59.04 Importance of Lymphodepletion prior to Cancer Immunotherapy with Specific T Cell Subsets

Posted on January 26, 2017

M. V. Beems1,2, A. Contreras1, T. K. Luther2, A. Tatar1, P. Srinand1, S. Sen1, C. S. Cho2  1University Of Wisconsin,Department Of Surgery,Madison, WI, USA 2University Of Michigan,Department Of Surgery,Ann Arbor, MI, USA

Introduction:
Adoptive cell transfer (ACT) immunotherapy traditionally involves the infusion of tumor-specific T cells into cancer patients after a lymphodepletion regimen designed to enhance T cell engraftment. Lymphodepletion is a potential source of patient morbidity. Our laboratory and others have shown that ACT using memory T cells is superior to traditional effector T cell-based ACT. Given the innate ability of memory T cells to persist well after antigen encounter, we hypothesized that ACT with memory cells would be less dependent on pre-transfer lymphodepletion.

Methods:
C57BL/6 mice were inoculated with B16GP33 melanoma flank tumors. Half of the mice underwent pre-transfer lymphodepletion using 5Gy total body irradiation. Equal numbers of tumor-specific effector and memory T cells were adoptively transferred. Serial tumor measurements and flow cytometric analyses of tumors, tumor draining lymph nodes (TDLNs), and circulating blood were performed.

Results:
Lymphodepletion significantly reduced tumor growth in all groups. Tumor control was strongest in mice receiving memory T cell ACT with lymphodepletion, with minimal tumor growth seen in this group. Flow cytometric analyses revealed a significantly higher proportion of adoptively transferred cells in the tumors, TDLNs, and circulating blood in mice treated with pre-transfer lymphodepletion. Lymphodepletion benefited memory ACT more than effector ACT in terms of increasing adoptively transferred T cell numbers in all lymphoid compartments.

Conclusion:
Contrary to our hypothesis, lymphodepletion with total body irradiation improved the efficacy of memory ACT to a greater extent than effector ACT. ACT of tumor-specific memory T cells following pre-transfer lymphodepletion may represent a novel modality of immunotherapy for melanoma cancer patients.