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  • 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)
  • Today’s Discussion
    • Historical Perspective
    • Advances in basic immunology
    • Tumor rejection antigens : do they truly exist?
    • Immunization strategies : can we generate sustained (antigen-specific) immunity against tumors?
  • Old, 1996
  • 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
    • age
    • co-morbid illness
    • medications
    • tumor burden
  • III. Tumor rejection antigens: Do they really exist?
    • unique mutated (host-specific)
            • p68 helicase
    • shared mutated (tumor-specific)
            • ras
    • shared non-mutated (cancer-testis)
            • MAGE family
    • shared non-mutated (lineage-restricted)
            • gp100/tyrosinase/MART1
  • 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
  • Vaccine Design
    • whole cell
    • protein (includes DNA)
    • peptide
    • conventional (alum, emulsions, microbial products, liposomes)
    • cytokines
    • dendritic cells
    • blockade of negative regulatory molecules
    Antigen + Adjuvant = VACCINE
  • Current Cancer Vaccine Studies in Patients 156 clinical vaccine trials are currently open in the US clinical trials.gov (April 16, 2002)
  • IV. Immunization Strategies: Can we generate sustained antigen-specific immunity?
    • Dendritic cells as adjuvants (Mayordomo)
    • Blockade of negative regulatory cell surface molecules and depletion of Treg cells (Sutmuller)
    Pre-clinical studies
  • Therapeutic immunization for established tumors Effector:target ratio DC/Mut1 DC/control Mayordomo et al. 1995, Nature Med. In vitro cytotoxicity assay
  • Tumor burden influences response to immunization Percent tumor-free Start of DC immunization (days post-tumor graft) Therapeutic Immunization -Peptide antigen -DC hyper-immunization -minimal tumor burden
  • Depletion of CD25+ Treg prior to vaccination promotes the rejection of melanoma in tumor bearing mice Day: -4 0 0,3,6 Anti-CD25 mAb B16/GM-CSF VAX given sc Anti-CTLA4 mAb Irradiated B16/GM-CSF melanoma vaccine Survival NO  CD25 Vax+  CTLA4 Vax+  CD25 Vax+  CD25+  CTLA4 Vax+  CD25+  CTLA4 Vax+  CTLA4  CD25 Vax alone is ineffective Sutmuller, JEM 2001
  • Therapeutic efficacy correlates with increased frequency of antigen-specific CTL Tetramer analysis Intracellular staining * * *
  • Clinical studies
    • Peptide with dendritic cells as adjuvants in melanoma vaccine (Nestle)
    • idiotype protein with GM-CSF as adjuvant in lymphoma vaccine (Bendandi)
  • Dendritic cell vaccination in humans F Nestle et al, 2001
  • Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells F.O. Nestle et al. Nature Med 4:328, 1998
    • Phase I clinical trial (n=16) in stage 4 melanoma using autologous DC.
    • Patients were immunized with 1x10 6 DC by direct injection into an uninvolved lymph node qweek x6.
    • 5 objective responses were recorded (2CR, 3PR) by week 10. Immunological reactivity to melanoma antigens was documented in 11 patients.
    • Treatment was safe, well-tolerated and feasible.
  • Clinical Trials for Melanoma: First Generation Dendritic Cell Vaccines
  • Idiotype serves as a tumor antigen
  • Complete molecular remissions induced by patient-specific vaccination plus GM-CSF against lymphoma M Bendandi et al. Nature Med 5:1171, 1999
    • Phase I/II clinical trial (n=20) in low-grade, stage III/IV NHL who achieved CR after combination chemotherapy.
    • Patients were immunized with Ig protein conjugated to KLH (beginning at 6 mo) q mo x 4
    • Immunological reactivity was seen in 19/20 patients.
    • 18/20 patients remain in first CR (median 42 mo; range 28-53+).
  • 8 (of 11) patients had a molecular CR after vaccination
  • Summary
    • Antigen identification and new vaccination strategies have been instrumental in advancing our knowledge of cancer vaccines.
    • Vaccines for melanoma and lymphoma show encouraging results.
    • Vaccines for other malignancies such as breast, colon, lung, and prostate carcinoma are in early stage clinical trials.
  • Summary
    • Past: cancer vaccine clinical trials have been conducted in patients with advanced (metastatic) disease.
    • Future: cancer vaccines will most likely be used as adjuvant therapy for patients with minimal or no measurable disease.