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تسجيل

CAR-T Combination with Immunomodulatory Agents: PD-1 Blockade

المؤلف:  Armin Ghobadi & John F. DiPersio

المصدر:  Gene and Cellular Immunotherapy for Cancer

الجزء والصفحة:  p76-77

2026-09-08

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(a) Hematologic malignancies

CAR-T19 cell therapy has been shown to induce complete remission in more than 90% of patients with ALL with durable remission rates of 50–60%; however, only 20–30% of CLL patients achieve sustained remission following CAR-T cell therapy. Transcriptomic analyses revealed that T cells obtained from non-responder CLL patients have upregulated pathways involved in exhaustion and apoptosis with increased expression of co-inhibitory receptors such as PD-1, TIM-3 and LAG-3. Pediatric patients with ALL who had failed previous CAR-T19 therapy displayed improved outcomes and better CAR-T persistence when the anti-PD-1 antibody pembrolizumab was added to the treatment regimen. These outcomes were similar to two other reports that evaluated the role of combining CAR-T19 cells with another anti-PD1 anti body, nivolumab, in 11 patients with refractory/relapsed B-NHL and refractory follicular lymphoma. Multiple clinical trials are currently exploring the role of immune checkpoint blockade with CAR-T cell therapy in diffuse large B cell lymphoma (DLBCL) (NCT02706405, NCT02926833, NCT03287817), aggressive B-NHL (NCT03310619), and MCL (NCT02650999).

(b) Solid tumors The application of CAR-T cell therapy to solid tumors has proven to be more challenging due to antigen sequestration in organ tissues (discussed below) and the immunosuppressive tumor microenvironment. The combination of immune checkpoint inhibition (ICI) with CAR-T cell therapy has proven to be beneficial in Her-2 transgenic mice models where anti-PD-1 antibody improved CAR-T proliferation and antitumor efficacy. Similar findings were also observed in an orthotopic mouse model of pleural mesothelioma, where anti-PD-1 antibody rescued the effector functions of exhausted CAR-T cells. Blocking PD-1 on liver myeloid-derived suppressor cells (L-MDSC) proved beneficial in a murine model of carcinoembryonic antigen+ liver metastases, where L-MDSCs are thought to suppress CAR-T function. On the other hand, not all trials yielded a clear benefit of adding PD-1 blockade to CAR-T cell therapy. In particular, one clinical trial investigated the efficacy of combining ICI with CAR-T cell therapy in patients with relapsed or refractory neuroblastoma. While lymphodepletion with fludarabine and cyclophosphamide increased CAR-T cell expansion and persistence, the addition of pembrolizumab did not yield additional benefit. This trial was conducted on 11 patients; therefore, larger trials are needed.