Title : Targeting high-grade anaplastic astrocytoma and glioblastoma with a first-in class anti-tgf?2 RNA therapeutic administered by convection-enhanced delivery
Transforming growth factor beta 2 (TGFβ2) has been implicated as a key contributor to the immunosuppressive landscape of the tumor microenvironment (TME) in high-grade gliomas (HGG) that is characterized by a T-cell exhaustion signature and pronounced T-cell hyporesponsiveness. OT-101 is a first-in-class RNA therapeutic designed to abrogate the immunosuppressive actions of TGFβ2. This plenary presentation will detail the safety profile and clinical single agent activity of OT-101 in a Phase 2 clinical trial. OT-101 was administered via high-flow microperfusion with an intratumoral catheter using a convection enhanced delivery (CED) system. 77 patients (Efficacy Population) received 4-11 cycles of OT-101 via continuous infusion over 7 days (d). 26 patients (33.8%) had marked reductions of their tumor volume after receiving OT-101: 19 achieved durable objective responses (CR: 3, PR: 16). The average (Mean ± SE) percent reduction for the 19 responders was 91.9 ± 2.6 (Median = 95.7, Range: 57.5-100). Six patients achieved 100% reduction in tumor volume over the course of the treatment. The median time for 90% reduction of the baseline tumor volume was 11.7 months (Range: 4.9-57.7 months). The mean log reduction of the tumor volume was 2.2 ± 0.4 (Median = 1.4: Range: 0.4-4.5) logs. 7 had stable disease (SD) lasting >6 months. The median progression-free survival (PFS) (1109d [95% CI: 992 - >1423] vs. 37d [95% CI: 35 – 59] (Log-rank Chi Square = 69.9, P-value <0.0001) and overall survival (OS) (1280d [95% CI: 1116 - >1743] vs. 240d [95% CI: 169 – 361] (Log-rank Chi Square = 47.0, P-value <0.0001) of these 26 patients (GBM:10, AA:16) with favorable responses was significantly better than the PFS or OS of the remaining 51 patients. The final generalized linear model (GLM) for best overall response (BOR) (Binomial distribution, chi-square value = 39.7, df = 12, P<.0001) and OS model (loglogistic best fit highly significant with a chi-square value = 56.0, df = 12, P<0.0001) identified 3 significant predictors: Baseline KPS score (P[BOR] = 0.011; P[OS] = 0.0004), cancer subtype (P[BOR] = 0.017, P[OS] = 0.036) and steroid use (P[BOR] = 0.0067, P[OS] = 0.0022). Being an AA rather than a GBM patient, having a higher baseline KPS score, receiving either no steroids or short-term steroids during management of AE were associated with favorable responses and improved OS for R/R GBM/AA patients treated with OT-101 as a single agent. These results demonstrate that OT-101, when administered via CED as second line therapy exhibits clinically meaningful single-agent activity and induces durable CR/PR/SD in R/R HGG patients.
Audience Take Away:
- The audience will learn about RNA therapeutics as a new class of precision medicines
- The audience will learn about the treatment options for high-grade gliomas
- The insights and lessons learned in our study will help the participants in their clinical research and design of safe and effective treatment strategies for therapy of brain tumors.
- The audience will learn of the immunosuppressive functions of TGF and the emerging role of TGF as a molecular target for immune-oncology drugs for treatment of solid tumors as well as hematologic malignancies.