Cancer Vaccines Gerald P. Linette, MD, PhD Divison of Oncology Siteman Cancer Center Washington University School of Medicine April 17, 2002
Tumor Immunology lies at the intersection of 2 distinct (and complex) disciplines Cancer Biology Immunology Tumor Immunology 1. Cancer Vaccines 2. Monoclonal Antibodies
Multiple cell-cell interactions influence anti-tumor immunity - primary histology (lung vs melanoma vs lymphoma) - local versus distant site
Why is there interest in cancer vaccines ?
Vaccination against microbes is efficacious and saves lives. (NEJM 345:1042, 2001)
Activation of the innate immune system can provide clinical benefit for select cancers. (Nature Immunology 2:293, 2001)
Identification of tumor antigens. (Immunity 10: 281, 1999)
New vaccination strategies. (Nature Med 4:525, 1998)
Advances in basic immunology
Tumor rejection antigens : do they truly exist?
Immunization strategies : can we generate sustained (antigen-specific) immunity against tumors?
Noble Prizes in Immunology: Impact on Tumor Immunology 1980 Benacerraf, Dausset, and Snell (immunogenetics) 1984 Milstein, Kohler, and Jerne (monoclonal antibodies) 1987 Tonegawa (antibody diversity) 1996 Doherty and Zinkernagel (MHC restriction)
II. Recent advances in basic immunology
Innate immune system
Precise monitoring of T cell immunity and the emerging model of T cell homeostasis
Tolerance as the essential determinant of anti-tumor immunity
Innate Immune System: Toll-like receptors allow pattern recognition of microbes T MHC II peptide
Immune monitoring: tetramer staining can quantitate antigen-specific CD8+ T cells MHC class I BAL fluid from Influenza virus infected mice Avidin-PE
T Cell Homeostasis: 3 distinct phases R. Ahmed
T cell frequencies in various disease states Tumors EBV infection Influenza infection Hepatitis virus P Klenerman et al., 2002
Immunologic response depends on the context of initial antigen-presentation 1. Activation -mature DC -pro-inflammatory -2 o lymphoid tissue 2. Tolerance -immature DC or other APC -non-inflammatory -non lymphoid tissue D. Pardoll
Additional mechanisms of tolerance MJ Smyth et al, 2001
Other variables that influence tolerance
III. Tumor rejection antigens: Do they really exist?
unique mutated (host-specific)
shared mutated (tumor-specific)
shared non-mutated (cancer-testis)
shared non-mutated (lineage-restricted)
JNCI 18:769, 1957 Tumor-rejection antigens are unique and not shared. What is the antigen?
Tumor-specific CD8+ CTL recognize a somatic mutation in p68 helicase (JEM 185:695, 1997) UV-induced mutation (C->T) at nt1812 generates a unique, mutated protein that is specific for this host. P5 residue is now an anchor residue for K b class I molecule. Is this a true tumor rejection antigen? HPLC Mass Spec Synthetic peptides
Ras is frequently mutated in human tumors Position 12 or 61mutated: gain of function Tumor % mutation pancreas 90 colon 40 liver 30
Mage Family - discovered in 1991 - silent in normal tissues except testis and placenta - expressed in tumors of various histologies - 13 subfamilies with 55 genes - function is unknown Chomez et al., 2001