Updated results from first-in-human phase 1 dose-escalation trial of TAK-102, a GPC3-targeted armored CAR T cells, in patients with advanced solid tumors.
Takako Eguchi Nakajima, Yasutoshi Kuboki, Masaru Fukahori, Yutaka Shimazu, Shunsuke Kondo, Yuki Katsuya, Masafumi Ikeda, Tomoyuki Satake, Hideaki Kagehara, Takenori Akaike, Aman P. Singh, Kondala R. Atkuri, Petar Pop-Damkov, Koji Tamada, Takafumi Koyama
Abstract
2543 Background: Glypican 3 (GPC3) is a member of the glypican family of heparan sulfate proteoglycans that are attached to the cell surface by a glycosylphosphatidylinositol anchor. High GPC3 expression rates are reported in numerous cancer types with a high unmet medical need, including hepatocellular carcinoma (HCC). TAK-102 is a GPC3-targeted autologous chimeric antigen receptor T cell (CAR-T) immunotherapy armored with IL-7 and CCL19. The addition of IL-7 and CCL19 to the construct was designed to support the expansion of memory subsets and persistence of CAR-T cells. We hypothesized TAK-102 would help overcome the challenges associated with an immunosuppressive tumor microenvironment that limit the activity of nonarmored CAR-T therapies in solid tumors. Methods: The first-in-human, Phase 1 dose escalation study evaluated TAK-102 in patients (pts) with GPC3-expressing solid tumors who were refractory or intolerant to standard treatments. TAK-102 was administered via a single infusion to 3 dose cohorts after lymphodepleting chemotherapy (LDC; consisting of fludarabine and cyclophosphamide): dose level (DL) 1 (starting cohort), 1x10 7 CAR+ cells/body; DL2, 1x10 8 CAR+ cells/body; DL3, 5x10 8 CAR+ cells/body. Objectives included evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, cellular kinetic (CK) parameters, tumor markers, cytokine/chemokine and antitumor activity based on RECIST 1.1. Results: Eleven pts were enrolled and infused TAK-102 (DL1: 3 pts, DL2: 3 pts, DL3: 5 pts): 1 gastric neuroendocrine carcinoma, 2 liposarcoma, 8 HCC. Five pts achieved stable disease (SD), HCC (GPC3 H-Score: 36) . In patients achieving SD, the greatest reduction in tumor size was 26.4%. No DLTs or neurotoxicity were observed. Six pts experienced cytokine release syndrome (Grade1: 5 pts, Grade2: 1 pt); all cases were manageable. AFP was measured as a tumor marker for HCC. Among 8 pts with HCC, 4 had SD after treatment with TAK-102 and 3 showed a decrease or stabilization of AFP levels corresponding to their clinical status. CK profiles for pts were assessed by flow cytometry and qPCR-based assays. Overall, there was improvement in TAK-102 exposure (Cmax, AUC) when escalating from DL1 to DL2. There was a slight decrease in Tmax from DL2 to DL3. Homeostatic cytokine (IL-7) spiked post-LDC and showed no further increase after TAK-102 infusion across all the DLs. There was dose-dependency observed in peak CCL19, IFN-γ and IL-6 levels. Conclusions: TAK-102, an armored CAR-T, is well tolerated and has a manageable safety profile with some early signs of anti-tumor activity. For CK, TAK-102 exposure (Cmax, AUC) showed improvement from DL1 to DL2, and slight decrease in Tmax from DL2 to DL3. Dose-dependency was observed in peak CCL19, IFN-γ and IL-6 levels, which may point towards increased signal of activity from DL1 to DL3. Clinical trial information: NCT04405778 .