33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018)

Abstract

Background CD137 (4-1BB/TNFRSF9) is a costimulatory receptor belonging to the TNF receptor superfamily. It was originally cloned as an inducible gene from stimulated helper and cytotoxic T cells and has since been shown to also be expressed on natural killer (NK) cells. Agonistic anti-CD137 antibodies have shown potent, often curative antitumour activity in preclinical models. These effects are mainly mediated by cytotoxic T cells and generate long lasting, memory responses. Two human anti-CD137 antibodies, binding to the extracellular domain of CD137, urelumab and utomilumab are currently undergoing clinical testing. Urelumab has shown several single-agent, partial responses, but its use has been hampered by hepatoxicity, whilst utomilumab has shown little or no single agent activity. Methods Bicycles® are a new class of drugs -fully synthetic, constrained bicyclic peptides that combine the attributes of three therapeutic modalities (antibodies, small molecules, and peptides) by delivering high affinity, good PK, and rapid clearance. Their small size (1.5-2 kDa) delivers advantages in tumour penetration, and rapid renal elimination

The Next-Generation Immune Checkpoint LAG-3 and Its Therapeutic Potential in Oncology: Third Time’s a Charm

“…Moreover, antibody FS118 from F-star therapeutics harbors an antigen-binding fragment targeting LAG-3 in its constant region, leaving the Fabs as PD-L1 targeting domains [ 110 ]. Xencors XmAb22841 is an antibody with one Fab targeting LAG-3, and the other Fab is replaced by a single-chain variable fragment (scFv) targeting CTLA-4 [ 115 ]. Future reports on these constructs are awaited to gather insight on their actual therapeutic efficacy.…”

Update of early phase clinical trials in cancer immunotherapy

“…MK-4280 monotherapy demonstrated an RR of 6% and DCR of 17% in patients with advanced solid tumors, whereas an MK-4280/pembrolizumab combination had an RR of 27% and DCR of 40% ( 13 ). Of note, a biomarker-directed randomized phase II (MK-3475-95/KEYNOTE-495) study of pembrolizumab in combination with MK-1308 (anti-CTLA4), MK-4208 or lenvatinib for treatment-naïve NSCLC patients is ongoing.…”

“…Of interest, CA-170, an oral inhibitor targeting both PD-L1 and VISTA, showed preliminary efficacy. In a phase II trial, the clinical benefit rate (CBR) by irRECIST was 52% in treated Hodgkin lymphoma and more than 70% in treated NSCLC, but no objective response was observed ( 17 , 18 ).…”

The Role of Metabolism in Tumor Immune Evasion: Novel Approaches to Improve Immunotherapy

“…CS3005 and DZD2269 [ 156 ] are A2AR inhibitors whose clinical trials were initiated in 2020. Regarding preclinical development, there are also various agents being tested: ES002 is an anti-CD39 monoclonal antibody; HBM1007 [ 157 ], PT199, and AK119 [ 158 ] are anti-CD73 monoclonal antibodies; AK123 is an anti-PD-1/CD73 bi-specific monoclonal antibody [ 158 ]; CB-708 [ 159 ], OP-5244 [ 160 ], OR-558 [ 161 ], and ORIC-533 as CD73 inhibitors [ 162 ], and AB745 [ 163 ], ARX001822 [ 164 ] and RVU330 [ 165 ] as A2AR antagonists.…”