Abstract 4839: Adoptive cell transfer of transgenic T cells elicited a two-wave antitumor cellular immune response consisted of engineered and endogenous T lymphocytes with different sets of functions
Authors: Ma Chao , Cheung Ann , Comin-Anduix Begonya , Chodon Thinle , Koya Richard , Wu Zhongqi , Witte Owen , Baltimore David , Chmielowski Bartosz , Economou James , Ribas Antoni , Heath James 
Published: August 2012

Abstract
Background: Adoptive cell transfer (ACT) of transgenic T lymphocytes expressing tumor antigen specific T cell receptor (TCR) can mediate an objective response in 30%-50% of the metastatic melanoma patients and result in long term tumor regression in certain subjects. However, little is known about the fate of engineered T cells once transferred and the dynamics of host immunity, important for understanding the biological mechanism of the therapy and differing long term efficacy between patients. Methods: We designed a comprehensive study that monitored the transgenic and endogenous immune response in 8 metastatic melanoma patients over 8-10 time points in an ACT therapy of transgenic F5 MART-1 TCR T cells, using newly developed, highly multiplexed clinical immune diagnostics methods (Ma, C. et al. Nature Medicine 17, 738-743 (2011)): (1) The abundance of 35 melanoma antigen specific T cell subsets was enumerated by peptide/MHC tetramer microarrays. (2) The functional performance of 6 phenotypically defined T cell subsets was evaluated via the quantitation of 19 functional proteins secreted from single cells, utilizing a clinical single cell barcode microchip coupled with florescent activated cell sorting. (3) A panel of 37 blood proteins incorporating melanoma associated markers, cytokines and chemokines were measured by an ELISA-like assay. Results: The change of blood marker abundance reflected the general course of the therapy, from pre-conditioning, immune system recovery, immune response, to tumor remission. Furthermore, we found that the TCR engineered T cells sustained a 2-3 week duration anti-tumor response in all patients and secreted large quantities of granzyme B, MIP-1α and MIP-1α. However, this first wave infused immune response vanished rapidly in terms of the number of polyfunctional cells and the amount of cytokines secreted. After day 30 a second wave anti-tumor immunity emerged, incorporating a rebound of the MART-1 TCR engineered population and a new endogenous multi-clonal melanoma specific T cell response. Both groups of cells secreted IFN-γ and TNF-α; however, later they shifted to inhibitory and non-specific functions, such as TGF-β, IL-10 and IL-13. The patient with the most endogenous melanoma specific T cell populations emerged and the strongest functions in the second wave response showed the most effective long term tumor control; weaker second wave response was associated with weaker therapeutic efficacy. Conclusions: The melanoma-specific T cells within the ACT went through a process of in vivo functional changes that correlated with clinical antitumor activity. The appearance and the persistence of the second wave immune response featured by engineered and newly appeared endogenous anti-tumor cellular immunity provided indications of long term therapeutic efficacy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4839. doi:1538-7445.AM2012-4839