Ralph Steinman, co-discoverer of the dendritic cell (DC) and its importance in adaptive immunity, developed experimental vaccines to combat his own pancreatic cancer. In this one-man trial, DC vaccines were designed and used in combination with standard cancer treatments. Steinman, along with collaborators from around the globe, employed several ideas to formulate the treatment. First, tumor tissue removed during surgery was grown in mice to be used for drug testing. Mutations in tumor DNA were used to inform drug choice and surface peptides were extracted from the tumor to be used in a vaccine.
In addition to conventional chemotherapy, three novel vaccines were used. Initially, tumor cells were removed and irradiated. The cells were then genetically modified to produce chemokines capable of attracting and activating DC’s and other lymphocytes. The next vaccine loaded Steinman’s DC’s with RNA extracted from the tumor. These dendritic cells, now presenting tumor antigens, were infused back into Steinman in hope of generating an adaptive response against tumor cells. The third vaccine approach was to load DC’s with peptides extracted from tumor cells and re-inject them back into Steinman.
It’s not clear which, if any, of the treatments extended Steinman’s life but prognosis for pancreatic cancer is usually measured in months. Steinman lived with his cancer for 4 years. It was found that 8% of his CTL population was directed against the tumor. If it was due to the therapies or Steinman’s own immunities is unknown. Two additional therapies that may have increased success include a checkpoint blockade inhibitor, which allows the cancer suppressed immune system to return to a normal operating level. The other is a monoclonal against CTLA-4, which has been implicated in immune suppression.
http://www.nature.com/news/2011/111011/full/478163a.html
For those unfamiliar with the background on this (because ScoWem7630 didn't include his source), this is the immunologist who was awarded the Nobel last month, but died about a day or so before the announcement.
ReplyDeleteIt is a really neat technique, but I wonder which step of the immune response prevents this from occurring in vivo? For whatever reason, the tumor grows in an immunosuppressed environment, and therefore either APCs are unable to pick up an Ag from the tumor to present to a T cell, and/or the T cell response is unable to kill off the tumor.
It turns out that last year, the first cancer treatment vaccine was approved. The vaccine, Provenge®, stimulates an immune response to a prostate cancer antigen. It is created in much the same fashion as Ralph Steinman's vaccine. The patient's own APCs are isolated and allowed to culture for awhile with the cancer antigen which is linked to a protein that can enhance antigen presentation, GM-CSF. The cells present the antigen and are injected back to the patient to activate T cells which should go off and kill the cancer.
When I read this I immediately started wondering if one of the side-effects of this treatment might be an increase in the risk of autoimmune diseases. The tumor cells are still your cells so modifying them to be antigenic and injecting them back into the body might override some of the controls that prevent the immune system from recognizing self. Is this really an issue or am I not thinking of something obvious?
ReplyDeleteForgive me. The article has been added to the post.
ReplyDeleteWell, the one thing I would like to add is that sadly, we don't know which/if/any of these vaccines actually worked. They all seem to do the same thing too. If I were a scientist trying 3 totally experiment cancer vaccines on myself, I would go with a range.
ReplyDeleteThese "vaccines" are too simplistic I think. There are many, many ways in which cancer invades the immune system.
SBrookshire495K
Cancer cells have immune-evasive abilities because they can either escape or even inhibit a body’s immune responses. This is one reason APCs are taken from the patient and exposed to antigen in vitro- to avoid the suppressive effects of the prostate tumor itself. In the treatment mentioned, Provenge, a patient’s APCs are exposed to a recombinant antigen known to be associated with the majority of prostate cancers (PAP). According to an article in the Wall Street Journal only days ago, Medicare announced that they would be covering the pricey Provenge treatment in patients. According to the Journal, this treatment typically costs $93,000 for a standard course of 3 infusions!
ReplyDeleteRegarding the previous comment on autoimmune issues, the antigen (PAP) used in the Provenge treatment is an enzyme normally produced by the prostate but in higher levels in prostate cancer and other diseases so it seems in the realm of possibility that there may be autoimmune issues. However, other articles citing recent studies, such as DC vaccinations for glioblastoma patients, relate the relatively mild side effects and safety of this approach. Also, and not surprisingly, the tumor microenvironments play a role in the efficacy of the vaccines.
http://online.wsj.com/article/SB10001424052970204443404577052061193685568.html
Gene Expression Profile Correlates with T-Cell Infiltration and Relative Survival in Glioblastoma Patients Vaccinated with Dendritic Cell Immunotherapy, Clin Cancer Res March 15, 2011 17:1603-1615; Published OnlineFirst December 6, 2010
As summarized in : http://www.sciencedaily.com/releases/2011/03/110317093111.htm
I think it would be great to eventually be able to use the human body's own immune system to treat and possibly even cure cancer in the future. However, there are a lot of issues that would be have to worked out, such as autoimmunity and overcoming the immune-evasive abilities of the cancer cells as well as properly triggering the immune system to destroy cancer cells or actual tumor tissues. Sadly, it seems that we haven't made much progress in this area of cancer research and I am hopeful that in the future we will have a greater understanding of the role our immune system can play in treating cancer.
ReplyDeleteI found this blog fascinating.
ReplyDeleteOne thing discussed that I wasn’t familiar with was immune checkpoint inhibitors. I found an online article that gave a brief description of two inhibitors that could be an adequate therapy for prostate cancer, so I could have an understanding of the mechanism of action.
The first inhibitor described focuses on making an antibody that targets CTLA-4; CTLA-4 is a surface protein that is expressed on CD4 and CD8 t-cells and serves as a regulatory component of the immune system. The relevance it has on inhibitory activities of the T-cells is that when the CTLA-4 is bound to the B7-1/B7-2 ligand it renders the T-cell inactive. With the introduction of the CTLA-4 antibody it interacts with the surface protein and can no longer bind to B7-1/B7-2. With the elimination of this interaction it allows for T- cells to not be restrained and can become activated and effective against the tumor cells. Though it sounds promising, in clinical trails it has showed a great number of patients developing immune related adverse effects and inflammation; we could suspect by eliminating a regulatory component it could lead to an over active immune system that leads to increase inflammation and immune-related diseases.
A second inhibitor described the activities of the co-receptor PD-1/CD279 which is responsible for programmed cell death. It was stated in the article that over 80% of the CD8 T-cells that enter the prostate gland expressed this co-receptor PD-1. The problem arises that when there is a tumor present it will express the ligand, B7-H1, which will bind to PD-1 allowing the induction of programmed cell death. Considering the amount of T-cells expressing the co-receptor the tumor has the ability to greatly eliminate the immune defense against it; blocking the interaction between PD-1 and B7-H1 causes the tumor to regress, which this observation indicated a target that might be beneficial in the fight against cancer. By creating an antibody to PD-1 will eliminate the interactions and could have therapeutic benefits.
Immunotherapies are very exciting but it is evident they can be tricky because of how important the immune system is in our daily lives. To try to have an effect at a localize area can be hard to achieve and if not achieved lead to adverse events that will diminish the effect of the immunotherapy in the first place.
Reference:
http://www.medscape.org/viewarticle/725985_6