Abstract
PRIME IL-15 (RPTR-147) is a novel non-genetically modified, autologous, multi-clonal T cell product loaded with an IL-15Fc nanogel. The product is derived from peripheral T cells that are ...primed and expanded against five tumor associated antigens (TAAs) known to be overexpressed in multiple different tumor types: PRAME, NY-ESO, SSX-2, WT-1 and Survivin.
17 patients with advanced or metastatic solid-tumor cancers were dosed in a Phase I dose escalation study. Where samples were available, we characterized the reactivity and specificity of the cellular product, and tracked its persistence and localization post administration in patients. We report cellular composition of the product, along with phenotype and TAA-specificity of the T cells. Antigen specificity of patient-derived product samples was determined by Repertoire Immune Medicines' proprietary DNA-barcoded pMHC tetramer platform (CIPHERTM), as well as by functional immunological methods including IFNg ELISpot and flow cytometry assessment of activation induced markers (AIM).
The CIPHER platform was used to identify TAA-specific CD8 T cell clonotypes, allowing decoding of T cell receptor (TCR) sequences and their cognate epitope/MHC. Distinct peptides binding from all five TAAs were observed across patients, and were presented across multiple HLA alleles. The phenotype of antigen-specific T cells identified via CIPHER was also assessed via single cell gene expression. Consistent with our previous studies on healthy donors, reactivity via IFNg ELISpot and AIM was also observed to all targeted TAAs.
TCR CDR3 sequences were used as molecular signatures of antigen-specific cells to track the product post administration. Bulk sequencing of TCRVβ was performed on tumors pre- and post-treatment. Several product-derived, TAA-specific CD8+ T cell clonotypes were observed in the post-, but not pre-treatment biopsies. We identified additional CD4+ and CD8+ clones that were enriched in the post-treatment biopsies, and some of these clonotypes were also enriched in the product. To de-orphan these tumor infiltrating lymphocytes (TIL) of interest, we cloned selected TIL TCRs to assess their reactivity using Repertoire Immune Medicines' proprietary MCR epitope screening platform.
In summary, characterization of antigen-specific T cells in the PRIME IL-15 product was performed by a variety of functional and molecular immune-based methods. Antigen specific T cell reactivities and clonotypes were identified in the peripheral repertoire. We confirmed that T cells were successfully expanded against TAAs and that these T cells do infiltrate the tumors as evidenced by bulk TCR sequencing of post-treatment tumor biopsies.
Citation Format: John David Pajerowski, William Gordon, Phil Bardwell, Christine McInnis, Ji Young Hwang, Tabasum Huseni, Parul Agnihotri, Josh Francis, Christina Tarr, Florian Renoux, Sebastian Heer, Nastassja Cerreghetti-Terraneo, Marisa Loi, Erika Hamilton, Sarah Nikiforow, George Blumenschein, Mihaela Christea, Keren Osman, Anthony Shields, Harriet Kluger, Franz-Josef Obermair, Daniel Pregibon, Jan Kisielow, Anthony Coyle, Mojca Skoberne. Tracking and decoding the antigen specificity of peripherally derived T cells that infiltrate into solid tumors in patients treated with an autologous T cell therapy, PRIME IL-15 (RPTR-147) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB027.
