Work

511. Enhanced-Affinity NY-ESO-1-Specific T Cells Exhibit Extended Functionality without Exhaustion in a Pattern of Effector and Memory Programming in Multiple Cancer Indications

Year: 2015

Type: article

Abstract: It is now well established that human tumors express unique antigens, however immunosuppressive mechanisms prevent natural immune responses. We hypothesized that infusion of T cells that have been genetically modified to express affinity-optimized tumor antigen-specific TCRs may overcome these barriers. We initiated several ongoing clinical studies to evaluate T cells engineered with an affinity-enhanced TCR specific for the NY-ESO-1 and LAGE-1 cancer testis antigens (NY-ESOc259-T), in synovial sarcoma (SS) and multiple myeloma (MM) patients with antigen-positive tumors. Here we report the initial findings from these correlative studies. Post infusion PBMCs were analyzed by flow cytometry evaluating memory and exhaustion markers (e.g. CD45RA, CCR7, PD-1) and polyfunctionality/cytotoxicity markers (e.g. IFN-γ and Granzyme B). NY-ESOc259-T cells were detected by pentamer staining and their phenotype was correlated with the clinical response. Once infused, NY-ESOc259-T rapidly expanded, peaking around day 21 and subsequently decreasing in frequency but remaining detectable up to one year after infusion. In MM, NY-ESOc259-T cells transitioned from a central memory phenotype to an effector phenotype, up-regulating markers of polyfunctionality and cytotoxicity. These markers decreased at later time points as the cells acquired an effector memory phenotype. In SS, NY-ESOc259-T also up-regulated these antitumor markers, but transitioned toward a phenotype closely related to T stem cell memory (see figure). In all clinical settings, no T regulatory NY-ESOc259-T cells were observed. Exhaustion markers analysis revealed no simultaneous expression of PD-1, LAG-3 and TIM-3 even at later time points, indicating that NY-ESOc259-T cells successfully clear the tumor without becoming exhausted. This correlated with up-regulation of anti-tumor molecules upon stimulation. These data show for the first time that affinity-enhanced, TCR transduced T cells exhibit robust expansion, durable persistence without exhaustion, and follow a natural immune expansion and contraction pattern consistent with an antigen-driven mechanism of action. Moreover the ability of the cells to respond to antigen even up to one year after tumor clearance indicates the onset of a functional memory that mimics a physiologic response to a pathogen.

Source: Molecular Therapy

DOI: 10.1016/s1525-0016(16)34120-x