ASN-002

Description

ASN-002 is an immunotherapy based on a virus engineered to destroy cancer cells when injected directly into the cancer.   The product is based on a genetically modified form of human adenovirus type 5 – one of the viruses responsible for the common cold in humans.  In ASN-002 the virus has been engineered to express the cytokine interferon-gamma (IFN-γ) which is a protein with powerful anti-cancer and immune promoting properties.  When injected into the tumour, the adenovirus infection produces  interferon-γ and interferon-α (as a response to the viral infection) locally resulting in an immune response against the cancer in addition to shutting off the blood supply into the cancer and  causing the cancer cells to enter a process of programmed self destruction termed apoptosis.  ASN-002 has been modified to be safe as the virus will not replicate after entering the cancer cells.

Ascend will focus the initial development of ASN-002 on nodular basal cell carcinoma, the most common form of skin cancer worldwide.

ASN-002 Diagram


ASN-002 mediates Anti-angiogenic effects

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A. Ad-null treated / D4 post injection / size : 716 mm3

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B. Ad-IFN-γ treated / D17 post injection/ size : 176 mm3

 

Evaluation of the density of tumour blood vessels in B16F0 tumours that were either untreated or treated i.t. with Ad-IFN-γ. Mice from the untreated group were sacrificed 10 days after tumour cell injections which correspond to the day of i .t. injections with Ad-IFN-γ*.  The latter group of mice was sacrificed 17 days after adenovirus injections.


Adaptive and Innate Pro-inflammatory Gene expression within the tumor microenvironment induced by ASN-002

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  • Treatment with Ad-IFN-γ stimulates the expression of type I and II IFN-inducible genes (e.g., chemokines)
  • Antigen Presentation: Adenoviral vectors activate both plasmacytoid DCs and myeloid DCs
  • Adaptive Immunity: Ad-IFN-y induced genes related to lymphocytes and cellular immunity (e.g., IL2, FAS-L, TRAT1, CD69, CCL5)
  • Innate Immunity: Ad-IFN-γ induced genes related to innate immune effectors (e.g., IL8, MYD88, MICA/B, CD164, TLR1/2, IL15)

Antibody response & CD8+ T cell infiltrate induced by ASN-002

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A.

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B.

A). Immune infiltrates in a CTCL complete responder before and after ASN-002 treatment. Patient #24 at baseline (left panels) and at last visit, 4 weeks after last ASN-002 injection (right panels).

B). Immune infiltrates in a CBCL complete responder before and  after ASN-002 injections. Patient #33 at baseline (left panels) and at ( D16, right panels)


Humoral Response induced by ASN-002

  • From 15 evaluable patients, a total 16 significant increases of specific antibodies to MAGE-A1 (one increase), MAGE-A3 (two), MAGE-A9  (two),  se57-1  (one),  c-TAGE5a (one for N- and C-terminus, respectively), p53 (two), and p16 (two)
  • No correlation between antibody reactivity and clinical response either local or distant was observed in Cutaneous Lymphoma patients

For more details please download the  ASE ASN-002 Overview For more details on current clinical trials : Current Clinical Trials


References

  1. Khorana, A.A., et al., A phase I trial of immunotherapy with intratumoural adenovirus-interferon-gamma (TG1042) in patients with malignant melanoma. Cancer gene therapy, 2003. 10(4): p. 251-9.
  2. Dummer, R., et al., Adenovirus-mediated intralesional interferon-gamma gene transfer induces tumour regressions in cutaneous lymphomas. Blood, 2004. 104(6): p. 1631-8.
  3. Urosevic, M., et al., Type I IFN innate immune response to adenovirus-mediated IFN-gamma gene transfer contributes to the regression of cutaneous lymphomas. The Journal of clinical investigation, 2007. 117(10): p. 2834-46.
  4. Dummer, R., et al., Phase II clinical trial of intratumoral application of TG1042 (adenovirus-interferon-gamma) in patients with advanced cutaneous T-cell lymphomas and multilesional cutaneous B-cell lymphomas. Molecular therapy: the journal of the American Society of Gene Therapy, 2010. 18(6): p. 1244-7.
  5. Accart N et al., Lymphocytic infiltration in the cutaneous lymphoma microenvironment after injection of TG1042. J Transl Med. 2013. 11:226.
  6. Dreno B, et al., TG1042 (Adenovirus-interferon-γ) in primary cutaneous B-cell lymphomas: a phase II clinical trial. PLoS One. 2014. 9(2):e83670.
  7. Khammari A, et al., Adoptive T cell therapy combined with intralesional administrations of TG1042 (adenovirus expressing interferon-γ) in metastatic melanoma patients. Cancer Immunol Immunother. 2015. 64(7):805-15