RESUMEN
Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%-50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.
RESUMEN
<p><b>OBJECTIVE</b>To analyze the clinical features, therapeutic methods and prognosis of primary breast lymphoma (PBL).</p><p><b>METHODS</b>Twenty-one PBL patients treated in Ruijin Hospital from January 2003 to December 2013 were included in this study, with 17 diffuse large cell lymphoma (DLBCL), 1 mucosa-associated lymphoid tumor (MALT), 1 follicular lymphoma (FL), 1 Burkitt lymphoma and 1 subcutaneous peniculitis T-cell lymphoma according to the WHO 2008 classification. Of 21 patients, only one patient with MALT has bulged tumor mass (>7 cm), other patients had tumor mass <5 cm. Six patients had core needle biopsy of tumor, 2 modified radical operation, and others tumor excision for diagnosis. All the patients received chemotherapy. The impacts of surgery, rituximab and prophylaxis with lumbar puncture on the outcomes of patients were analyzed. Survival was estimated using Kaplan-Meier method and compared by log-rank test. All the results were analyzed by SPSS 10.0.</p><p><b>RESULTS</b>Among 21 PBL patients, 19 achieved complete remission (CR), 1 partial remission (PR) and 1 disease progression (PD). Followed-up till July 2014, with median follow-up of 14 months (6-75 months), only one patient died, with 3-year survival of 92.3%. Compared with chemotherapy alone, the progression-free survival (PFS) of combination therapy (surgery plus chemotherapy) was significant longer (P=0.015), but without statistic differences of CR rate and overall survival (OS) between two groups. Among the 20 patients with CD20-positive tumor cells, 17 received Rituximab. PFS and OS, as well as CR rate of PBL had no difference between the treatment with and without Rituximab. The incidence of central nervous system (CNS) infiltration had no difference between patients with and without CNS prophylaxis through lumber-puncture and intrathecal injection.</p><p><b>CONCLUSION</b>With the common subtype of DLBCL, PBL patients had good outcome. Surgery, as a method to obtain tumor samples for diagnosis, could not prolong OS of patients. Therefore, radical operation shouldn't be recommended. PBL was reported to have high risk of CNS events, but prophylaxis with lumber puncture and intrathecal injection couldn't decrease the incidence of CNS infiltration.</p>