Gnjatic, Sacha

11006 Background: CMB305 is an active immunotherapy regimen designed to generate and expand anti-NY-ESO-1 T cells. It consists of LV305, a dendritic cell targeting lentiviral vector encoding NY-ESO-1, and a boost with G305, an NY-ESO-1 recombinant protein plus GLA-SE, a TLR-4 agonist. An LV305 phase 1 study demonstrated a 1-yr survival of 81% and induction of anti-NY-ESO-1 T cells in sarcoma patients (pts). This first-in-human study of CMB305 examined safety, immunogenicity, and efficacy in pts with NY-ESO-1 positive (+) solid tumors. Methods: Adults with previously treated NY-ESO-1+ sarcomas, NSCLC, ovarian cancer were enrolled in a 3+3 dose-escalation with an expansion phase 1 study. The CMB305 regimen included 4 intradermal injections of LV305 at 109 or 1010 vector genomes, alternating with 3 intramuscular G305 injections at 250 µg for 3 months, then bimonthly G305 injections up to 1 yr. Results: As of 31Dec2016, 25 pts with STS (15 synovial (SS), 8 myxoid/round cell liposarcoma (MRCL), 2 other) were evaluable for safety; 23 SS/MRCL pts were evaluable for immune response (IR) and efficacy. All SS and MRCL pts received prior therapy for locally advanced/metastatic disease, 67% > = 2 prior chemo regimens. No DLTs were observed; treatment related AEs were grade 1 and 2, except 1 pt with grade 3 SAE (prostatic pain). Of 11 SS/MRCL pts tested, 64% pts developed NY-ESO-1 specific T cells and 72% pts anti-NY-ESO-1 antibodies. T cell receptor sequencing indicated increased clonality, and antigen spreading after CMB305. Best response by immune related response criteria was stable disease in 8/15 (53%) SS pts and 6/8 (75%) MRCL pts. The 3 month PFS rate was 74% and 75% for SS and MRCL pts. Median survival has not been reached with 1-yr survival rate of 86% and 100% for SS and MRCL pts. Conclusions: CMB305 is safe, well tolerated, and demonstrates a survival rate that is favorable when compared with approved agents for recurrent STS. CMB305 resulted in a stronger and broader integrated IR than LV305, including antigen spreading. These data warrant further investigation of CMB305 as a monotherapy in a randomized clinical study in STS. A randomized study of CMB305 in combination with atezolizumab in SS/MRCL pts is ongoing. Clinical trial information: NCT02387125.

3090 Background: The correlation of immune response (IR) and clinical benefit in patients (pts) who receive active immunotherapy remains controversial. CMB305 is an active immunotherapy designed to generate and expand anti-NY-ESO-1 T cells, consisting of LV305 (a DC targeting lentiviral vector encoding NY-ESO-1) and a boost (NY-ESO-1 recombinant protein plus GLA-SE, a TLR-4 agonist). Phase 1 studies of LV305 and CMB305 evaluated the IR and survival of pts with NY-ESO-1 positive tumors. Methods: 62 pts with recurrent NY-ESO-1 expressing (by IHC) solid tumors were enrolled in 2 Phase 1 trials (31 pts each: 43 sarcomas, 12 ovarian, 4 melanomas, and 3 NSCLC). Peripheral blood was assessed pre and post therapy for anti-NY-ESO-1 T cell responses (IFNγ ELISPOT) and antibodies (Ab) (ELISA) (n = 62), TCR-β CDR3 repertoire and conserved (public) TCR (n = 28), and antigen spreading (ELISA, ELISPOT) (n = 23). Relationship between progression-free survival (PFS), overall survival (OS) and up to 15 biomarkers were analyzed by the Kaplan-Meier method. Results: Preexisting anti-NY-ESO-1 T cells and Ab were identified in 34% and 40% of pts. LV305 and CMB305 induced (de novo or increased) anti-NY-ESO-1 T-cells in 51% and 65% pts, and anti-NY-ESO-1 Ab responses in 13% and 68% pts, respectively. LV305 and CMB305 induced antigen spreading in 17% and 36% pts. TCR clonality increased after CMB305 as compared to LV305. The TCRβ-CDR3 amino acid sequences of three NY-ESO-1 specific TCR clones in a patient with a > 2-year response were fully conserved in 20/28 patients. Biomarkers showing the strongest association with OS and PFS were pre-existing anti-NY-ESO-1 T-cell response and Ab, integrated IR (T cells and antibodies), and NY-ESO-1 expression level. Presence of public TCRs was associated with longer survival, particularly in pts with high ( > 50%) NY-ESO-1 expression. Conclusions: While LV305 and CMB305 are both immunogenic, CMB305 resulted in a stronger and broader integrated IR, including antigen spreading. The three identified survival variables, preexisting and treatment-induced NY-ESO-1 IR and the presence of public TCRs, warrant validation in randomized studies of CMB305.