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DLT) during cycle 1. Six dose levels were planned. The CRM design allowed more rapid accrual: once the maximum 3 patients were on the dose level under evaluation, further patients received the dose level below, with all data contributing to dose decisions. Ph 2 used a single stage A'Hern design to assess best ORR during the first 8 cycles (assessed using the Revised Response Criteria for Malignant Lymphoma) of the combination in all participants (pts) treated at the MTD. ROMI was given IV on days 1, 8 and 15 of a 28d cycle; CAR IV on days 1, 2, 8, 9, 15 and 16. HR23B expression was performed on formalin fixed paraffin embedded tissue.Results: 33 pts enrolled to Ph 1 with 27 evaluable for MTD assessment. 34 pts were treated at the MTD and evaluable for Ph 2. Median age 62y (22-82y); 69% male; median prior treatment lines 2 performance status 0 (44%), 1 (44%) or 2 (10%) (1 unknown); 53% refractory to last treatment. 51% had PTCL Not Otherwise Specified; 40% angioimmunoblastic T-cell lymphoma. 7 DLTs were seen in 6 patients during phase 1. The MTD was defined as ROMI 10 mg/m 2 with CAR 20mg/m 2 for 2 doses then 40mg/m 2 , giving an estimated posterior DLT probability of 0.216 with a 90% credible interval (0.106, 0.352). The ORR at the MTD was 32% (95% confidence interval 19-49%): 15% complete response, 18% partial response, 18% stable disease. Grade 3/4 adverse events in ≥ 10% pts were anaemia (17%); neutropenia (35%); thrombocytopenia (42%). Median PFS was 4.0 months (median follow up 19 months); 4 participants remain on treatment. HR23B expression was not associated with response with 27% (3 of 11) HR23B positive pts responding.

Cholesterol is often enriched in tumor microenvironment (TME); however, its impact on disease progression varies in different tissues and cells. Monocytes/macrophages (Mφ) are major components and regulators of the TME and play pivotal roles in tumor progression and therapeutic responses. We aimed to investigate the profile, effects, and regulatory mechanisms of Mφ cholesterol metabolism in the context of human hepatocellular carcinoma (HCC). Here, we found that patients with high serum levels of cholesterol had shorter survival times and lower response rates to anti-PD-1 treatment. However, the cholesterol content in tumor-infiltrating monocytes/Mφ was significantly lower than that in their counterparts in paired non-tumor tissues. The expression of the cholesterol efflux transporter, ABCA1, was upregulated in tumor monocytes/Mφ, and ABCA1 upregulation positively associated with decreased cellular cholesterol content and increased serum cholesterol levels. Mechanistically, autocrine cytokines from tumor-treated monocytes increased LXRα and ABCA1 expression, which led to the generation of immature and immunosuppressive Mφ. Although exogenous cholesterol alone had little direct effect on Mφ, it did act synergistically with tumor-derived factors to promote ABCA1 expression in Mφ with more immunosuppressive features. Moreover, high numbers of ABCA1+ Mφ in HCC tumors associated with reduced CD8+ T-cell infiltration and predicted poor clinical outcome for patients. Our results revealed that dysregulated cholesterol homeostasis, due to the collaborative effects of tumors and exogenous cholesterol, drives the generation of immunosuppressive Mφ. The selective modulation of cholesterol metabolism in Mφ may represent a novel strategy for cancer treatment.