In TRAIL-sensitive colon cancer cells (COLO205, HCT-116), P-cDR5 showed efficacy comparable to anti-DR5 mAb Drozitumab (DRO), but P-cDR5 outperformed DRO in TRAIL-resistant cells (HT-29), highlighting the importance of efficient receptor clustering...Combining P-cDR5 with valproic acid, a histone deacetylase inhibitor, resulted in further enhancement of apoptosis inducing efficacy, along with destabilizing mitochondrial membranes and increased sensitivity of TRAIL-resistant cells. These findings suggest that attaching multiple cDR5 peptides to a flexible water-soluble polymer carrier not only overcomes the limitations of previous designs but also offers a promising avenue for treating resistant cancers, pointing toward the need for further preclinical exploration and validation of this innovative strategy.

Proof-of-concept studies showed that Conatumumab, an agonistic TRAIL-R2 antibody, promoted vascular sprouts from explanted patient arteries. Single-cell RNA sequencing revealed heparin-binding EGF-like growth factor in mediating EC-pericyte communications dependent on TRAIL. These studies highlight unique TRAIL-dependent mechanisms mediating neo-angiogenesis and vessel stabilization and the potential of repurposing TRAIL-R2 agonists to stimulate stable and functional microvessel networks to treat ischemia in PAD.

The combination of DR5 agonists and commonly used chemotherapeutic agents, such as doxorubicin, can promote cell death...There are currently two ongoing clinical trials focusing on the activation of DR5, namely, IGM-8444 and INBRX-109, which have progressed to phase 2. Further modifications of TRAIL delivery with fusion to single-chain variable fragments (scFv-TRAIL), directed against tumor-associated antigens (TAAs), and in the use of stem cells focus on targeted TRAIL delivery to cancer cells using bi-functional strategies. In vitro, in vivo, and clinical trials, as well as advances in imaging and theranostics, indicate that targeting DR5 remains a valid strategy in the treatment of some relapsed and refractory cancers.

P1, N=272, Active, not recruiting, IGM Biosciences, Inc. | Recruiting --> Active, not recruiting | N=430 --> 272

P1, N=40, Active, not recruiting, AbbVie | Trial completion date: Jul 2024 --> Jan 2025 | Trial primary completion date: Jul 2024 --> Jan 2025

P1, N=40, Active, not recruiting, AbbVie | Phase classification: P1b --> P1 | Trial completion date: Oct 2024 --> Jul 2024 | Trial primary completion date: Oct 2024 --> Jul 2024

The chemically modified TRA-8 antibody [anti-death receptor 5 (DR5) antibody] with PEG-lipid (DSPE-PEG) demonstrated significant cytotoxic activity in vitro without the need for crosslinking with a secondary antibody, which is typically required...Nevertheless, by designing new PEG-lipids that are intended to be resistant to enzymatic degradation, we were able to prevent this degradation and restore the cytotoxic activity of the modified antibody. These findings provide valuable insights for the design of PEG-lipid-modified antibodies and suggest their potential effectiveness in enhancing cancer therapy.

P2, N=201, Recruiting, Inhibrx, Inc. | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Feb 2024 --> Dec 2024

P1, N=240, Recruiting, Inhibrx, Inc. | Trial completion date: Dec 2024 --> Jul 2026 | Trial primary completion date: Aug 2024 --> Dec 2025

P1, N=13, Completed, Boehringer Ingelheim | Terminated --> Completed

Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.

P1, N=430, Recruiting, IGM Biosciences, Inc. | Trial completion date: Jan 2027 --> Aug 2027 | Trial primary completion date: Nov 2026 --> Jun 2026

P1, N=110, Completed, Boehringer Ingelheim | Active, not recruiting --> Completed

P1, N=13, Terminated, Boehringer Ingelheim | Phase classification: P1a/1b --> P1 | Trial completion date: Mar 2024 --> Oct 2023 | Active, not recruiting --> Terminated; Company decision

P1, N=430, Recruiting, IGM Biosciences, Inc.

P1, N=110, Active, not recruiting, Boehringer Ingelheim | Trial primary completion date: Jan 2024 --> Jul 2023

P1, N=430, Recruiting, IGM Biosciences, Inc. | Phase classification: P1a/1b --> P1

P1a/1b, N=13, Active, not recruiting, Boehringer Ingelheim | Trial primary completion date: Mar 2024 --> Oct 2023

The identified immune risk signature was demonstrated to be associated with the favorable immune infiltration, prognosis and immunotherapeutic efficacy, which may provide clues for survival evaluation and immune treatment.

Collectively, our findings demonstrate that treatment with CPT in combination with Dox exerts synergistic antitumor effects through activation of the caspase cascade pathway, a mechanism that is partly dependent on the Dox-induced upregulation of death receptor 4 and death receptor 5. Therefore, CPT combined with Dox may be a feasible therapeutic strategy for the management of TNBC.

INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase 2 trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.

Irinotecan (IRI) and temozolomide (TMZ) are frequently used in the relapsed setting, but prognosis remains poor. INBRX-109+IRI/TMZ led to high response rates in pts with EWS (71%) and DSRCT (33%), with an ORR of 60% in cohort C3; no grade ≥2 hepatotoxicity or significant AEs leading to discontinuation were observed. Our findings support further evaluation of INBRX-109+IRI/TMZ in these tumors. Cohort C3C is now enrolling (n≈10) at the RP2D of 3 mg/kg.

Herein, we report that SDH-def tumors are sensitive to TMZ, which induces ER stress and upregulates DR5, a pro-apoptotic receptor that can be targeted by INBRX-109 (Figure 1). In turn, TMZ+INBRX-109 additively/synergistically reduces SDH-def GIST cell viability in vitro. These data provide the preclinical evidence for a Phase I clinical trial (3+3 dose escalation design with two dosing cohorts, NCT03715933) to study the safety/tolerability of TMZ+INBRX-109 in patients with aggressive SDH-def cancers, including GIST (Figure 2).

Designed to achieve a best-in-class therapeutic index, INBRX-109 induces robust apoptosis of cancer cells in vitro and in vivo while sparing healthy tissues. INBRX-109 was well tolerated and had anti-tumor activity in unresectable/metastatic conventional chondrosarcoma in a phase I study and is currently being evaluated in a blinded, placebo-controlled pivotal phase II trial.

Ga-C2Am showed predominantly renal clearance and low retention in the liver, spleen, small intestine, and bone and generated a tumor-to-muscle (T/m) ratio of 2.3 ± 0.4, at 2 h post probe administration and at 24 h following treatment. Ga-C2Am has the potential to be used in the clinic as a PET tracer for assessing early treatment response in tumors.

These data indicate that combination therapy with eftoza plus venetoclax to simultaneously activate the extrinsic and intrinsic apoptosis-signaling pathways may improve clinical benefit compared with venetoclax monotherapy in relapsed/refractory AML with an acceptable toxicity profile. Registered at www.clinicaltrials.gov as NCT03082209.

This Phase Ia/Ib, open-label, multicenter study (NCT05087992) aims to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDE), pharmacokinetics (PK), and efficacy of BI 905711 with CT (FOLFIRI; irinotecan, leucovorin, and fluorouracil) ± bevacizumab (BEV) in pts with advanced GI cancers...In the CRC cohort, pts with prior progression on oxaliplatin-based therapy will be randomized 2:1 to receive FOLFIRI and BEV ± BI 905711. In the PDAC cohort, pts with CDH17+ PDAC with prior progression on gemcitabine-based first-line therapy will receive FOLFIRI + BI 905711...The study is ongoing. Clinical trial information: NCT05087992.

In heavily pretreated pts, BI 905711 was associated with a tolerable safety profile and early signs of disease control. BI 905711 will be further assessed in Phase Ib in 4 dose groups: 0.6/1.2/2.4 mg/kg every 14 days, and 0.6 mg/kg weekly. Clinical trial information: NCT04137289.

The DR5 agonist antibody AMG655 (Conatumumab) was selected as an example of TRAIL-based therapy...We proposed two independent strategies to overcome this issue: (1) a proof-of-concept targeting of RIPK1 by shRNA approach and (2) the use of a novel highly-potent TRAIL-receptor agonist; both shifting the balance in favor of apoptosis. These observations are paving the way to resurrect TRAIL-based therapies in pediatric bone tumors to help predict the response to treatment, and propose a relevant adjuvant strategy for future therapeutic development.

Conclusions BI 905711 showed a tolerable safety profile with favourable PK properties. Early signs of disease control in these heavily pretreated pts was observed and will be further assessed in phase Ib in 4 dose groups: 0.6/1.2/2.4 mg/kg every 14 days, and 0.6 mg/kg weekly.

No abstract available

Subsequent MEDI3039 combination-screening of TRAIL-R2, caspase-8, FADD and BID knockout models with 60 compounds with varying mechanisms-of-action identified 2 inhibitor of apoptosis proteins (IAPs) that exhibited strong synergy with MEDI3039 that could reverse resistance only in BID-deleted models. In summary, we identify the ratios of caspase-8:FLIP(L) and caspase-8: MCL-1 as potential predictive biomarkers for second generation TRAIL-R2 agonists and loss of key effectors like FADD and caspase-8 as likely drivers of clinical resistance in solid tumors.

P1, N=153, Completed, AbbVie | Active, not recruiting --> Completed

Taken together, the preclinical efficacy of ONC201 and TLY012 represents a novel therapeutic option for further testing in pancreatic cancer patients. This combination showed marked efficacy in tumor cells that are both sensitive and resistant to the pro-apoptotic effects of ONC201, providing rationale to further investigate the combination of ONC201 plus TLY012 in patients with pancreatic cancer.

In preclinical assays, BI 905711 demonstrated a potency shift of ̃1000 fold versus the 1st-generation TRAILR2 agonist lexatumumab. Secondary endpoints include PK parameters and OR in pts with measurable disease (phase Ia), and disease control, tumor shrinkage, duration of response, and progression-free survival (phase Ib). Trial enrollment is ongoing, with 33 pts enrolled to date.

P1, N=153, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting | Trial completion date: Aug 2022 --> Feb 2022 | Trial primary completion date: Aug 2022 --> Feb 2022

P1, N=12, Completed, NYU Langone Health | Active, not recruiting --> Completed | N=36 --> 12 | Trial completion date: Mar 2024 --> Jan 2021

FLIP inhibitors also demonstrated in vitro efficacy in combination with KRAS G12C inhibitors in KRAS G12C mutant NSCLC and in vitro and in vivo efficacy in combination with the 3rd generation EGFR inhibitor Osimertinib in EGFR mutant NSCLC. We have also observed single agency nM efficacy in lymphoma and leukemia models and significant efficacy in combination with standard-of-care chemotherapeutics in KRAS mutant colorectal and pancreatic cancers.In summary, we have identified novel FLIP-targeted activators of caspase-8 with a unique mechanism-of-action and the potential for use in the treatment of several human cancers and leukemias either as a single agent, or in combination with standard-of-care chemotherapeutics and other clinically-relevant targeted agents.

Responders to BI 905711 were identified primarily within the classical and quasi-basal/hybrid subtypes when TRAILR2 was adequately co-expressed. This correlates with an enrichment pattern of CDH17 gene expression that is mostly within the classical gene cluster and strongly anti-correlated with basal-like cluster enrichment.Robust preclinical anti-tumor activity of BI 905711 in TRAILR2 and CDH17-expressing PDAC PDX models, along with this antibody’s potential for a favorable safety profile, has justified the enrollment of pancreatic cancer patients in the ongoing BI 905711 FIH Phase I clinical trial (NCT04137289).

In DLBCL cell line-derived xenograft (CDX) preclinical models, we observed combination activity of ABBV-621 with pevonedistat (PEV) a selective NEDD8 inhibitor. Additionally, synergistic activity was observed with ABBV-621 with either bendamustine (BED) or rituximab (RTX) alone, or BED/RTX together...The pre-clinical data presented here support expanding the indications and settings where ABBV-621 may have utility. A clinical trial assessing the activity of ABBV-621 in combination with bortezomib and dexamethasone in R/R MM patients is planned.

Addition of APG-1387 potentiated this effect, with the combination treatment leading to T/C values of 3% to 15%, and complete regression, PR, or stable disease in all treated tumors. In summary, our results suggest great potential of combination therapy with APG-1387 and CTB-006 for solid tumor therapy and deserves further clinical investigation.