Ny-Eso-1 Specific Public Tcr Clonotypes in Patients with Ny-Eso-1 Expressing Solid Cancers and Healthy Blood Donors
Hailing Lu1, Seth Pollack2, Marissa Vignali3, Julie Rytlewski3, Erik Yusko3, Jan ter Meulen1
1Immune Design, Seattle WA & South San Francisco, CA; 2Fred Hutchinson Cancer Research Center, Seattle WA; 3Adaptive Biosystems, Seattle WA
T cell clonotypes with public T-cell receptors (TCRs) have been shown to be involved in the immune response to chronic viral infections such as EBV, CMV, and HIV. Using PBMC from a phase 1 study with the investigational agent LV305 (a dendritic cell targeting lentiviral vector expressing NY-ESO-1) in patients with NY-ESO-1 expressing soft tissue sarcoma (STS), we identified three NY-ESO-1 specific TCRs in a patient with a deep durable response, whose TCRβ-CDR3 regions were fully conserved on the amino acid level in seven other patients. One of the shared CDR3 sequences was detected in 2/8 patients before LV305 treatment, and in 6/8 patients after. The public TCRs were also detected in 9/13 NY-ESO-1 positive STS patients from a trial investigating a prime-boost regimen of LV305 with adjuvanted recombinant NY-ESO-1, as well as in a trial in Merkel cell carcinoma and other STS patients treated with intratumoral injection of the synthetic TLR4 agonist Glucopyranosyl lipid adjuvant (G100). In a Merkel Cell carcinoma patient with a NY-ESO-1 expressing tumor who had a complete response following G100 treatment, the public TCRs were detectable in a post-therapy, but not pre-therapy biopsy. Querying TCR databases from multiple published clinical trials involving different solid tumors showed that the conserved TCRβ-CDR3 sequences were detectable in blood of patients with melanoma (6/13), renal cancer (1/3), and glioblastoma (6/13), and with a lower incidence in tumor biopsies. Surprisingly, in 78.9% of blood donors (463/587) the public TCR sequences were also detected, pointing to pre-existing NY-ESO-1 immune responses in healthy individuals. In summary, we have identified T cells with public TCRβ-CDR3 that are shared by patients with different types of solid cancers known to express NY-ESO-1 and healthy blood donors. These T cells can be induced or expanded in cancer patients with either NY-ESO-1 specific immunotherapy or intratumoral immune modulation. Their association with clinical responses is currently under investigation.
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