Chemo-Immunotherapy

Overview

Many cancers undergo genetic and epigeneitc alterations that subvert programmed cell death pathways as part of tumorigenesis.   These alterations can upregulate inhibitors (eg. Bcl-2, iAP) of apoptosis, or cause the loss of key cell death signalling and effector molecules (RIPK1, RIPK3, MLKL, Caspases).  The use of specific chemotherapeutic agents when combined with ASN-002 can down-regulate some of these pro-survival proteins, thereby enabling cell death programs to proceed, or provide additional cues that can engage parallel death pathways. ASN-002 chemotherapy combinations can also induce immunogenic cell death leading to potent anti-cancer immune responses.

Local expression of IFNγ can lead to:

  • The induction of cell death program in many cancer cell types e.g., induction of death receptors (FAS/FAS-L/TNFR) & build up of Reactive oxygen species (ROS)
  • ER Stress gene expression: XBP-1; CHOP; ATF4 – causes autophagic cell death
  • The induction of pro-apoptosis proteins: PUMA; CHOP, BAX, BID, DP5, caspases – causes apoptosis
  • The induction of both innate and adaptive immune response programs: chemokines, MHC, cytokines leading to enhanced innate & adaptive immune responses (E.g., Granzyme/Perforin CD8+ T cells and NK cells)

Recent data generated by Ascend has demonstrated that ASN-002 chemo-combinations can overcome defects in specific programmed cell death pathways, overcoming deficiencies and inducing cell death in cancer cells that may have defective caspase pathways, and also cancer cells that have specific defects in the RIPK1/RIPK3 axis.

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Chemo-Immunotherapy can provide significant clinical benefit and the induction of a systemic immune response.  The use of intra-lesional chemo-Immunotherapy that drives immunogenic cell death can potentially convert local tumours into highly potent multi-epitope (neo and shared epitope) cancer vaccines without the need for personalized sequencing & in silico neoantigen identification and selection strategies.