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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 (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.