Pipeline  ›  Cancer Signaling
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Overview
Autoimmune Treg Activator
Fibrosis (lung and liver)
Cancer Signaling
Novel TLR4 agonist-STAT3 P705 activator

Cancer Signaling

A new approach blocking the upregulation of Tumor Released Exosomes (TRE)

Exosomes are small extracellular vesicles that originate in and are shed from cancer cells to carry out, or influence, almost all pathogenic actions of tumor cells:

Exosomal release is a normal cellular function that is highly upregulated in cancer, releasing 10-to-100-fold elevated amounts of exosomes. The field of exosome research has produced abundant literature on these processes, and exosomes are increasingly recognized as central mediators in cancer formation, progression, metastasis, metabolic dysregulation, and resistance to both chemotherapies and checkpoint inhibitors.

Schematic of Vimentin's roles in exosomal biogenesis and release and impacts of ALD-R491

By targeting vimentin, ALD-R491 modulates the mechanics and transport of exosomes inside a tumor cell, an action that blocks packaging of payloads into exosomes as well as their trafficking across the cell and release through exocytosis.

In in vitro studies, ALD-R491 reduces exosome release in multiple cell lines and has been shown to reduce the impact of vimentin in the epithelial-mesenchymal transition (EMT).

In vivo models must be based on syngeneic tumor models (grown, not implanted) to have intact immune systems that present the setting where immune response is redirected by uTRE communication, and the ALD-R491 effect can be observed.

Quantification of ALD-R491 effect on tumor-released exosomes

Literature shows that upregulated Tumor Released Exosomes (uTRE) enable resistance, direct and promote metastasis, deliver checkpoints systemically in a manner that escapes immunotherapy, and drive metabolic dysregulation that leads to cachexia. In in vivo data, ALD-R491 reduced signs of systemic disease in a 30-day model with an immediate benefit in health, a successful reduction in weight loss (anti-cachexia), and an increased survival of 50%.

These actions may be present in a small cohort of compassionate use patients in China. In six end-stage cancer patients who had not responded to surgery or multiple other agents, ALD-R491 demonstrated a profile similar to in vivo evidence, with immediate response in general health, and anti-tumor and systemic disease benefits that increased the longer patients were on ALD-R491. This was not a formal clinical trial, and cannot be used to establish statistically significant efficacy or safety, but is suggestive of potential activity worthy of further exploration. In three of the six patients who were able to take ALD-R491 longer term, a similar correspondence to in vivo data was seen that included reduction in tumor size, number of metastatic loci, and other measures of systemic disease through physician clinical assessments (weight, immune blood panels, and cancer biomarkers). No adverse events led to a discontinuation in these compassionate use patients.

Compassionate Use / FDA Expanded Access

ALD-R491 is now available for compassionate use in appropriate cases under physician direction through the FDA process for Expanded Access. For more information, please email us at Copied!.

References

Early papers on functions and forms of exosomes

Exosomes enable resistance (escape from existing drugs and defeat of immune surveillance)

Exosomes play a critical role in all systemic manifestations of cancer

...in directing cancer metastasis to specific organs

...in enabling the delivery of pro-cancer payloads into other cells in a critical early mechanobiological step in metastasis

...in metabolic adaptation required for cancer cells to survive

...in delivering inflammatory mediators that serve as potent inducers of EMT

Recognition of the role of Vimentin across the tumor microenvironment

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