title: Tracking the Fate and Origin of Clinically Relevant Adoptively Transferred CD8+T CellsIn Vivo.
abstract: Adoptively transferred tumor-specific cells can mediate tumor regression in cancers refractory to conventional therapy. Autologous polyclonal tumor-specific cytotoxic T cells (CTL) generated from peripheral blood and infused into patients with metastatic melanoma show enhanced persistence, compared to equivalent numbers of more extensively expanded monoclonal CTL, and are associated with complete remissions (CR) in select patients. We applied high-throughput T cell receptor Vβ sequencing (HTTCS) to identify individual clonotypes within CTL products, track themin vivopost-infusion and then deduce the pre-adoptive transfer (endogenous) frequencies of cells ultimately responsible for tumor regression. The summedin vivopost-transfer frequencies of the top 25 HTTCS-defined clonotypes originally detected in the infused CTL population were comparable to enumeration by binding of antigen peptide-HLA multimers, revealing quantitative HTTCS is a reliable, multimer-independent alternative. Surprisingly, the polyclonal CTL products were composed predominantly of clonotypes that were of very low frequency (VLF) in the endogenous samples, often below the limit of HTTCS detection (0.001%). In patients who achieved durable CRs, the composition of transferred CTLs was dominated (57-90%) by cells derived from a single VLF clonotype. Thus, HTTCS now reveals that tumor-specific CTL enabling long-term tumor control originate from endogenous VLF populations that exhibit proliferative/survival advantages. Along with results indicating that naïve cell populations are most likely to contain cells that exist at VLF within the repertoire, our results provide a strong rationale for favoring T cells arising from VLF populations and with early-differentiation phenotypes when selecting subset populations for adoptive transfer.
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109.
authors.forename: Aude G
authors.initials: AG
authors.lastname: Chapuis
authors.affiliation: Adaptive Biotechnologies, 1551 Eastlake Ave N, Suite 200, Seattle, WA 98103.
authors.forename: Cindy
authors.initials: C
authors.lastname: Desmarais
authors.affiliation: Adaptive Biotechnologies, 1551 Eastlake Ave N, Suite 200, Seattle, WA 98103.
authors.forename: Ryan
authors.initials: R
authors.lastname: Emerson
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Schmitt
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109.
authors.forename: Kendall
authors.initials: K
authors.lastname: Shibuya
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109.
authors.forename: Ivy
authors.initials: I
authors.lastname: Lai
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109.
authors.forename: Felecia
authors.initials: F
authors.lastname: Wagener
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chou
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109.
authors.forename: Ilana M
authors.initials: IM
authors.lastname: Roberts
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109.
authors.forename: David G
authors.initials: DG
authors.lastname: Coffey
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109.
authors.forename: Edus
authors.initials: E
authors.lastname: Warren
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109; Adaptive Biotechnologies, 1551 Eastlake Ave N, Suite 200, Seattle, WA 98103.
authors.forename: Harlan
authors.initials: H
authors.lastname: Robbins
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109; Department of Immunology, University of Washington, South Lake Union, Bldg E, 750 Republican Street, Seattle WA 98109.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
authors.affiliation: Program in Immunology, Fred Hutchinson Cancer Research Center (FHCRC), 1100 Fairview Ave N, Seattle, WA 98109.
authors.forename: Cassian
authors.initials: C
authors.lastname: Yee