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Abstract Relapsed/refractory (R/R) primary and secondary central nervous system lymphomas (PCNSL, SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. We retrospectively compared the safety and efficacy of CD19/22 CAR-T-cell therapy following ASCT (ASCT + CAR-T group), CD19/22 CAR-T-cell cocktail therapy (CAR-T group) and chemoimmunotherapy (CIT group) in treating R/R CNSL patients. Analysis of the differences in clinical characteristics among the three groups revealed that the median age in the CIT group was older than that in the ASCT + CAR-T group and CAR-T group, and the median number of prior lines of therapy in the CIT group was less than that in the other groups. Patients in the two CAR-T-therapy groups exhibited comparable incidences and severities of CRS and ICANS. Grade 4–5 CRS and ICANS were not observed in either CAR-T-cell therapy group. The incidence of Grade 3/4 hematological toxicity in the ASCT + CAR-T and CAR-T groups was greater than that in the CIT group. The ORR was 82.75% in the ASCT + CAR-T group, 60.00% in the CAR-T group and 58.83% in the CIT group. As of December 31, 2022, the median follow-up after therapy was 16.73 months (range, 0.67-42.00 months). The median durations of PFS and OS were not reached in the ASCT + CAR-T group. The median PFS in the CAR-T group was 4.72 months, and OS was not reached. In the CIT group, the median PFS and OS were 6.63 months and 16.77 months, respectively. The 2-year PFS rate of patients in the ASCT + CAR-T group (65.52%) was significantly greater than that of patients in the CAR-T group (30.00%, P = 0.0321) and CIT group (23.53%, P = 0.0043). Our results support the development of CAR-T-cell therapy for R/R CNSL. With the durability of remission and low toxicity, ASCT combined with CAR-T-cell therapy appears to be a more effective and safer treatment option for primary and secondary R/R CNS lymphoma.

Background Our previous study showed that transmembrane tumor necrosis factor alpha (tmTNF-α) is overexpressed in primary breast cancers including triple-negative breast cancers (TNBCs). Chimeric antigen receptor engineered-T (CAR-T) cells have been successfully used mainly in B-cell malignancies.Methods We generated CAR-T cells targeting tmTNF-α but not secreted tumor necrosis factor alpha and assessed the antitumor effect of the CAR-T cells on tmTNF-α-expressing breast cancer cells in vitro and in vivo.Results Our tmTNF-α CAR-T cells showed potent cytotoxicity against tmTNF-α-expressing breast cancer cells but not tmTNF-α-negative tumor cells with increased secretion of interferon gamma (IFN-γ) and interleukin (IL)-2 in vitro. In tmTNF-α-overexpressing TNBC-bearing mice, the tmTNF-α CAR-T therapy induced evident tumor regression, prolonged survival and increased serum concentrations of IFN-γ and IL-2. However, we found thattmTNF-α induced programmed death-ligand 1 (PD-L1) expression through the p38 pathway via TNF receptor (TNFR) and through the NF-κB and AKT pathways via outside-to-inside (reverse) signaling, which might limit the efficacy of the CAR-T cell therapy. Blockage of the PD-L1/programmed death-1 (PD-1) pathway by PD-1 monoclonal antibody significantly enhanced the antitumor effect of the tmTNF-α CAR-T cell therapy in vitro and in vivo, and the combination was effective for antiprimary tumors and had a tendency to increase the antimetastasis effect of the CAR-T cell therapy.Conclusion Our findings suggest a potent antitumor efficacy of the tmTNF-α CAR-T cells that can be enhanced by anti-PD-L1/PD-1 because high PD-L1 expression in TNBC was induced by the tmTNF-α signaling, indicating a promising individual therapy for tmTNF-α-positive breast cancers including TNBC.