A Phase 1b Study Evaluating the Safety, Tolerability, and Immunogenicity of CMB305, a Lentiviral-Based Prime-Boost Vaccine Regimen, in Patients with Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1

Abstract

Preclinical data suggest that a "prime-boost" vaccine regimen using a target-expressing lentiviral vector for priming, followed by a recombinant protein boost, may be effective against cancer; however, this strategy has not been evaluated in a clinical setting. CMB305 is a prime-boost vaccine designed to induce a broad anti-NY-ESO-1 immune response. It is composed of LV305, which is an NY-ESO-1 expressing lentiviral vector, and G305, a recombinant adjuvanted NY-ESO-1 protein. This multicenter phase 1b, first-inhuman trial evaluated CMB305 in patients with NY-ESO-1 expressing solid tumors. Safety was examined in a 3 + 3 dose-escalation design, followed by an expansion with CMB305 alone or in a combination with either oral metronomic cyclophosphamide or intratumoral injections of a toll-like receptor agonist (glucopyranosyl lipid A). Of the 79 patients who enrolled, 81.0% had sarcomas, 86.1% had metastatic disease, and 57.0% had progressive disease at study entry. The most common adverse events were fatigue (34.2%), nausea (26.6%), and injection-site pain (24.1%). In patients with soft tissue sarcomas, a disease control rate of 61.9% and an overall survival of 26.2 months (95% CI, 22.1-NA) were observed. CMB305 induced anti-NY-ESO-1 antibody and T-cell responses in 62.9% and 47.4% of patients, respectively. This is the first trial to test a prime-boost vaccine regimen in patients with advanced cancer. This approach is feasible, can be delivered safely, and with evidence of immune response as well as suggestion of clinical benefit.

Targeting cancer testis antigens in synovial sarcoma

“…58 In an initial Phase 1 trial, CMB305 was safe and elicited antibody responses against NY-ESO-1 in 62.9% of patients and T-cell responses in 47.4%; 22.8% of patients had both. 59 A randomized Phase 2 study with the programmed death-ligand 1(PD-L1) inhibitor atezolizumab with or without CMB305 showed no statistically significant differences between the groups in OS and progression free survival (PFS), and no further study is planned with this vaccine regimen. 60 CHP-NYESO-MIS416 is a vaccine which is a polysaccharide-ligated to NY-ESO-1 used to stimulate MHC I and 2 with a T cell stimulator (MIS416), with NOD2 and TLR9 added as stimulants.…”

Immune and Cell Cycle Checkpoint Inhibitors for Cancer Immunotherapy

“…A 2011 clinical trial conducted by the National Cancer Institute was the first to report promising anticancer effects of NY-ESO-1-targeted immunotherapy in patients with metastatic synovial sarcoma using adoptively transferred autologous T-cells containing a T-cell receptor against NY-ESO-1 [46], suggesting its potential to be effective in other sarcomas as well. Since then, numerous trials targeting NY-ESO-1 in various cancer types using both adoptive T-cell therapy and vaccination approaches have concluded that there is a clear clinical benefit in pursuing NY-ESO-1 as an immunotherapeutic target [47].…”

Phase II Randomized Study of CMB305 and Atezolizumab Compared With Atezolizumab Alone in Soft-Tissue Sarcomas Expressing NY-ESO-1

“…6 In a phase Ib study of 79 patients with solid tumors that express NY-ESO-1, CMB305 vaccination resulted in the induction of anti-NY-ESO-1 antibodies and CD4 and CD8 T cells in 62.9% and 47.4% of patients, respectively, and 61.9% of patients with soft-tissue sarcomas (STS) exhibited stable disease (SD). 7…”

“…6 In a phase Ib study of 79 patients with solid tumors that express NY-ESO-1, CMB305 vaccination resulted in the induction of anti-NY-ESO-1 antibodies and CD4 and CD8 T cells in 62.9% and 47.4% of patients, respectively, and 61.9% of patients with softtissue sarcomas (STS) exhibited stable disease (SD). 7 Two sarcoma subtypes, synovial sarcoma (SS) and myxoid liposarcoma (MLS), have high frequency and homogeneity of NY-ESO-1 expression, [8][9][10][11] making these tumors most suitable for CMB305 vaccination. These translocation-associated tumors have limited treatment options, affect young adults, and have an annual incidence of 800-1,000 cases in the United States.…”