Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma

Abstract

August 2018 CANCER DISCOVERY | OF2 abstRactWe evaluated the safety and activity of autologous T cells expressing NY- , an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1 c259 T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1 c259 T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1 c259 T cells exhibited an effector memory phenotype following ex vivo expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8+ NY-ESO-1 c259 T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1 c259 T cells produced a continuing supply of effector cells to mediate sustained, clinically meaningful antitumor effects. SIGNIFICANCE:Metastatic synovial sarcoma is incurable with standard therapy. We employed engineered T cells targeting NY-ESO-1, and the data suggest that robust, self-regenerating pools of CD8T cells produce a continuing supply of effector cells over several months that mediate clinically meaningful antitumor effects despite prolonged exposure to antigen. Cancer Discov;8(8);

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

“…It is important to note, however, that development of off‐tumor/off‐target toxicities is by no means a universal property of all affinity‐enhanced TCRs. Indeed, an affinity‐enhanced anti‐NY‐ESO‐1 TCR has demonstrated exceptional anti‐tumor efficacy in multiple clinical trials without evidence of off‐target toxicities …”

“…Among the CGAs, NY‐ESO‐1 and MAGE‐A3 have been the two most commonly tested in ACT TCR clinical trials to date. NY‐ESO‐1 has been targeted using an unmodified endogenous TCR from a HLA‐DPB1*04:01 (DPB1)‐restricted CD4 + T cell clone raised by IVS and gene engineering with an affinity‐enhanced HLA‐A2*01:01 (A2)‐restricted TCR . Despite mediating cancer regression, including durable CRs, no evidence of off‐tumor toxicity was observed in these trials.…”

“…This can be accomplished by the ex vivo introduction of a TCR conferring anti‐tumor specificity into non‐specific T cells through genetic engineering followed by ACT . Powerful proof of principle of this approach is evident in HLA‐A*02:01 + patients with metastatic synovial cell sarcoma receiving adoptive transfer of NY‐ESO‐1 TCR engineered T cells . Synovial cell sarcoma is genomically simple, typically not associated with a T cell infiltrate, and largely unresponsive to immune checkpoint inhibitors .…”

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…In sarcomas, conserved targets for adoptive cellular therapies are limited, but have been best explored for NY‐ESO‐1 autologous engineered TCRs in synovial sarcomas and myxoid round cell liposarcomas, as well as CAR‐T directed at HER2 and various gangliosides including GD2 . Autologous TILs are currently being explored in osteosarcomas (NCT03610490).…”

“…Importantly, patients with metastatic melanoma with prior ipilimumab exposure demonstrated inferior objective response rates and durability of response to autologous TIL therapy. 74 This is critical given that In sarcomas, conserved targets for adoptive cellular therapies are limited, but have been best explored for NY-ESO-1 autologous engineered TCRs in synovial sarcomas 75 and myxoid round cell liposarcomas, 76 as well as CAR-T directed at HER2 77 and various gangliosides including GD2. 78 Autologous TILs are currently being explored in osteosarcomas (NCT03610490).…”