Cancer Vaccines Laboratory
Research of our laboratory is focused on the development of new and effective cancer vaccines based on a novel cancer-testis (CT) antigen, the Brother of the Regulator of Imprinted Sites (BORIS). The CT-gene BORIS was identified as a mammalian paralogue of CTCF by our current collaborators at NIAID (Loukinov D. et al., 2002; Klenova E.M. et al., 2002). BORIS is a unique epigenetically acting, tumor-promoting, transcription factor expressed in testis that may also regulate the expression of other oncogenic molecules including MAGE-A1, NY-ESO-1, and SPANX (D’Arcy V. et al., 2008; Hong J.A. et al., 2005; Kouprina N. et al., 2007; Vatolin S. et al., 2005; Woloszynska-Read A. et al., 2007). Importantly, it was recently demonstrated that silencing of the BORIS gene by specific siRNA induces apoptosis of breast cancer cells and these data suggested that BORIS may be directly involved in oncogenic transformation (Dougherty C.J. et al, 2008).
Based on these observations, the current goals of our laboratory are the understanding of biology and the mechanism of action of BORIS-based anti-cancer vaccines. To achieve these goals we developed a zinc finger deleted (mutated and non-functional) BORIS (mBORIS) antigen and analyzed its immunogenicity as well as protective and therapeutic efficacy in various animal models of cancer. Data generated in our laboratory suggest that mBORIS based vaccines are highly:
- Immunogenic – because they induce robust Th1-type of cellular immune responses, including cytotoxic T cell responses which were capable of killing BORIS expressing tumor cell lines of different histological origins in MHC class I-dependent manner (Ghochikyan A. et al., 2007)
- Protective – because they protect mice from challenge with poorly immunogenic, very aggressive, and highly metastatic mouse mammary carcinoma (Loukinov D. et al., 2006; Mkrtichyan M. et al., 2008)
- Therapeutic – because in a mouse model of 4T1 mammary carcinoma they inhibit both growth (18.75% of mice remained tumor-free) and spontaneous clonogenic metastases in the lungs (50% of mice remained metastases-free) and lower the number of tumor associated myeloid derived suppressor cells, MDSC in the tumor sites, but not in the spleens (Mkrtichyan M., et al., 2010 – submitted)
- Therapeutic – because in a Fisher 344 rat model of breast cancer (13762 MAT B III) they reject tumor growth (Laust A. et al., 2010 – submitted)
Collectively, our published and unpublished results generated with our collaborators imply that mBORIS in combination with various agents attenuating tumor associated immune suppression (MDSC and Treg cells) could be a translatable and effective cancer vaccine strategy. Several Phase I trials are planned to test the efficacy of various strategies based on non-functional target human mBORIS antigen.
- de Necochea-Campion R, Ghochikyan A, Josephs SF, Zacharias S, Woods E, Karimi-Busheri F, Alexandrescu DT, Chen CS, Agadjanyan MG, Carrier E. Expression of the epigenetic factor BORIS (CTCFL) in the human genome. J Transl Med. 2011 Dec 14;9:213.
- Mkrtichyan M, Ghochikyan A, Davtyan H, Movsesyan N, Loukinov D, Lobanenkov V, Cribbs DH, Laust AK, Nelson EL, Agadjanyan MG. Cancer-testis antigen, BORIS based vaccine delivered by dendritic cells is extremely effective against a very aggressive and highly metastatic mouse mammary carcinoma. Cell Immunol. 2011, 270(2):188-97.
- Dougherty CJ, Ichim TE, Liu L, Reznik G, Min WP, Ghochikyan A, Agadjanyan MG, Reznik BN. Selective apoptosis of breast cancer cells by siRNA targeting of BORIS. Biochem Biophys Res Commun. 2008 May 23;370(1):109-12.
- Mkrtichyan M, Ghochikyan A, Loukinov D, Davtyan H, Ichim TE, Cribbs DH, Lobanenkov VV, Agadjanyan MG. DNA, but not protein vaccine based on mutated BORIS antigen significantly inhibits tumor growth and prolongs the survival of mice. Gene Ther. 2008 Jan;15(1):61-4.
- Ghochikyan A, Mkrtichyan M, Loukinov D, Mamikonyan G, Pack SD, Movsesyan N, Ichim TE, Cribbs DH, Lobanenkov VV, Agadjanyan MG. Elicitation of T cell responses to histologically unrelated tumors by immunization with the novel cancer-testis antigen, brother of the regulator of imprinted sites. J Immunol. 2007 Jan 1;178(1):566-73.
- Zhong Z, Kusznieruk KP, Popov IA, Riordan NH, Izadi H, Yijian L, Sher S, Szczurko OM, Agadjanyan MG, Tullis RH, Harandi A, Reznik BN, Mamikonyan GV, Ichim TE. Induction of antitumor immunity through xenoplacental immunization. J Transl Med. 2006 May 25;4:22.
- Loukinov D, Ghochikyan A, Mkrtichyan M, Ichim TE, Lobanenkov VV, Cribbs DH, Agadjanyan MG. Antitumor efficacy of DNA vaccination to the epigenetically acting tumor promoting transcription factor BORIS and CD80 molecular adjuvant. J Cell Biochem. 2006 Aug 1;98(5):1037-43.
- Agadjanyan MG, Chattergoon MA, Holterman MJ, Monzavi-Karbassi B, Kim JJ, Dentchev T, Wilson D, Ayyavoo V, Montaner LJ, Kieber-Emmons T, Sekaly RP, Weiner DB. Costimulatory molecule immune enhancement in a plasmid vaccine model is regulated in part through the Ig constant-like domain of CD80/86. J Immunol. 2003 Oct 15;171(8):4311-9.