Sarcoma Immunotherapy

Published OnlineFirst March 28, 2013; DOI: 10.1158/2159-8290.CD-RW2013-067

RESEARCH WATCH

Immunotherapy

Major finding: CD19-specific CAR Mechanism: The response to 19–28z Impact: 19–28z+ T cells may induce T cells rapidly eradicate resistant B-ALL CAR-modified T cells was evaluated in complete molecular remission in and provide a bridge to allo-HSCT. 5 patients with relapsed B-ALL. patients with relapsed B-ALL.

CAR-MODIFIED T CELLS HAVE ANTITUMOR ACTIVITY IN REFRACTORY ADULT B-ALL Relapsed adult B-cell acute lymphoblastic leukemia residual tumor burden prior to T-cell infusion, neces- (B-ALL) is an aggressive disease with an extremely poor sitating high-dose steroid treatments to reduce toxicity. prognosis. The standard of care is treatment with salvage Following 19–28z+ T-cell therapy, 4 patients received allo- chemotherapy followed by allogeneic hematopoietic stem HSCT, including 2 patients with refractory disease after cell transplant (allo-HSCT) if patients are clinically eligible, chemotherapy who would have otherwise been ineligible, but long-term survival is dependent on achieving remis- indicating that CAR-modifi ed T cells provide a bridge to sion without minimal residual disease (MRD) after chemo- allo-HSCT and may induce durable antitumor responses. therapy. Transfer of autologous T cells modifi ed to express One patient experienced tumor relapse that was not associ- chimeric antigen receptors (CAR) specifi c for the B-cell ated with antigen loss or insensitivity to T-cell–mediated antigen CD19 has shown antitumor activity in low-grade lysis but was possibly due to steroid-induced reduction in B-cell malignancies, but it is not known whether this strat- T-cell persistence, suggesting that repeated T-cell infusions egy is also effective in refractory B-ALL. Brentjens and col- may extend remission. Although allo-HSCT precluded leagues treated 5 adult patients with relapsed B-ALL who long-term follow-up in most patients, these results show had received salvage chemotherapy but not allo-HSCT with that 19–28z+ T cells have antitumor activity in patients autologous T cells expressing a second-generation CD19- with refractory B-ALL and support additional studies of targeted CD28/CD3ζ CAR (19–28z). Infusion of modifi ed this therapeutic strategy. ■ T cells resulted in rapid elimination of resistant tumor cells and MRD– complete remission in all 5 patients, independ- Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, ent of tumor burden prior to T-cell therapy. CAR T cells et al. CD19-targeted T cells rapidly induce molecular remissions in expanded in vivo and were well tolerated but triggered eleva- adults with chemotherapy-refractory acute lymphoblastic leukemia. tions in proinfl ammatory cytokines in patients with greater Sci Transl Med 2013;5:177ra38.

Sarcoma

Major finding: The SS18–SSX fusion Mechanism: The altered SWI/SNF com- Impact: Understanding the function protein evicts wild-type SS18 and plex reverses H3K27me3-mediated re- of SS18–SSX can lead to improved SNF5 from the SWI/SNF complex. pression at the SOX2 locus. therapies for synovial sarcoma.

SS18–SSX DRIVES SYNOVIAL SARCOMA BY ALTERING SWI/SNF COMPOSITION Synovial sarcomas are soft-tissue malignancies tion of SOX2, a pluripotency gene with known roles in distinguished by a chromosomal translocation that oncogenesis. SOX2 expression was essential for syno- fuses SS18 to one of 3 closely related genes, SSX1, vial sarcoma cell proliferation and was associated with SSX2, or SSX4. Although it is clear that the SS18–SSX increased SWI/SNF occupancy and decreased levels of fusion drives synovial sarcoma, the underlying mecha- histone H3 lysine 27 trimethylation (H3K27me3) at nism remains unknown. Kadoch and Crabtree report the SOX2 locus. Remarkably, a 2-amino acid segment that SS18 is a stable subunit of SWI/SNF nucleo- that distinguished SSX1, SSX2, and SSX4 from non- some remodeling complexes, but in synovial sarcoma, oncogenic SSX proteins was suffi cient for SNF5 ejec- incorporation of SS18–SSX into SWI/SNF complexes displaces tion and SOX2 induction, providing further support for the role wild-type SS18 and the tumor suppressor subunit SNF5 (also of altered SWI/SNF subunit composition in synovial sarcoma known as BAF47 and INI1) from SWI/SNF complexes. SS18– and implicating this SSX region as a potential drug target. The SSX and wild-type SS18 compete for assembly into SWI/SNF fi nding that altered gene expression caused by a dysfunctional complexes, as formation of abnormal SWI/SNF complexes SWI/SNF complex lacking SS18 and SNF5 underlies SS18–SSX- could be reversed and synovial sarcoma cell growth was inhib- induced transformation thus not only provides crucial insight ited by overexpressing wild-type SS18. Knockdown of SS18–SSX into the etiology of synovial sarcoma but also suggests potential or the SWI/SNF ATPase subunit also signifi cantly inhibited therapeutic strategies for this cancer. ■ synovial sarcoma proliferation, indicating that synovial sarcoma cells were dependent on the activity of aberrant residual SWI/ Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF SNF complexes. In fi broblasts, forced SS18–SSX expression or (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sar- knockdown of SS18 or SNF5 signifi cantly increased transcrip- coma. Cell 2013;153:71–85.

MAY 2013CANCER DISCOVERY | 481

CAR-Modified T Cells Have Antitumor Activity in Refractory Adult B-ALL

Cancer Discovery 2013;3:481. Published OnlineFirst March 28, 2013.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2013-067

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