STRATEGIES TO ENHANCE ADOPTIVE TRANSFER OF T CELL CLONES

University Of Washington, Seattle WA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have made progress on our studies investigating the use of IL-15 to enhance the in vivo persistence of adoptively transferred central memory (TCM) derived effector T cells (TE). Our prior work in NHP showed that CD8+ TE derived from CD62L+ TCM but not from CD62L- TEM were capable of surviving long-term in vivo, migrating to memory niches, and reverting to the memory (TM) pool. A distinguishing feature of TCM-derived TE was the ability to survive in low-dose IL-15 in the absence of TCR stimulation, suggesting that supplementing IL-15 in vivo might further improve persistence of transferred cells. We established an intermittent regimen of IL-15 that was safe, increased the proliferation of endogenous CD8+ TM, and yielded peak serum levels of IL-15 that exceed the level needed to promote the survival of TCM-derived TE in vitro. We treated 2 groups of animals with gene marked T cells. Group 1 consisted of 6 animals that received CD19-marked TCM-derived CMV-specific TE clones either alone (3 animals) or with IL-15 (3 animals). Group 2 consisted of 3 animals that received sequential infusions of polyclonal TCM TE cells without or with IL-15. The cells were gene-marked with either CD19 or CD20 to enable us to distinguish T cells infused without or with IL-15, respectively. We found that IL-15 enhanced transferred T cell persistence in 2 of 3 animals in each group. The persisting T cells acquired a memory phenotype in vivo and migrated to lymph nodes and bone marrow in all of the animals. This data suggests that IL-15 supports the survival of the adoptively transferred T cells, and may be useful in clinical immunotherapy for cancer.