IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy

Karan Kohli, Lu Yao, Theodore Scott Nowicki, Shihong Zhang, Ralph Graeme Black, Brett A. Schroeder, Erik A. Farrar, Jianhong Cao, Heather Sloan, Dawn Stief, Lee D. Cranmer, Michael J. Wagner, Douglas S. Hawkins, Venu G. Pillarisetty, Antoni Ribas, Jean Campbell, Robert H. Pierce, Edward Y. Kim, Robin L. Jones, Stanley R. RiddellCassian Yee, Seth M. Pollack*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-Testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression. Method We performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15. Results Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-Treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers. Conclusions ETC targeting NY-ESO-1 with single-Agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.

Original languageEnglish (US)
Article numbere002232
JournalJournal for immunotherapy of cancer
Volume9
Issue number5
DOIs
StatePublished - May 7 2021

Keywords

  • adoptive
  • antigens
  • cell engineering
  • cellular
  • cytokines
  • immunity
  • immunotherapy
  • neoplasm

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Fingerprint

Dive into the research topics of 'IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy'. Together they form a unique fingerprint.

Cite this