Promise of Immunotherapy for Sarcomas
An ESUN Editorial
Editor's Note: This editorial is part of an ongoing series of Op Ed pieces written by one of the members of the Board of Directors of the Connective Tissue Oncology Society (CTOS). Dr. Maki is the current President of CTOS. These editorials are intended to address important and controversial issues in the field. The "Questions, Comments & Counterpoint" column allows readers to express their opinions in response to these Op Ed pieces. Click here to send in an opinion.
Coordinating Editor's Note: There are many controversies in sarcoma. I summarized a number of them in my CTOS Op Ed Controversies in Sarcoma in the April 2009 issue of ESUN. This issue of Controversies in Sarcoma focuses on the problems with immunotherapy in the treatment of sarcomas. Sarcomas are a very diverse group of tumors. In order to attack these tumors, researchers have used the science of adaptive immunotherapy to teach the immune system to develop a response to a specific target and develop an immune response. Bob Maki does an outstanding job pulling these concepts together and outlining the difficulties in immunotherapy in sarcomas. - Doug Letson, MD
There are reports of spontaneous responses of kidney cancer and melanoma without intervention. These findings, as well as suggestions of less aggressive courses of melanoma in people who develop vitiligo, responses of melanoma to blockers of T cell immune inhibitor CTLA4, and the finding of better clinical outcomes with small cell lung cancer, ovarian cancer, and breast cancer in patients who develop autoimmunity against proteins found both in the tumor and the brain of patients, have given investigators tantalizing evidence that the immune response can be harnessed to fight cancer.
However, there are a number of problems regarding using the immune system against sarcoma. First, there are over 50 types of sarcoma, so what may work for one sarcoma "flavor" may not work for another. For similar reasons, it is difficult to identify proteins targets that may be of general usefulness for the treatment of sarcomas. Second, it is hard to monitor immune responses against most tumors. You can follow the blood for presence of antibodies or anti-tumor T cells (a type of white blood cell that attacks tumors), but is looking in the blood appropriate when so many T cells are in lymph node? Should we be looking at T cells in the tumor? If so, then patients would need many biopsies to find out if an immune therapy is working in the predicted manner. This is invasive, potentially painful, expensive, and thus very difficult to do.
One intriguing line of therapy regards cell surface molecules called gangliosides, a type of molecule built of special sugars (sialic acid) attached to fat molecules that then float in the membrane of the cell. It turns out that gangliosides are common in melanoma cells, but surprisingly even more common in several types of sarcomas examined. Thus gangliosides may serve as relatively tumor-specific approach to treat sarcomas. Research is soon to be underway in which several hospitals will look to vaccinate patients against gangliosides once lung metastases of sarcoma have been surgically removed, typically from the lungs, to see if one can prevent further recurrence by mounting an immune response, either using a non-specific immune stimulant, or using that same immune stimulant with gangliosides mixed in. Monitor the listings at SarcomaHelp.org or ClinicalTrials.gov as to the availability of this and other such vaccine studies. For example, studies in Japan are investigating whether vaccines against synovial sarcoma can be helpful in treating that form of metastatic sarcoma, and at the National Cancer Institute in the U.S. there has been an ongoing interest in vaccine therapy against sarcomas, in particular those that occur in children.
This vaccine study is tempered by the finding that in all, vaccines have benefited fewer than 5% of the people who have received them (for any type of cancer). Building on this concept, there is now an effort underway by Steven Rosenberg and his colleagues at NCI to use "adoptive immunotherapy" to treat synovial sarcoma. This involves taking T cells (a type of white blood cell) and teaching them to develop an attack against a protein called NY-ESO-1 that is found on synovial sarcoma tumor cells, on the ovary, and on the testis. Since one does not need the ovary or testis to survive, even if there were an immune response against these proteins in ovary or testis, it should not be life threatening. After 3-6 months, enough T cells are grown to attack the tumor in numbers far larger than anyone has been able to generate with tumor vaccines. If this approach is successful, it may set a new standard for immunotherapy trials, not just for sarcoma, but perhaps cancer in general.
The other way investigators are trying to harness the immune system is to provide extra signals to T cells and other immune cells that keep them active for longer, or that cause them to increase in number. These targets are called costimulatory molecules, and the first of these, with agents that recognize CTLA4, have been associated with people benefiting with melanoma and other cancers. Since there is a tremendous increase in the understanding of these sorts of molecules and how they interact in the immune system, this could, with vaccination, provide another robust approach to treating cancer with immune therapy. However, these compounds can be toxic, since they non-specifically turn on the immune system—so immune responses can develop against normal tissues such as the colon/intestines to cause diarrhea and "colitis" (inflammation in the colon) as well as rash from immune responses against the skin, and other side effects. The fine tuning of these responses will be a challenge for the next several years at least.
Thus, while some investigators are looking at new drugs to treat cancer, turning the immune system on in specific ways is an area of active research among many physicians and scientists, and as we have seen with advances in chemotherapy, we hopefully will see novel and effective therapeutics developed within the next few years to treat at least a subset of patients with sarcomas.
V6N5 ESUN Copyright © 2009 Liddy Shriver Sarcoma Initiative.