Haval Shirwan, Ph.D.

Haval Shirwan, Ph.D.

Research Interests:

The primary focus of our translational research program in immunomodulation is to develop novel vaccines for the prevention and treatment of various immune based disorders ranging from infections, cancer, graft rejection, and autoimmunity.  To achieve this goal, we recently pioneered a patented platform technology designated as ProtEx™ that accomplishes two important goals.  First, it allows for the generation of recombinant novel immunological proteins by fusing the functional domain of any ligand of interest with a modified form of core streptavidin (SA).  The chimeric proteins exist as tetramers and higher structures, owing to the physical properties of SA, and as such have potent immune functions in soluble forms by crosslinking their respective receptors on the surface of immune cells for effective signal transduction.  These chimeric proteins, therefore, have great potential to serve as potent adjuvants for the development of subunit vaccines against cancer and infections.  Second, the chimeric proteins can transiently be displayed on the surface of any biological membrane modified with biotin taking advantage of the unsurpassed affinity of biotin for SA.  This protein display technology serves as a rapid, efficient, safe, and clinically applicable alternative to gene therapy for immunomodulation.  Using ProtEx™ technology, we generated a library of proprietary immunological ligands with distinct functions and have been testing these molecules either individually or in combination to develop “tolerogenic” vaccines for the treatment of graft rejection (including hematopoietic stem cells, pancreatic islets, and solid organs), autoimmunity (with particular focus on type 1 diabetes), and standard vaccines for the prevention and treatment of infections and cancer.

Selected peer-reviewed publications (out of 102) 

  1. Kaminitz A., E.S. Yolcu ES, J. Stein, I. Yaniv, H. Shirwan, N. Askenasy. Killer Treg restore immune homeostasis and suppress autoimmune diabetes in prediabetic NOD mice. J. Autoimmun. 37:39-47, 2011. http://www.ncbi.nlm.nih.gov/pubmed/21497486
  2. Ildstad S.T., H. Shirwan, J. Leventhal. Is durable macrochimerism key to achieving clinical transplantation tolerance? Curr. Opin. Organ. Transplant. 16(4):343-4,2011.  http://www.ncbi.nlm.nih.gov/pubmed/21681096
  3. Kaminitz A, Yolcu ES, Askenasy EM, Stein J, Yaniv I, Shirwan H, Askenasy N. Effector and naturally occurring regulatory T cells display no abnormalities in activation induced cell death in NOD mice. PLOS One 6:e21630, 2011. http://www.ncbi.nlm.nih.gov/pubmed/21738739
  4. Yolcu, E.S. H. Zhao, C. Lacelle, L. Bandura-Morgan, N. Askenasy, and H. Shirwan. Pancreatic islets engineered with SA-FasL protein establish robust localized tolerance by inducing T regulatory cells in mice. J. Immunol. 187:5901-9, 2011. http://www.ncbi.nlm.nih.gov/pubmed/22068235
  5. Askenasy, EM, Y. Shushlav, Z Sun, H. Shirwan, ES Yolcu, N. Askenasy. Engineering of bone marrow cells with Fas-ligand protein enhances donor specific tolerance to solid organs. Transplant Proc. 43:3545-8, 2011. http://www.ncbi.nlm.nih.gov/pubmed/22099838
  6. Madireddi, S., R.-H. Schabowsky, A. Srivastava, R.K. Sharma, E.S. Yolcu, and H. Shirwan. SA-4-1BBL costimulation inhibits conversion of naïve CD4+ T cells into CD4+CD25+FoxP3+ T regulatory cells by production of IFN-g. PLoS One 7:e42459, 2012. http://www.ncbi.nlm.nih.gov/pubmed/22870329
  7. Srivastava, A., R.K. Sharma, E.S. Yolcu, V. Ulker, K MacLeod, and H. Shirwan. Prime-boost vaccination with SA-4-1BBL costimulatory molecule and survivin eradicates lung carcinoma in CD8+ T and NK cell dependent manner.  PLoS One 7:e48463, 2012. http://www.ncbi.nlm.nih.gov/pubmed/23144888
  8. Zhao, H., K.B. Woodward, O. Grimany-Nuno, H. Shirwan, and E.S. Yolcu.  Post-transplant systemic immunomodulation with SA-FasL-engineered donor splenocytes has robust efficacy in preventing cardiac allograft rejection in mice. Transplant. Proc. 45:1805-7, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23769048
  9. Yolcu, E.S. H. Zhao, K. Woodward, and H. Shirwan. Immunomodulation with SA-FasL protein as an effective means of preventing islet allograft rejection in chemically diabetic NOD mice. Transplant. Proc. 45:1889-9, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23769064
  10. Yolcu, E.S., A. Kaminitz, K. Mizrahi, S. Ash, I. Yaniv, J. Stein, H.Shirwan, N. Askenasy. Immunomodulation with donor regulatory T cells armed with Fas-ligand alleviates graft versus host disease. Exp Hematol. 10:903-11, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23743300
  11. Kaminitz, A, E.S. Yolcu, K. Mizrahi, H. Shirwan, N. Askenasy. Killer Treg cells ameliorate inflammatory insulitis in non-obese diabetic mice through local and systemic immunomodulation. Int Immunol. 25:485-94, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23657001
  12. Shirwan, H, RK Sharma, AK Srivastava, and ES Yolcu. Tumor necrosis factor costimulatory ligands as adjuvant for the development of subunit cancer vaccines. OncoImmunol. 2(4):e23440, 2013 http://www.ncbi.nlm.nih.gov/pubmed/23734306
  13. Sharma, RK, ES Yolcu, AK Srivastava, and H. Shirwan.  CD4+ T cells play a critical role in the generation of primary and memory antitumor immune responses elicited by SA-4-1BBL and TAA-based vaccines in mouse tumor models. PLoS ONE 8(9): 16;8(9):e73145. doi: 10.1371/journal.pone.0073145, 2013. http://www.ncbi.nlm.nih.gov/pubmed/24066030
  14. Sharma, RK, ES Yolcu, and H. Shirwan. SA-4-1BBL as a novel adjuvant for the development of therapeutic cancer vaccines. Expert Rev. Vaccines 13:387-398, 2014. doi: 10.1586/14760584.2014.880340. http://www.ncbi.nlm.nih.gov/pubmed/24521311
  15. Hakim F, Y Wang, SX Zhang, J Zheng, ES Yolcu, A Carreras, A Khalyfa, H Shirwan, I Almendros, and D Gozal. Fragmented sleep accelerates tumor growth and progression through recruitment of tumor-associated macrophages and TLR4 signaling. Cancer Res, 1;74(5):1329-37, 2014.http://www.ncbi.nlm.nih.gov/pubmed/24448240
  16. Shirwan, H., E.S. Yolcu, R.K. Sharma, H. Zaho, and O. Grimany-Nuno.  The Direct Display of Costimulatory Proteins on Tumor Cells as a Means of Vaccination for Cancer Immunotherapy. Methods Mol Biol.1139:269-85, 2014. http://www.ncbi.nlm.nih.gov/pubmed/24619687
  17. Dinc, G, JM Pennington, ES Yolcu, MB Lawrenz, and H. Shirwan Improving the Th1 cellular efficacy of the lead Yersinia pestis rF1-V subunit vaccine using SA-4-1BBL as a novel adjuvant. Vaccine. 32(39):5035-40, 2014. http://www.ncbi.nlm.nih.gov/pubmed/25045812
  18. Srivastava, A., Dinc, G, Sharma, RK, Zhao H, Yolcu ES, and H. Shirwan SA-4-1BBL and monophosphoryl lipid A constitute an efficacious combination adjuvant for cancer vaccines. Cancer Res, 2014. http://www.ncbi.nlm.nih.gov/pubmed/25252915

 

Issued patents (out of 19)

 

  1. Shirwan, H.  Alteration of Cell Membrane with B7. US Patent 7,238,360. 06/03/07
  2. Shirwan, H., K.G. Elpek, and E.S. Yolcu. Immunostimulatory compositions and methods. US Patent 7,598,345. 10/6/2009
  3. Shirwan, H. Methods and Compositions for Expanding T Regulatory Cells. US Patent 7,745,215.  6/29/2010
  4. Shirwan, H.  Immune modulation with death-receptor-induced apoptosis. EU Patent 1250055. 9/15/10
  5. Shirwan, H. Fas ligand-avidin/streptavidin fusion proteins US Patent 7,927,602. 8/19/2011
  6. Shirwan, H., K.G. Elpek, and E.S. Yolcu. Immunostimulatory compositions and methods. US patent 8,017,582. 9/13/2011
  7. Shirwan, H. Alteration of cell membrane for new functions. EU patent 1299522. 11/2/2011
  8. Shirwan, H. Alteration of cell membrane with FasL. US patent 8,076,096, 12/13/2011
  9. Shirwan, H.  Immune modulation with death-receptor-induced apoptosis. Japanese patent JP 4898049. 01/06/2012
  10. Shirwan, H. Methods of immune modulation with death receptor-induced apoptosis. US patent 8,551,494, 10.08/2013
  11. Shirwan, H. Alteration of cell membrane for new functions. CA patent 2413237. 09/10/2013
  12. Shirwan, H. Alteration of cell membrane for new functions. US patent US patent 8,728,747, 05/20/2014