Tisagenlecleucel, a chimeric antigen receptor T-cell therapy, has demonstrated efficacy and manageable safety in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r ...DLBCL) in the global, multicenter, pivotal, phase 2, JULIET trial (NCT02445248). The primary endpoint, overall response rate (ORR), was met at the interim analysis (ORR: 59% CR, 43%; PR, 16%). Here, we report an updated analysis with a median 19 mo follow-up.
Adult pts ≥18 y with r/r DLBCL that had progressed after ≥2 lines of therapy including rituximab and an anthracycline and who were ineligible for or failed autologous stem cell transplant (ASCT) were enrolled. Tisagenlecleucel was manufactured from autologous T cells at 2 facilities (Morris Plains, NJ, USA main cohort. and Leipzig, Germany cohort A) and provided to pts at 27 treatment centers in 10 countries across the globe. Efficacy analyses include all pts with ≥3 mo of follow-up or earlier discontinuation. Safety analyses include all infused pts.
In the JULIET study, 115 pts (99 in main cohort; 16 in cohort A) received a single dose of tisagenlecleucel infusion as of 21 May 2018. Prior to infusion, 90% of infused pts received bridging chemotherapy and 93% received lymphodepletion chemotherapy. Pts were a median 56 y (range, 22-76 y); 77% of pts had stage III/IV and 17% had double/triple-hit disease at the time of entry. Approximately half (51%) of pts had received ≥3 prior lines of chemotherapy (range, 1-6); 49% received prior ASCT. ORR was 54% (40% CR, 13% PR; 95% CI, 43%-64%) with a median follow-up of 19.3 mo post-infusion. Median duration of response (DOR) was not reached. The relapse-free probability was 66% (95% CI, 51%-78%) at 6 mo and 64% (95% CI, 48%-76%) at 12 or 18 mo. Consistent ORR was reported across prognostic subgroups (eg, prior ASCT; double/triple-hit lymphoma) and DOR was similar among age groups and disease status (Figure). Median OS was not reached for pts in CR and was 11.1 mo (95% CI, 6.6 mo-NE) for all infused pts. The probability of OS was 48% (95% CI, 38%-57%) at 12 mo and 43% (95% CI, 33%-53%) at 18 mo (max follow-up, 29 mo). No pts proceeded to allogeneic SCT or ASCT while in remission. During the first 8 wks post-infusion, grade 3/4 adverse events of special interest were cytopenias lasting >28 days (34%), cytokine release syndrome (CRS; 23%, by the Penn scale), infections (19%), febrile neutropenia (15%), neurologic events (11%; 1 case of grade 2 cerebral edema), and tumor lysis syndrome (2%). Tocilizumab was administered to 16% of pts with CRS, and no treatment-related death was reported.
This updated analysis with longer follow-up confirms earlier findings. Tisagenlecleucel produced a durable high ORR, consistent efficacy across all predefined subgroups, and had a manageable safety profile in pts with r/r DLBCL.
This study evaluated the safety and efficacy of inotuzumab ozogamicin (INO), a targeted humanized anti-CD22 antibody conjugated to calicheamicin, plus rituximab (R-INO) every 3 weeks, up to six ...cycles, followed by high dose therapy and autologous stem cell transplant (HDT-aSCT) in patients with high-risk relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The primary endpoint was overall response (OR) rate after three cycles of R-INO. Sixty-three patients were enrolled. Common grade 3/4 adverse events during R-INO treatment were thrombocytopenia, lymphopenia and neutropenia. OR rate after three cycles of R-INO was 28.6% (95% confidence interval: 17.9-41.4). Eighteen patients underwent HDT-aSCT; 2-year progression-free survival (PFS) for these patients was 61.1%. Serious infections and hepatic toxicity following aSCT occurred in 33% and 22%, respectively. One- and 2-year PFS rates for all enrolled patients were 28.9% and 25.3%, respectively (median, 3.0 months). R-INO had lower than expected activity as a salvage regimen for transplant eligible patients with DLBCL.
Transfection with synthetic mRNA is a safe and efficient method of delivering antigens to dendritic cells for immunotherapy. Targeting antigens to the lysosome can sometimes enhance the CD4+ T-cell ...response. We transfected antigen-presenting cells (APCs) with mRNA encoding Gag-p24 and cytoplasmic, lysosomal, and secreted forms of Nef. Antigen-specific cytotoxic T cells were able to lyse the majority of transfected targets, indicating that transfection was efficient. Transfection of APCs with a Nef construct bearing lysosomal targeting signals produced rapid and prolonged antigen presentation to CD4+ and CD8+ T cells. Polyclonal CD4+ and CD8+ T-cell lines recognizing multiple distinct epitopes were expanded by coculture of transfected dendritic cells with peripheral blood mononuclear cells from viremic and aviremic HIV-infected subjects. Importantly, lysosome-targeted antigen drove a significantly greater expansion of Nef-specific CD4+ T cells than cytoplasmic antigen. The frequency of recognition of CD8 but not CD4 epitopes by mRNA-expanded T cells was inversely proportional to sequence entropy and was similar to ex vivo responses from a large chronic cohort. Thus human dendritic cells transfected with mRNA encoding lysosome-targeted HIV antigen can expand a broad, polyclonal repertoire of antiviral T cells, offering a promising approach to HIV immunotherapy.
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