Lu, Hailing

PURPOSE CMB305 is a heterologous prime-boost vaccination regimen created to prime NY-ESO-1–specific CD8 T-cell populations and then activate the immune response with a potent TLR-4 agonist. This open-label randomized phase II trial was designed to investigate the efficacy and safety of adding the CMB305 regimen to atezolizumab (anti–programmed death ligand-1 therapy) in comparison with atezolizumab alone in patients with synovial sarcoma or myxoid liposarcoma. PATIENTS AND METHODS Patients with locally advanced, relapsed, or metastatic synovial sarcoma or myxoid liposarcoma (any grade) were randomly assigned to receive CMB305 with atezolizumab (experimental arm) or atezolizumab alone (control arm). The primary end points were progression-free survival (PFS) and overall survival (OS) analyzed using the Kaplan-Meier method. Safety and immune responses were assessed. RESULTS A total of 89 patients were enrolled; 55.1% had received ≥ 2 prior lines of chemotherapy. Median PFS was 2.6 months and 1.6 months in the combination and control arms, respectively (hazard ratio, 0.9; 95% CI, 0.6 to 1.3). Median OS was 18 months in both treatment arms. Patients treated with combination therapy had a significantly higher rate of treatment-induced NY-ESO-1–specific T cells ( P = .01) and NY-ESO-1–specific antibody responses ( P < .0001). In a post hoc analysis of all dosed patients, OS was longer (36 months) in the subset who developed anti-NY-ESO-1 T-cell immune response (hazard ratio, 0.3; P = .02). CONCLUSION Although the combination of CMB305 and atezolizumab did not result in significant increases in PFS or OS compared with atezolizumab alone, some patients demonstrated evidence of an anti-NY-ESO-1 immune response and appeared to fare better by imaging than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti–programmed death ligand-1 therapies merits further evaluation in other clinical contexts.

Abstract Purpose: LV305 is a modified, third-generation, nonreplicating, integration-deficient lentivirus-based vector designed to selectively transduce dendritic cells in vivo. LV305 induces expression of the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) cancer testis antigen in dendritic cells, promoting immune responses against NY-ESO-1–expressing tumors. This phase I study evaluated the safety, immunogenicity, and preliminary efficacy of LV305 in patients with sarcoma or other solid tumors. Patients and Methods: Adults with previously treated, advanced, NY-ESO-1–positive solid tumors and limited tumor burden were eligible. LV305 was administered every 3 weeks by intradermal injection in four dose cohorts (Cohort 1: 108 vector genomes (vg) x 3 doses; Cohorts 1A, 2, and 3: 108 vg, 109 vg, 1010 vg x 4 doses). Results: Thirty-nine patients were enrolled: 3 patients each in Cohorts 1, 1A, and 2, and 30 patients in Cohort 3. No dose-limiting toxicities were observed. Tumor types included sarcoma (n = 24), ovarian (n = 8), melanoma (n = 6), and lung cancer (n = 1). All treatment-related adverse events were grade 1 or 2. Common treatment-related adverse events were fatigue (49%), injection site reactions (46%), and myalgia (21%). The disease control rate was 56.4% in all patients and 62.5% in sarcoma patients. One patient with synovial sarcoma achieved a partial response lasting &gt;36 months. Anti–NY-ESO-1-specific CD4+ and/or CD8+ T cells were induced in 57% of evaluable sarcoma patients. Induction of an anti–NY-ESO-1 immune response was associated with improved 1-year survival in an exploratory analysis. Conclusions: This first-in-class, first-in-human study of LV305 demonstrated a favorable safety profile, induction of antigen-specific responses, and potential clinical activity in patients with advanced cancer.

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.

Abstract Tumors evade both natural and pharmacologically induced (e.g., vaccines) immunity by a variety of mechanisms, including induction of tolerance and immunoediting. Immunoediting results in reshaping the immunogenicity of the tumor, which can be accompanied by loss of Ag expression and MHC molecules. In this study, we evaluated immunoediting in the neu-transgenic mouse model of breast cancer. A tumor cell line that retained expression of rat neu was generated from a spontaneous tumor of the neu-transgenic mouse and, when injected into the non-transgenic parental FVB/N mouse, resulted in the development of a strong immune response, initial rejection, and ultimately the emergence of neu Ag-loss variants. Morphologic and microarray data revealed that the immunoedited tumor cells underwent epithelial to mesenchymal transition accompanied by an up-regulation of invasion factors and increased invasiveness characteristic of mesenchymal tumor cells. These results suggest that immunoediting of tumor results in cellular reprogramming may be accompanied by alterations in tumor characteristics including increased invasive potential. Understanding the mechanisms by which tumors are immunoedited will likely lead to a better understanding of how tumors evade immune detection.

Abstract Studies in cancer patients have suggested that breast tumors recruit regulatory T cells (Tregs) into the tumor microenvironment. The extent to which local Tregs suppress antitumor immunity in breast cancer is unknown. We questioned whether inhibiting systemic Tregs with an IL-2 immunotoxin in a model of neu-mediated breast cancer, the neu-transgenic mouse, could impact disease progression and survival. As in human breast cancer, cancers that develop in these mice attract Tregs into the tumor microenvironment to levels of ∼10–25% of the total CD4+ T cells. To examine the role of Tregs in blocking immune-mediated rejection of tumor, we depleted CD4+CD25+ T cells with an IL-2 immunotoxin. The treatment depleted Tregs without concomitant lymphopenia and markedly inhibited tumor growth. Depletion of Tregs resulted in a persistent antitumor response that was maintained over a month after the last treatment. The clinical response was immune-mediated because adoptive transfer of Tregs led to a complete abrogation of the therapeutic effects of immunotoxin treatment. Further, Treg down-modulation was accompanied by increased Ag-specific immunity against the neu protein, a self Ag. These results suggest that Tregs play a major role in preventing an effective endogenous immune response against breast cancer and that depletion of Tregs, without any additional immunotherapy, may mediate a significant antitumor response.