CAR-T cells designed to activate JAK–STAT signaling show enhanced persistence and antitumor activity.

  • Major finding: CAR-T cells designed to activate JAK–STAT signaling show enhanced persistence and antitumor activity.

  • Concept: CD19 CAR-T cells that induce cytokine signaling after antigen stimulation may have improved activity.

  • Impact: This next-generation CAR design strategy may allow for targeting of solid tumors or diverse antigens.

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Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a therapeutic strategy for cancer. CAR-T cells targeting the B lymphocyte antigen CD19 have proven beneficial in patients with refractory B-cell malignancies, but CAR-T cell therapies have not achieved the same success in other malignancies. Full T-cell activation requires three signals: T-cell receptor (TCR) engagement, co-stimulation, and cytokine engagement. Previous CAR constructs contain the TCR signaling and co-stimulatory domains, but lack a domain to transmit cytokine signals, prompting Kagoya and colleagues to develop a next-generation CD19 CAR, termed 28-ΔIL2RB-z(YXXQ), to deliver cytokine signaling after antigen engagement to enhance the antitumor activity of CAR-T cells. These 28-ΔIL2RB-z(YXXQ) CAR-T cells contained the CD3z TCR signaling domain, the CD28 stimulatory domain, and two domains designed to induce JAK–STAT pathway activation in an antigen-dependent manner, an IL2Rβ cytoplasmic domain and a STAT3 binding motif (YXXQ). In vitro, the 28-ΔIL2RB-z(YXXQ) CAR-T cells showed increased proliferation compared with control CAR-T cells lacking the JAK–STAT activation domains, which was abrogated by cotreatment with STAT3 and STAT5 inhibitors. Gene set enrichment analysis confirmed that genes induced by IL21 and STAT3 were upregulated in addition to a number of effector molecules. In vivo, 28-ΔIL2RB-z(YXXQ) CAR-T cells had enhanced proliferation and reduced terminal differentiation in immunodeficient mice bearing NALM6 human leukemia cells. Further, 28-ΔIL2RB-z(YXXQ) CAR-T cells suppressed leukemia progression in mouse models with similar efficiency to CAR-T cells lacking the JAK–STAT activation domains. However, 28-ΔIL2RB-z(YXXQ) CAR-T cells had superior persistence in the peripheral blood, resulting in improved disease control. 28-ΔIL2RB-z(YXXQ) CAR-T cells also had activity in melanoma xenografts. These findings support further investigation of 28-ΔIL2RB-z(YXXQ) CAR-T cells, which may achieve superior antitumor effects. Moreover, this CAR design may extend to solid tumors or be used to generate CAR constructs with different antigen specificity.

Kagoya Y, Tanaka S, Guo T, Anczurowski M, Wang CH, Saso K, et al. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nat Med 2018;24:352–9.

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