Immune activation in first-in-human anti-macrophage antibody (anti-Clever-1 mAb; FP-1305) phase I/II MATINS trial: Part I dose-escalation, safety, and efficacy results.

Abstract

3097 Background: The scavenger receptor CLEVER-1 mediates the clearance of “unwanted” self-components and is highly expressed on tumor associated macrophages (TAMs). CLEVER-1 expression is associated with immunotherapy resistance and poor survival in several cancers. Pre-clinical studies demonstrate that CLEVER-1 inhibition increases TAM pro-inflammatory cytokine secretion and antigen presentation reactivating CD8 T cell responses with robust anti-tumor activity. Targeting CLEVER-1 could therefore overcome the immunosuppressive tumor microenvironment and has led to the development of FP-1305, a humanized anti-CLEVER-1 IgG4-antibody. Methods: The MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a multicenter first-in-human phase I/II study (NCT03733990) to assess the tolerability, safety and preliminary efficacy of FP-1305 in patients (pts) with advanced cancers including immunotherapy-refractory melanoma, cholangiocarcinoma, hepatocellular carcinoma, ovarian cancer, colorectal (CRC), and pancreatic ductal adenocarcinoma. Part 1 consisted of a dose escalation phase; 30 pts (median age 65, range 30-81) were enrolled to examine 5 dose levels (0.1, 0.3, 1.0, 3.0, 10 mg/kg), to determine the optimal dose of FP-1305 for Parts 2 and 3. Two-stage time-to-event continual reassessment method (TITE-CRM) was utilized for the dose escalation in Part 1. Pts received 1-8 cycles (median 3) of FP-1305 Q3w. FP-1305 was well tolerated without dose-limiting toxicities. A consistent increase in blood NK cells, CD8/CD4 T cell ratio, B cells and a decrease in regulatory T cells was demonstrated. FP-1305 dosing led to the activation (CD25+) and Th1 skewing (CXCR3+) of T cell populations including increase in effector CD8 T-cells with downregulation of several inhibitory immune checkpoint molecules (PD-1, PD-L1, CTLA-4, and LAG3). Increased circulating IFNɣ levels were detected, with the highest levels in a heavily pretreated metastatic, microsatellite stable (MSS) colorectal cancer patient leading to a partial tumor response (-52%). FP-1305 is the first macrophage checkpoint inhibitor candidate promoting immune switch with promising tolerability and clinical anti-tumor activity. FP-1305 represents a novel treatment option to provoke immune response especially in non-inflamed tumors. Full safety, pharmacokinetic and efficacy results of MATINS trial (Part 1) will be presented for the first time in a final late breaking abstract. Clinical trial information: 2018-002732-24 .

Systemic blockade of Clever-1 elicits lymphocyte activation alongside checkpoint molecule downregulation in patients with solid tumors

“…The tumor types were selected based on the association of Clever-1 expression (mRNA) with survival data obtained from the TCGA repository, analysis of Biobank material for macrophage Clever-1 positivity (Auria Biobank, University of Turku), and published research (Algars et al, 2012). Full clinical data were presented at ASCO 2020 virtual meeting (Bono et al, 2020). The drug was well-tolerated and no dose-limiting toxicity was observed during the dose-escalation phase with a maximum dose of 10 mg/kg.…”

“…Immunotherapeutic targeting of Clever-1 in various tumor models delays tumor growth (Karikoski et al, 2014) by activating cytotoxic CD8 + T cells and renders refractory tumors more responsive to anti-PD-1 therapy (Viitala et al, 2019). To elucidate the significance of Clever-1 in suppressing antitumor immune responses in cancer patients, a phase I/II first-in-man clinical trial (MATINS; NCT03733990) was initiated to study the safety, tolerability and early efficacy of FP-1305, a humanized anti-Clever-1 antibody, in patients with selected advanced or metastatic solid tumors (Bono et al, 2020). FP-1305 antibody contains IgG4(S241P) heavy-chain and kappa light-chain constant regions and has further been optimized by introducing the L248E mutation to avoid Fcγ receptor binding (Reddy et al, 2000).…”

Next generation of immune checkpoint inhibitors and beyond

“…FP-1305, a humanized IgG4 mAb targeting CLEVER-1, is being studied as monotherapy in a phase I/II clinical trial in patients with advanced and refractory solid malignancies ( NCT03733990 ). Preliminary results are available for 30 patients (22 females and 8 males) with a median age of 65 years [ 133 ]. ORR was 3% and DCR was 27% with 2 patients achieving PR (one was a heavily treated CRC), 6 SD, and 22 PD.…”

“…ORR was 3% and DCR was 27% with 2 patients achieving PR (one was a heavily treated CRC), 6 SD, and 22 PD. At the time of cutoff, only 1 patient remained in the study, and the other 29 patients had been unenrolled due to PD or provider’s choice [ 133 ]. Patients’ serum Treg levels decreased, and CD8 + T cells and NK cells were increased compared to baseline.…”

“…One individual developed serious AEs including pneumonitis (grade 1), dermatitis, myositis, and thyroiditis (each grade 2). The most common grade 1 and 2 AEs included fatigue, fever, elevated transaminases, and gastrointestinal toxicities [ 133 ]. This trial is active and recruiting.…”