Focus

Sindbis viral vectors (SV Vectors) target and kill cancer cells in small animal studies by simultaneously activating the immune system and targeting specific tumors. CYN102, our lead SV vector candidate, targets late-stage ovarian cancer cells. Ovarian cancer therapies are currently an unmet medical need. This treatment is designed by engineering a Sindbis vector with a tumor-associated antigen (TAA), NYESO-1, to promote a memory T cell response. NYESO-1 is naturally found in approximately 25–45% of melanoma, lung, esophageal, liver, gastric, prostate, ovarian, and bladder cancers and 80% of synovial sarcomas. NYESO-1 expression is associated with the more highly aggressive ovarian tumors.


How it works

Sindbis virus (SV) vectors use the subject’s body to help fight cancer tumors. When administered systemically by injection, Sindbis can simultaneously target tumor cells throughout the body and activate the subject’s immune system. Both processes can help eradicate the cancerous cells. In pre-clinical animal studies, SV vectors have achieved up to a 90% survival in animals growing various cancers. Further, the treatment with SV vectors can elicit a long-term memory response that makes the treated hosts resistant to tumor re-growth. Cynvec is currently planning Phase I clinical studies to begin in 2021.

Most oncolytic vectors in use today are administered intratumorally, owing to barriers that prevent systemic targeting, which include dilution of the virus in the bloodstream, neutralization by antiviral antibodies and complement proteins, and virus particle sequestration in liver. These barriers do not impact systemic administration of SV to a significant degree. Because SV is a blood-borne virus with a relatively long half-life, SV vectors can be administered systemically and reach tumor cells throughout the body, targeting tumors without infecting normal tissues.

Cynvec’s first clinical indication targets epithelial ovarian cancer (EOC). The SV vector CYN102 has been shown to successfully prolong survival and cure ovarian cancer in mice. This vector encodes the tumor-associated antigen NYESO-1, present in approximately 25–45% of human ovarian, melanoma, lung, esophageal, liver, gastric, prostate, and bladder cancers, and 80% of synovial sarcomas. See references 1-5 below.

While EOCs are “immunogenic tumors” that produce spontaneous antitumor immune responses detectable in peripheral blood, and the presence of tumor-infiltrating lymphocytes (TILs) in tumors and ascites of patients is associated with improved survival, a number of factors impair the presence or activity of TILs in EOC, thereby facilitating cancer progression. SV vectors can overcome some of these limitations.

Mechanistically, SV vectors also elicit a potent, long-lasting, diversified anti-tumor immune response that boosts neoantigen-specific cytotoxic T cells to eradicate tumors and prevent recurrence. They are more effective when combined with immunomodulatory antibodies, like anti-OX40, anti-PD-1 and anti-CTLA4. Mechanistically, the combination of systemically administered SVs and immunomodulatory antibodies markedly changes the transcriptome signature and metabolic program of T cells, driving the development of highly activated, terminally differentiated, effector T cells. These metabolically reprogrammed T cells demonstrate enhanced tumor infiltration capacity as well as anti-tumor activity throughout the body, overcoming the repressive tumor microenvironment. This represents an important step forward in treating tumors with low mutational load (i.e., neoantigens) and fewTILs (“cold”).

Delivery
Sindbis is administered systemically by IV or IP.
  • No intra-tumoral injections
  • Systemic administration possible allowing Sindbis to reach all major organs of the body and metastatic tumor cells
Efficacy
Up to 90% cancer remission achieved in animal models
  • Capable of achieving complete remission and prevention of tumor recurrences in animal studies
  • Effective without payload, enhanced anti-tumor activity with payload
  • Resistant to tumor re-challenge
Specificity
Sindbis targeting hones on all developing cancers tumors.
  • Ability to target tumor cells throughout the body while sparing healthy cells
  • Ability to induce a long lasting and effective memory T cell response

References

1. Schwab, C. L., D. P. English, D. M. Roque, M. Pasternak, and A. D. Santin. 2014. Past, present and future targets for immunotherapy in ovarian cancer. Immunotherapy 6: 1279-1293.

2. Vaughan, H. A., S. Svobodova, D. Macgregor, S. Sturrock, A. A. Jungbluth, J. Browning, I. D. Davis, P. Parente, Y. T. Chen, E. Stockert, F. St Clair, L. J. Old, and J. Cebon. 2004. Immunohistochemical and molecular analysis of human melanomas for expression of the human cancer-testis antigens NY-ESO-1 and LAGE-1. Clin Cancer Res 10: 8396-8404.

3. Caballero, O. L., and Y. T. Chen. 2009. Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci 100: 2014-2021.

4. Esfandiary, A., and S. Ghafouri-Fard. 2015. New York esophageal squamous cell carcinoma-1 and cancer immunotherapy. Immunotherapy 7: 411-439.

5. Fourcade, J., P. Kudela, Z. Sun, H. Shen, S. R. Land, D. Lenzner, P. Guillaume, I. F. Luescher, C. Sander, S. Ferrone, J. M. Kirkwood, and H. M. Zarour. 2009. PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol 182: 5240-5249.