Host-conditioning strategies for adoptive T cell immunotherapy of cancer
Open Access
- Author:
- Cozza, Eugene Michael
- Graduate Program:
- Cell and Molecular Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- April 06, 2015
- Committee Members:
- Todd Schell, Dissertation Advisor/Co-Advisor
Todd Schell, Committee Chair/Co-Chair
Aron Eliot Lukacher, Committee Member
Neil David Christensen, Committee Member
Jianxun Song, Committee Member
Edward Joseph Gunther, Special Member - Keywords:
- CD8+ T cell
Whole-body irradiation
CD40 agonist
choroid plexus tumor
SV40 T antigen transgenic mice - Abstract:
- Cancer immunotherapy is poised at the cutting edge of cancer research due to higher response rates and the potential for long-lasting cancer regressions. T cells are critical immune effectors that can identify and eliminate cancerous host cells. Adoptive T cell transfer (ACT) is an emerging immunotherapy in which the patient’s own T cells are isolated and optimized to target the tumor, expanded in culture, and re-infused into the cancer patient. To improve the survival and function of the re-infused T cells, patients are pre-conditioned with chemotherapy or whole-body irradiation (WBI) to deplete host immune cells prior to ACT. Use of host-conditioning regimens significantly improves response and cure rates, but the reasons for failure are unknown. Investigation of the underlying mechanisms of ACT therapy and host-conditioning regimens is necessary to improve the success and applicability of this promising immunotherapeutic approach. Here, we focus on the influence of WBI and agonist anti-CD40 antibody (which stimulates antigen-presenting cells to activate T cells) host-conditioning regimens on ACT therapy of established murine brain tumors. SV11 mice develop autochthonous tumors of the choroid plexus of the brain due to transgenic expression of the SV40 large Tumor antigen (T Ag) oncoprotein. Using T Ag-specific transgenic T cells, we investigate the underlying mechanisms of WBI and anti-CD40 that promote the in vivo accumulation and persistence of donor T cells during ACT-mediated tumor regression and protection from tumor recurrence. First, we show that WBI conditioning induces a prolonged window of opportunity during which ACT can be administered to mediate regression of established tumors. However, ACT early after WBI is required to achieve maximum survival benefit. Thus, the mechanisms promoting tumor regression and long-term survival are distinct. We also demonstrate a time-dependent reduction in early donor T cell accumulation when ACT is delayed after WBI that correlates with recovery from host lymphodepletion. Next, we dissect the local and systemic influences of WBI and show that irradiation conditioning can promote successful ACT-mediated tumor regression independently of local irradiation to the brain or tumor. Therefore, the systemic effects of WBI are critical determinants of ACT therapeutic success. Irradiation localized to the body was sufficient to promote long-term survival and donor T cell persistence in the brain. Local irradiation to the tumor site enhanced donor T cell accumulation in the tumor-draining lymph nodes and resulted in modest survival benefit but did not promote tumor regression. Finally, we show that anti-CD40 conditioning can promote ACT-mediated tumor regression in the absence of irradiation, but that only WBI conditioning promotes durable protection from tumor recurrence, demonstrating the differential efficacy of two clinically relevant immunotherapies. Protection from tumor recurrence was associated with the establishment of persistent donor T cells in the brain that were resistant to antibody-mediated depletion. Collectively, these studies illustrate the impact of host-conditioning regimens on ACT therapy and define the requirements relevant to success.