Blocking the function of CTLA-4, a receptor on T cells that negatively regulates T cell responses, has led to tumor eradication in preclinical mouse models and patients. This treatment is more effective when combined with therapies that increase antigen presentation such as GM-CSF-secreting, irradiated tumor vaccines. Here we explore this synergy in the treatment of mouse TRAMP C2 prostate tumors, using anti-CTLA-4 monoclonal antibodies together with an irradiated tumor vaccine consisting of TRAMP C2 secreting GM-CSF (TRAMP-GM). In order to track the T cell response in mice receiving this combination treatment, we have developed a TCR transgenic mouse whose CD8+ T cells recognize the previously identified TRAMP C2 antigen, SPAS-1. Anti-CTLA-4 and TRAMP-GM combination therapy stimulates T cells from these mice (SPASTCs) to proliferate and accumulate in TRAMP-C2 tumors compared to untreated controls. However, the combination therapy does not increase the percentage of SPASTCs producing the effector cytokine IFNγ. Investigation of the individual components of this therapy reveals that TRAMP-GM drives SPASTCs to proliferate in the lymph node, while anti-CTLA-4 monotherapy mediates the accumulation of SPASTCs within the tumor. We hypothesize that in the TRAMP-C2 system, CTLA-4 blockade mediates increased T cell trafficking to tumors and while the therapy does not increase effector function on a per cell basis, the overall increase in effector T cells within the tumor leads to tumor eradication.
We are also investigating clinically relevant therapies that release antigens through the destruction of tumor tissue. These therapies augment antigen presentation and therefore have the potential to synergize with CTLA-4 blockade. For example, we determined the effects of cryoablating an established TRAMP-C2 tumor in combination with anti-CTLA-4 on the growth of a second tumor challenge at a distant site. While growth of the second tumor is unaffected by cryoablation alone, the combination treatment leads to slower tumor growth or rejection. Additionally, secondary tumors from combination treated mice are highly infiltrated by SPAS-1 specific CD8+ T cells. While cryoablation is currently used clinically to treat the targeted tumor nodule, our results suggest that combination therapy with CTLA-4 blockade can induce anti-tumor immunity and rejection of tumor metastases.
|Advisor:||Allison, James, Sha, William|
|School:||University of California, Berkeley|
|School Location:||United States -- California|
|Source:||DAI-B 70/04, Dissertation Abstracts International|
|Keywords:||Blockade combination therapy, Cryoablation, Prostate cancer, T cell responses|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be