nibrozetone (RRx-001)

Nanoprodrugs orchestrate a sophisticated cascade of immune activation through four synergistic mechanisms: 1) size-switchable disassembly upon glutathione/ cholesterol exposure for deep tumor penetration; 2) redox imbalance driven by reactive nitrogen species accumulation and glutathione depletion via the synergistic action of oxaliplatin, ferrocene, and RRx-001 for ferroptosis augmentation; 3) immunogenic cell death induction via ferroptosis-apoptosis to initiate tumor immunity cycle, promoting T cell infiltration; and 4) T cell function reinvigoration with the downregulation of programmed cell death protein 1 and T-cell immunoglobulin 3 expression through cholesterol depletion in TME. This integrated approach achieved primary and distant tumor growth suppression, established durable immune memory against recurrence, and systemically enhanced the antitumor immunity. By concurrently targeting tumor immunogenicity, TME immunosuppression, and T cell exhaustion, this multidimensional strategy represents a transformative advancement in cancer immunotherapy.

In conclusion, this study systematically characterizes the clinical and immunological associations of CD47 across multiple cancers and highlights its potential role in pancreatic adenocarcinoma, supporting the further investigation of CD47 as a therapeutic target.

In this study, we propose a Gas-Metal Synergy Strategy, which integrates immune activation and biosafety, by engineering a pH-responsive manganese-based zeolitic imidazolate framework (named MRPH) nanoplatform co-loaded with the nitric oxide (NO) donor RRX-001...Both in vitro and in vivo studies demonstrate that MRPH significantly enhances gas-amplified metalloimmunotherapy. This work pioneers a low-toxicity paradigm that integrates gas therapy and metal-based immunotherapy, offering a transformative approach to solid tumor immunotherapy.

To further counter immune evasion, we encapsulated the CD47/SIRPα inhibitor RRX-001 into reactive oxygen species (ROS)-responsive carriers, yielding RRX@RCD...In CT26 tumor-bearing mice, RRX@RCD achieved superior tumor regression, doubled median survival. Overall, RRX@RCD synchronizes innate and adaptive immune activation, offering a safe and potent nanomedicine strategy for durable antitumor immunity.

The therapeutic effects can be further improved through encapsulation of RRx-001, a small molecule inhibitor of the CD47-SIRPα signaling. Compared to the antibody approach, the synthetic nanoparticle approach offers greater efficacy with lower side effects and enables combination therapy through a simple formulation. Moreover, the approach is versatile and could be adapted for targeting other ICB signaling, advancing the next generation of cancer immunotherapy.

Compared to the classical Gasdermin D (GSDMD)-mediated pyroptosis that has been extensively explored for cancer immunotherapy, the direct induction of Gasdermin E (GSDME) pyroptosis has been rarely reported, likely due to the well-recognized reduced GSDME levels in solid tumors. This nanoplatform, CDDP/1-bromoacetyl-3,3-dinitroazetidine (RRx-001) @iRGD-Pla-Exo nanoparticles (CRRPE NPs) leads to almost complete tumor eradication in a Hepa1-6-luc orthotopic liver cancer model by activating macrophages, and can be combined with the commercially available programmed death ligand 1 (PD-L1) antibody immunomodulator to maintain T cells' effector function for a prolonged survival lifetime. Overall, this study provides a conceptual advance in revealing the role of chemotherapy in mediating tumor cell pyroptosis and immune cell activation.

RRx-001 reduces the viability of HCC cells and induces apoptosis. This effect may be due to the downregulation of CD47 expression and the alteration of the TP53 protein regulatory pathway.

P2, N=53, Completed, EpicentRx, Inc. | Phase classification: P2a --> P2

P3, N=292, Active, not recruiting, EpicentRx, Inc. | Recruiting --> Active, not recruiting

P1, N=2, Terminated, EpicentRx, Inc. | N=24 --> 2 | Trial completion date: Dec 2024 --> Jul 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Jul 2024; Low Enrollment

To overcome these issues, in this study, we have developed a multifunctional Immunosome where αCD40 is conjugated on the surface and RRX-001, a small molecule immunomodulator was encapsulated inside it...In addition, Immunosomes treated long-term surviving mice showed tumor specific immune memory response which prevented tumor growth upon rechallenge. Our results suggested that this novel formulation can be further explored in clinics to improve in vivo anti-tumor efficacy of αCD40 with long-lasting tumor specific immunity while reducing the associated toxicities.

Our pre-basic found excellent anti-tumor effects of c-di-AMP and RRx-001, respectively, and we further explored whether they could be combined synergistically for anti-tumor immunotherapy...Moreover, the combination of the two presented more powerful pro-vascular normalization and reversed tumor immunosuppression than the drug alone. This study demonstrates a new design option for anti-tumor combination therapy and the potential of tumor environmentally responsive hydrogel scaffolds in combination with anti-tumor immunotherapy.