Anti-CD19 chimeric antigen receptor (CAR) T cells have the potential to be a curative therapy for lymphoma patients. However, most patients either fail to respond to this treatment or relapse after achieving initial remission^1-3. To improve the therapeutic benefits of CAR-T cells, many innovative CAR designs have been developed to enhance the antitumor efficiency and overcome treatment resistance related to inadequate expansion, infiltration, and persistence of CAR-T cells^4-7. In this regard, fourth-generation CARs (referred to as “armored” CARs) that incorporate cytokines (IL-7, IL-15, or IL-21) are being developed to try to improve CAR-T cell persistence, tumor targeting, and antitumor capacity^8-12. Another strategy is to modify CAR-T cells with the expression of a chemokine receptor or chemokine (CCL19, CCL21) that guides the CAR-T cells to the tumor site^4,13. The feasibility of these strategies has been demonstrated in preclinical settings and evaluated in clinical trials across a range of malignancies^14-16. Recently, anti-CD20 CAR-T cells expressing IL-7 and CCL19 have demonstrated enhanced antitumor activity compared to parental CAR-T cells and achieved complete elimination of pre-established solid tumors in mice^15,16. Although preclinical evidences in different solid tumor models support the potential antitumor efficacy of armored CAR-T strategies, however, clinical results in humans are lacking.

In this study, Lei et al. developed a novel CAR-T therapy for patients with R/R LBCL by engineering CD19-specific CAR-T cells to secrete IL-7 and CCL19 (7 × 19 CAR-T cells) upon CD19 antigen engagement. IL-7 is a crucial T-cell homeostatic cytokine that plays essential roles in promoting T cells survival, expansion, and differentiation. CCL19 is a main chemokine that promotes leukocyte chemotaxis. Thus, 7 × 19 CAR-T cells were designed to co-express IL-7 to promote T-cell fitness and persistence and CCL19 to enhance the recruitment of leukocytes towards the tumor sites, thereby eliciting a potent and durable anti-lymphoma response against lymphoma(Figure 1) .

Figure 1. Schematic diagram of 7 × 19 CAR and its antitumoral model

Indeed, the preclinical study demonstrated that 7 × 19 CAR-T cells exhibited dramatically increased proliferation, a high proportion of stem memory T cell (T_SCM), enhanced migration capability, and improved in vitro and in vivo anti-lymphoma activity compared to conventional anti-CD19 CAR-T cells .

Furthermore, the phase 1 clinical trial of 7 × 19 CAR T cell therapy in patients with R/R LBCL showed only 12.8% and 10.3% ≥ grade 3 CRS and neurotoxicity, respectively, and achieved an overall response rate of 79.5% (complete remission, 56.4%; partial response, 23.1%) in patients with R/R LBCL, with PFS of 13 months and OS of 53.8% at 2 years .

Furthermore, they also found that some biomarkers are associated with clinical response and toxicity, such as IFN-γ, TNF-α, IL-6, IL-7, IL-13, IL-8, IFN-gamma-inducible protein-10 (IP-10), Macrophage inflammatory protein-1-beta (MIP-1β), Stromal cell-derived factor-1α (SDF-1α), and CCL19, and patients received high proportion of subtypes of T_SCM CAR-T  cells favoring better antitumor function .

These results indicate that 7 × 19 CAR-T cell therapy has not only a favorable safety profile but also superior efficacy against B-cell lymphoma to previously reported conventional anti-CD19 CAR T cell therapies. The study by Lei et al. suggests a significant clinical benefit of 7 × 19 CAR T-cell therapy for patients with R/R LBCL and supports 7 × 19 CAR T-cell therapy as a promising treatment strategy for B-cell malignancies.    

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