Progress in development of iNKT cell therapeutics based on synthetic analogues of α-galactosyl ceramides — ASN Events
  1. Schedule
  2. Session 6 - Effector Function I
  3. Progress in development of iNKT cell therapeutics based on synthetic analogues of α-galactosyl ceramides

Progress in development of iNKT cell therapeutics based on synthetic analogues of α-galactosyl ceramides (#40)

Steven A Porcelli 1 , Leandro Carreno 1 , Shalu Sharma 1 , Pooja Arora 1 , Alena Donda 2 , Weiming Yuan 3 , Amy R Howell 4 , Gurdyal S Besra 5
  1. Albert Einstein College of Medicine, Bronx, NY, United States
  2. Department of Oncology, University of Lausanne, Lausanne, Epilanges, Switzerland
  3. Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA
  4. Department of Chemistry, University of Connecticut, Storrs, CT, USA
  5. School of Biosciences, University of Birmingham, Birmingham, UK

A major focus of our research is to develop approaches that will improve the potential of synthetic glycolipid activators of iNKT cells as vaccine adjuvants and agents for immunotherapy of cancer.  We have demonstrated that analogues of α-galactosyl ceramide (αGalCer) are highly effective and practical adjuvants when used with live bacterial vaccines and vectors.  Studies in mice have been undertaken to optimize this approach with live mycobacterial vaccine strains, including both attenuated Mycobacterium tuberculosis and BCG. A partially humanized mouse model (i.e., human CD1d-knock in mice) has been used to assist in narrowing the range of αGalCer analogues that are likely to be effective in vivo in humans.  This has also been used as a tool to assist in selecting optimal glycolipid analogues for moving forward into more detailed testing of adjuvant effects in nonhuman primates.  An initial study of the αGalCer glycolipid 7DW8-5 as an adjuvant with a recombinant BCG vaccine in rhesus macaques has shown this to be well tolerated and to provide potential improvements in vaccine efficacy.  In complementary studies, we have developed a novel series of photoactivatable analogues of αGalCer that we have shown can form highly stable covalent complexes with CD1d.  These compounds are being used to develop soluble CD1d-αGalCer covalent complexes that are precisely targeted to tumor specific antigens.  The major goals of this work are to create optimal methods for activating anti-infectious and anti-tumor properties of iNKT cells, without inducing anergy or other adverse effects that have been frequently observed with systemic exposure to αGalCer.