Koji Tamada

Chimeric antigen receptor (CAR) T-cell therapies have shown limited promise in solid tumors owing to the immunosuppressive tumor microenvironment. TAK-102 is a next-generation, glypican 3 (GPC3)-targeted CAR T-cell therapy engineered to coexpress IL7 and chemokine ligand 19 (CCL19), enhancing T-cell survival and trafficking. In this first-in-human, open-label, phase I, dose-escalation study (ClinicalTrials.gov: NCT04405778), we evaluated a single TAK-102 infusion in 11 patients with GPC3+ advanced solid tumors refractory or intolerant to standard therapies. Patients received TAK-102 at one of three dose levels following leukapheresis and lymphodepletion chemotherapy. The primary endpoints were the incidences of dose-limiting toxicities, treatment-emergent adverse events (TEAE), and adverse events of special interest. No dose-limiting toxicities were observed. The most common TEAEs were hematologic, including neutropenia and leukopenia (81.8%), and cytokine release syndrome (54.5%), all grade 1 to 2. No objective responses were observed; however, five patients achieved stable disease (disease control rate, 45.5%). One patient had a 26.1% reduction in tumor size lasting 9 months, accompanied by a 51.6% decline in serum α-fetoprotein. Cellular kinetics showed dose-dependent expansion, with the highest exposure at 5 × 108 CAR+ cells/body. Posttreatment biopsies revealed increased CD8+ T-cell infiltration and activation markers, although CAR+ cells were undetectable in tumor tissue. Serum CCL19 levels increased with dose, suggesting immune priming. These findings support a manageable safety profile for TAK-102 and provide early evidence of biological activity in solid tumors. Further studies are warranted to optimize dosing, improve CAR T-cell persistence, and evaluate efficacy in larger patient cohorts.

Purpose:Durvalumab therapy following concurrent chemoradiotherapy (cCRT) improves progression-free survival (PFS) in patients with unresectable locally advanced non–small cell lung cancer. In this prospective observational study, we evaluated the changes in peripheral blood immune cell counts to elucidate the immunologic mechanisms underlying cCRT and durvalumab therapy. Experimental Design:Peripheral blood mononuclear cell (PBMC) samples were collected at four time points: before cCRT, after cCRT, at the start of durvalumab, and 8 weeks after the start of durvalumab, and analyzed by multicolor flow cytometry. Results:Of the 149 enrolled patients, 115 received durvalumab consolidation therapy after cCRT. The median PFS in the overall population was 24.2 months, and the 3-year PFS rate was 38.9%. PBMC analysis showed an increased effector fraction of CD4+ T cells before and after cCRT but no change in CD8+ T cells. Following durvalumab therapy, the effector fraction ratio of CD8+ T cells (CD62Llow CD8+ T cells) increased and positively correlated with increased CD62Llow CD4+ T cells during cCRT. Patients whose proportion of CD62Llow CD4+ T cells exceeded the threshold for cCRT had better PFS than those below the threshold. Patients whose CD62Llow CD8+ T-cell proportion exceeded the threshold after durvalumab therapy showed prolonged PFS compared with those below the threshold. Conclusions:cCRT promotes an increase in effector CD4+ T cells, and the subsequent increase in CD8+ T cells following durvalumab therapy prolongs PFS. Peripheral blood effector–type CD4+ and CD8+ T cells are potential biomarkers for evaluating the immune status of patients and predicting treatment efficacy.

Supplementary Figure 1 from Sequential Immune Activation of Effector T Cells as Biomarkers of Response to Durvalumab in Patients with Locally Advanced NSCLC

Supplementary Figure 3 from Sequential Immune Activation of Effector T Cells as Biomarkers of Response to Durvalumab in Patients with Locally Advanced NSCLC

Supplementary Figure 2 from Sequential Immune Activation of Effector T Cells as Biomarkers of Response to Durvalumab in Patients with Locally Advanced NSCLC

Supplementary Figure 5 from Sequential Immune Activation of Effector T Cells as Biomarkers of Response to Durvalumab in Patients with Locally Advanced NSCLC

Supplementary Figure 4 from Sequential Immune Activation of Effector T Cells as Biomarkers of Response to Durvalumab in Patients with Locally Advanced NSCLC

Supplementary Figure 6 from Sequential Immune Activation of Effector T Cells as Biomarkers of Response to Durvalumab in Patients with Locally Advanced NSCLC

Supplementary Table 1 from Sequential Immune Activation of Effector T Cells as Biomarkers of Response to Durvalumab in Patients with Locally Advanced NSCLC

CAR-T cell therapy has achieved remarkable success in the treatment of certain blood cancers, but its efficacy against solid tumors remains limited. One of the key strategies is the improvement of manufacturing methods for the rapid production of high-functioning CAR-T cells. We have improved the manufacturing method for CAR-T cells simultaneously expressing IL-7 and CCL19 (referred to as 7×19 CAR-T cells), armored CAR-T cells which we developed for treating solid tumors. We generated 7×19 CAR-T cells using a short-term culture method without expansion phase (referred to as Swift 7×19 CAR-T cells), then compared them with regular culture methods (referred to as Standard 7×19 CAR-T cells). Swift CAR-T cells are distinguished by a high frequency of early memory phenotypes, including stem cell memory and central memory T cells, which showed superior effector functions over Standard CAR-T cells. In a stress test in which effector cells are repeatedly stimulated by target-positive tumor cells, Swift 7×19 CAR-T cells and Swift conventional CAR-T cells initially exhibited similar antitumor effects. However, after repetitive stimulations, only Swift 7×19 CAR-T cells maintained a robust response. Furthermore, Swift 7×19 CAR-T cells demonstrated in vivo antitumor activity by substantially fewer cells compared to Standard 7×19 CAR-T cells, and conferred a long-term resistance to tumor rechallenge without autonomous proliferation indicative of malignant transformation. These results highlight the potential of the innovative “Swift” short-term culture methods combined with 7×19 CAR-T technology to provide a new treatment option for refractory solid tumors.