Post by Allen on Sept 2, 2014 15:18:39 GMT -8
This continues the discussion of radioimmunotherapy begun in the thread on repurposing of existing immunotherapies, but takes it in another direction, so I started a new thread for it.
An oncologist who studies immunotherapy for cancer said, "the immune system makes me believe that there is no God - no Sane Entity would ever invent a system as insane as this." While he was kidding (I think), his point is well taken - using the immune system to fight cancer is more complex than anyone ever imagined. Case in point is a recent research paper:
Tumor-associated autoantibodies correlate with poor outcome in prostate cancer patients treated with androgen deprivation and external beam radiation therapy
Here's what I wrote to the lead author (I had only seen the abstract at the time):
Dr. Lisa Johnson graciously replied:
An oncologist who studies immunotherapy for cancer said, "the immune system makes me believe that there is no God - no Sane Entity would ever invent a system as insane as this." While he was kidding (I think), his point is well taken - using the immune system to fight cancer is more complex than anyone ever imagined. Case in point is a recent research paper:
Tumor-associated autoantibodies correlate with poor outcome in prostate cancer patients treated with androgen deprivation and external beam radiation therapy
Here's what I wrote to the lead author (I had only seen the abstract at the time):
I was wondering why you concluded "immunomodulation to prevent autoantibody development may improve BFFS for select, high-risk prostate cancer patients receiving both ADT and EBRT." From the abstract, at least, it seems that autoantibody formation was associated with biochemical progression, but it wasn't necessarily a causal factor. It seems more likely to me that there is a virulent prostate cancer phenotype that is more likely to stimulate antibody formation and that also has a poorer prognosis. In that case, autoantibodies may be an interesting biomarker for high risk PC variants that are not likely to respond well to immunotherapy, but suppressing their formation may not be a good idea.
I wanted to get your thoughts on this because it seems to conflict with the idea of an abscopal effect caused by ADT+RT.
I wanted to get your thoughts on this because it seems to conflict with the idea of an abscopal effect caused by ADT+RT.
Dr. Lisa Johnson graciously replied:
Thank-you for your interest and thoughts on our recent paper in Oncoimmunology. I have attached the complete text for you.
You raise an interesting point about what actually causes the presence of autoantibodies in prostate cancer patients. We found that autoantibodies are only detectable after treatment is initiated. Potentially, patients who develop autoantibodies have tumors which are more poorly differentiated. We found in previous studies that autoantibodies develop primarily in the highest risk patients that receive androgen deprivation and external beam radiation as opposed to patients with intermediate risk cancer who received brachytherapy. Given the difference in treatment modality, it is difficult to ascribe the occurrence of autoantibodies only by risk factor, but it does open up that question.
We feel that immunomodulation, that specifically enhances a cytolytic response generated by T cells, as opposed to antibody producing B cells would be beneficial in high-risk prostate cancer patients. Thus, we propose to shift the immune responses away from a humoral response. In pre-clinical models, our experiments show that enhancing T cell function using a therapeutic antibody called ipilimumab (currently approved for use in melanoma)[Yervoy] in conjunction with radiation improves overall survival and generates long-lasting immunity to specific tumor antigens. In this setting, mice are resistant to tumor re-challenge (in essence a temporal abscopal effect).
In some very preliminary data in a mouse model, I have also found that the preventing the production of autoantibodies at the time of androgen deprivation improves the ability of T cells to proliferate indicating that they are more able to recognize and kill tumor cells. It is likely that by eliminating the ability of the immune system to generate autoantibodies, we are slightly shifting the balance of the tumor microenvironment towards a stronger T cell response. From studies of high-risk patients receiving radiation therapy, we know that there is great variation in immune responses and indications of a process called immunogenic cell death and T cell proliferation. Although further study would be required, I would suggest that patients that do not exhibit signs of immunogenic cell death and/or the development of autoantibodies would be excellent candidates for immunotherapy. Identifying those patients prior to beginning treatment remains an important research question. We are very fortunate at the BC Cancer Agency to have many prostate cancer patients donate their time and blood for that exact purpose!
You raise an interesting point about what actually causes the presence of autoantibodies in prostate cancer patients. We found that autoantibodies are only detectable after treatment is initiated. Potentially, patients who develop autoantibodies have tumors which are more poorly differentiated. We found in previous studies that autoantibodies develop primarily in the highest risk patients that receive androgen deprivation and external beam radiation as opposed to patients with intermediate risk cancer who received brachytherapy. Given the difference in treatment modality, it is difficult to ascribe the occurrence of autoantibodies only by risk factor, but it does open up that question.
We feel that immunomodulation, that specifically enhances a cytolytic response generated by T cells, as opposed to antibody producing B cells would be beneficial in high-risk prostate cancer patients. Thus, we propose to shift the immune responses away from a humoral response. In pre-clinical models, our experiments show that enhancing T cell function using a therapeutic antibody called ipilimumab (currently approved for use in melanoma)[Yervoy] in conjunction with radiation improves overall survival and generates long-lasting immunity to specific tumor antigens. In this setting, mice are resistant to tumor re-challenge (in essence a temporal abscopal effect).
In some very preliminary data in a mouse model, I have also found that the preventing the production of autoantibodies at the time of androgen deprivation improves the ability of T cells to proliferate indicating that they are more able to recognize and kill tumor cells. It is likely that by eliminating the ability of the immune system to generate autoantibodies, we are slightly shifting the balance of the tumor microenvironment towards a stronger T cell response. From studies of high-risk patients receiving radiation therapy, we know that there is great variation in immune responses and indications of a process called immunogenic cell death and T cell proliferation. Although further study would be required, I would suggest that patients that do not exhibit signs of immunogenic cell death and/or the development of autoantibodies would be excellent candidates for immunotherapy. Identifying those patients prior to beginning treatment remains an important research question. We are very fortunate at the BC Cancer Agency to have many prostate cancer patients donate their time and blood for that exact purpose!