The safety profile of FAP-IL2v in combination with cetuximab was acceptable and pharmacodynamic markers support the proposed mode-of-action of this combination, but the overall low antitumor activity does not warrant further clinical exploration in HNSCC. [Part C of Study BP29842 (NCT02627274).].

FAP-IL2v plus atezolizumab is clinically active and has manageable safety in patients with recurrent and/or metastatic cervical SCC.

P2, N=279, Suspended, Kezar Life Sciences, Inc. | Recruiting --> Suspended

P2, N=24, Active, not recruiting, Kezar Life Sciences, Inc. | Trial completion date: Mar 2025 --> Aug 2025 | Trial primary completion date: Sep 2024 --> Feb 2025

P2, N=24, Active, not recruiting, Kezar Life Sciences, Inc. | Recruiting --> Active, not recruiting

These results suggest that ONX-0914 prevents the internal destructive cleavage of WT1235 by IP, thereby promoting the specific presentation of the WT1 epitope by MESO-4. In conclusion, selective IP inhibitors might offer a means to modulate cancer cell immunogenicity by directing the presentation of particular tumor epitopes.

P2; FAP-IL2v plus atezolizumab demonstrated clinical activity and was tolerable in patients with previously treated esophageal SCC.

Administration of YU102 in the DSS-treated colitis model mice caused suppression of the NLRP3 protein levels and accompanied inflammatory cytokine release in the intestinal epithelium. Taken together, we demonstrated that inhibiting IP under inflammatory conditions induces E3 ligase TRIM31-mediated NLRP3 degradation, leading to attenuation of the NLRP3 inflammatory response that triggers disruption of intestinal barrier.

FAP-IL2v had a manageable safety profile and showed initial signs of antitumor activity in advanced/metastatic solid tumors.

P1/2, N=69, Completed, Kezar Life Sciences, Inc. | Phase classification: P1b/2 --> P1/2

P2, N=279, Recruiting, Kezar Life Sciences, Inc. | Initiation date: May 2023 --> Nov 2023

P2, N=24, Recruiting, Kezar Life Sciences, Inc. | Phase classification: P2a --> P2

P2, N=279, Recruiting, Kezar Life Sciences, Inc.

P2, N=279, Recruiting, Kezar Life Sciences, Inc. | Phase classification: P2b --> P2

These results suggest that pharmacological inhibition of the immunoproteasome may be useful in treating metastatic gastric cancers.

We define a critical role of the immunoproteasome in CRPC and propose immunoproteasome inhibition as a promising therapeutic approach to suppress CRPC progression.

In this paper, we applied the protein homeostasis disruptors bortezomib (BTZ), ONX0914, RA190 and PR619 to various MM cell lines and primary patient samples to investigate their ability to induce immunogenic cell death (ICD). The immunological relevance of blocking de-ubiquitination in MM was further reflected by the ability of PR619-induced apoptotic cells to facilitate dendritic cell (DC) maturation via type I IFN-dependent mechanisms. Altogether, our findings identify de-ubiquitination inhibition as a promising strategy for inducing ICD of MM to expand current available treatments.

P2, N=256, Terminated, Hoffmann-La Roche | Completed --> Terminated; The Sponsor discontinued the development of Simlukafusp alfa due to portfolio prioritization, not due to any safety, efficacy, or quality issues.

The anti-tumor effect of immunoproteasome inhibitor ONX 0914 was tested in mouse and human PC cells and the in vivo therapeutic efficacy of immunoproteasome inhibition was analyzed in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice in preventive and therapeutic settings and in castration-resistant (CR)PC after castration...Thus, immunoproteasome inhibition shows remarkable efficacy against PC progression in vivo and impedes tumor recurrence in CRPC-TRAMP mice by blocking the immunosuppressive inflammatory response in the tumor microenvironment. In conclusion, we show that the immunoproteasome is a promising drug target for the treatment of PC.

In an orthotopic mouse model, TMZ plus ONX-0914 reduced tumor progression better than the control or TMZ alone. These data suggest that ONX-0914 is a novel therapeutic drug for glioblastoma.

P1a/1b, N=134, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

Inhibition of immunoproteasome with ONX-0914 suppressed activity of immunoproteasome and synergized with venetoclax against primary CLL cells. Inhibition of p38 MAPK or immunoproteasome triggered apoptosis in CLL cells and overcame the resistance to venetoclax of MEC-1 VER cells and venetoclax-insensitive primary CLL cells. In conclusion, the p38 MAPK pathway and immunoproteasome represent novel targets to combat venetoclax resistance in CLL.

P1, N=83, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P1/2, N=290, Recruiting, Hoffmann-La Roche | Active, not recruiting --> Recruiting

P2, N=256, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P1/2, N=290, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Nov 2022 --> Jun 2024 | Trial primary completion date: Nov 2022 --> Jun 2024

P1a/1b, N=134, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022

Surprisingly, PR957 alone had no effects on the neuroinflammation response and the activation of TGFβ/Smad signaling in the sham-operated (BCAS-nonoperated) mice. The possible mechanism underlying this was attributed to that the immunoproteasome regulates TGFβ/Smad signaling-mediated neuroinflammation and oligodendrocyte remyelination.

P1b, N=69, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

P1/2, N=290, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

SIM in combination with ATZ demonstrated an acceptable safety profile in pts with R/M cervical SCC . The anti-tumor activity compares favorably to the approved PD-1 inhibitors in this setting and supports further exploration of IL-2v and checkpoint inhibition in this patient population of high unmet medical need.

The combination of SIM with ATZ ± BEV was feasible with an acceptable safety profile . Clinical activity was more favorable for the triplet among the study Arms, but comparable to the ATZ + BEV combination in the IMmotion151 (Rini B, et al 2019) . Observed pharmacodynamic findings were consistent with the expected effects.

P1/2, N=290, Recruiting, Hoffmann-La Roche | Trial completion date: Nov 2021 --> Nov 2022 | Trial primary completion date: Nov 2021 --> Nov 2022

Moreover, lymphoma-FRCs upregulated expression of inhibitory PD-1 ligands that reduced the anti-tumor cytolytic activity of CD8+ T cells, a T cell bispecific antibody (CD20-TCB, glofitamab) and anti-CD19 CAR T cells in our coculture models.To overcome the immunosuppressive activity of DLBCL-FRCs, we investigated the use of CD20-TCB in combination with stroma-targeting immunocytokine fusion protein drug (FAP-IL2v, RG7461) or costimulatory fusion protein (FAP-4-1BBL, RG7827). In addition, the ability of immune- /stroma- targeted combination immunotherapy to trigger anti-tumor activity and CD8+ T cell retention within the FRC-TME was demonstrated using 3D precision-cut lymph node slice-based organotypic cultures of DLBCL and other B cell malignancies.In conclusion our data reveal that lymphoma cells actively reprogram FRCs that acquire altered immunoregulatory function which prevents effective T cell motility and suppresses the anti-tumor function of cytolytic T cells. Importantly, we demonstrate that combination immunotherapy incorporating fibroblast-targeting fusion proteins could effectively recover anti-tumor T cell activity.

P1a/1b, N=134, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting

P1, N=83, Active, not recruiting, Hoffmann-La Roche | Recruiting --> Active, not recruiting | N=150 --> 83

The expression of immunoproteasome can be explored as both a prognostic factor and a potential therapeutic target in NSCLCs. Since immunoproteasomes have crucial role in the antigen presentation, further studies may help to provide essential knowledge for therapeutic strategies in anticancer immunotherapy.

P1a/1b; N=150; Recruiting; Sponsor: Hoffmann-La Roche; Trial completion date: May 2020 --> Dec 2021; Trial primary completion date: May 2020 --> Dec 2021