Cancer Vaccines Gerald P. Linette, MD, PhD Divison of Oncology Siteman Cancer Center Washington University School of Medic...
Tumor Immunology lies at the intersection of 2 distinct (and complex) disciplines Cancer Biology   Immunology   Tumor Immu...
Multiple cell-cell interactions influence  anti-tumor immunity   - primary histology (lung vs melanoma vs lymphoma) - loca...
Why is there interest in cancer vaccines ?   <ul><li>Vaccination against microbes is efficacious and saves lives.  (NEJM 3...
Today’s Discussion <ul><li>Historical Perspective </li></ul><ul><li>Advances in basic immunology </li></ul><ul><li>Tumor  ...
Old, 1996
Noble Prizes in Immunology: Impact on Tumor Immunology 1980 Benacerraf, Dausset, and Snell   (immunogenetics) 1984 Milstei...
II. Recent advances in basic immunology <ul><li>Innate immune system </li></ul><ul><li>Precise monitoring of T cell immuni...
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 v...
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., ...
Immunologic response  depends on the context of initial antigen-presentation 1.  Activation -mature DC -pro-inflammatory  ...
Additional mechanisms of tolerance MJ Smyth et al, 2001
Other variables that influence tolerance <ul><li>age </li></ul><ul><li>co-morbid illness </li></ul><ul><li>medications </l...
III. Tumor rejection antigens:  Do they really exist?   <ul><li>unique mutated (host-specific) </li></ul><ul><ul><ul><ul><...
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 nt...
Ras is frequently mutated in human tumors Position 12 or 61mutated: gain of function   Tumor   % mutation pancreas 90 colo...
Mage Family   - discovered in 1991 - silent in normal tissues except testis and placenta - expressed in tumors of various ...
Vaccine Design <ul><li>whole cell </li></ul><ul><li>protein (includes DNA) </li></ul><ul><li>peptide </li></ul><ul><li>con...
Current Cancer Vaccine Studies in Patients 156 clinical  vaccine  trials are currently open in the US clinical trials.gov ...
IV. Immunization Strategies:  Can we generate sustained   antigen-specific immunity? <ul><li>Dendritic cells as adjuvants ...
Therapeutic immunization for established tumors Effector:target ratio DC/Mut1 DC/control Mayordomo et al. 1995, Nature Med...
Tumor burden influences response to immunization Percent tumor-free Start of DC immunization (days post-tumor graft) Thera...
Depletion of CD25+ Treg prior to vaccination promotes the rejection of melanoma in tumor bearing mice Day: -4 0 0,3,6 Anti...
Therapeutic efficacy correlates with increased frequency of antigen-specific CTL Tetramer analysis Intracellular staining ...
Clinical studies <ul><li>Peptide with dendritic cells as adjuvants in melanoma vaccine (Nestle) </li></ul><ul><li>idiotype...
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,...
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. Natur...
8 (of 11) patients had a molecular CR after vaccination
Summary <ul><li>Antigen identification  and new  vaccination strategies  have been instrumental in advancing our knowledge...
Summary <ul><li>Past: cancer vaccine clinical trials have been conducted in patients with advanced (metastatic) disease. <...
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  1. 1. Cancer Vaccines Gerald P. Linette, MD, PhD Divison of Oncology Siteman Cancer Center Washington University School of Medicine April 17, 2002
  2. 2. Tumor Immunology lies at the intersection of 2 distinct (and complex) disciplines Cancer Biology Immunology Tumor Immunology 1. Cancer Vaccines 2. Monoclonal Antibodies
  3. 3. Multiple cell-cell interactions influence anti-tumor immunity - primary histology (lung vs melanoma vs lymphoma) - local versus distant site
  4. 4. Why is there interest in cancer vaccines ? <ul><li>Vaccination against microbes is efficacious and saves lives. (NEJM 345:1042, 2001) </li></ul><ul><li>Activation of the innate immune system can provide clinical benefit for select cancers. (Nature Immunology 2:293, 2001) </li></ul><ul><li>Identification of tumor antigens. (Immunity 10: 281, 1999) </li></ul><ul><li>New vaccination strategies. (Nature Med 4:525, 1998) </li></ul>
  5. 5. Today’s Discussion <ul><li>Historical Perspective </li></ul><ul><li>Advances in basic immunology </li></ul><ul><li>Tumor rejection antigens : do they truly exist? </li></ul><ul><li>Immunization strategies : can we generate sustained (antigen-specific) immunity against tumors? </li></ul>
  6. 6. Old, 1996
  7. 7. 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)
  8. 8. II. Recent advances in basic immunology <ul><li>Innate immune system </li></ul><ul><li>Precise monitoring of T cell immunity and the emerging model of T cell homeostasis </li></ul><ul><li>Tolerance as the essential determinant of anti-tumor immunity </li></ul>
  9. 9. Innate Immune System: Toll-like receptors allow pattern recognition of microbes  T MHC II peptide
  10. 10. Immune monitoring: tetramer staining can quantitate antigen-specific CD8+ T cells MHC class I BAL fluid from Influenza virus infected mice Avidin-PE
  11. 11. T Cell Homeostasis: 3 distinct phases R. Ahmed
  12. 12. T cell frequencies in various disease states Tumors EBV infection Influenza infection Hepatitis virus P Klenerman et al., 2002
  13. 13. 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
  14. 14. Additional mechanisms of tolerance MJ Smyth et al, 2001
  15. 15. Other variables that influence tolerance <ul><li>age </li></ul><ul><li>co-morbid illness </li></ul><ul><li>medications </li></ul><ul><li>tumor burden </li></ul>
  16. 16. III. Tumor rejection antigens: Do they really exist? <ul><li>unique mutated (host-specific) </li></ul><ul><ul><ul><ul><ul><li>p68 helicase </li></ul></ul></ul></ul></ul><ul><li>shared mutated (tumor-specific) </li></ul><ul><ul><ul><ul><ul><li>ras </li></ul></ul></ul></ul></ul><ul><li>shared non-mutated (cancer-testis) </li></ul><ul><ul><ul><ul><ul><li>MAGE family </li></ul></ul></ul></ul></ul><ul><li>shared non-mutated (lineage-restricted) </li></ul><ul><ul><ul><ul><ul><li>gp100/tyrosinase/MART1 </li></ul></ul></ul></ul></ul>
  17. 17. JNCI 18:769, 1957 Tumor-rejection antigens are unique and not shared. What is the antigen?
  18. 18. 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
  19. 19. Ras is frequently mutated in human tumors Position 12 or 61mutated: gain of function Tumor % mutation pancreas 90 colon 40 liver 30
  20. 20. 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
  21. 21. Vaccine Design <ul><li>whole cell </li></ul><ul><li>protein (includes DNA) </li></ul><ul><li>peptide </li></ul><ul><li>conventional (alum, emulsions, microbial products, liposomes) </li></ul><ul><li>cytokines </li></ul><ul><li>dendritic cells </li></ul><ul><li>blockade of negative regulatory molecules </li></ul>Antigen + Adjuvant = VACCINE
  22. 22. Current Cancer Vaccine Studies in Patients 156 clinical vaccine trials are currently open in the US clinical trials.gov (April 16, 2002)
  23. 23. IV. Immunization Strategies: Can we generate sustained antigen-specific immunity? <ul><li>Dendritic cells as adjuvants (Mayordomo) </li></ul><ul><li>Blockade of negative regulatory cell surface molecules and depletion of Treg cells (Sutmuller) </li></ul>Pre-clinical studies
  24. 24. Therapeutic immunization for established tumors Effector:target ratio DC/Mut1 DC/control Mayordomo et al. 1995, Nature Med. In vitro cytotoxicity assay
  25. 25. 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
  26. 26. 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
  27. 27. Therapeutic efficacy correlates with increased frequency of antigen-specific CTL Tetramer analysis Intracellular staining * * *
  28. 28. Clinical studies <ul><li>Peptide with dendritic cells as adjuvants in melanoma vaccine (Nestle) </li></ul><ul><li>idiotype protein with GM-CSF as adjuvant in lymphoma vaccine (Bendandi) </li></ul>
  29. 29. Dendritic cell vaccination in humans F Nestle et al, 2001
  30. 30. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells F.O. Nestle et al. Nature Med 4:328, 1998 <ul><li>Phase I clinical trial (n=16) in stage 4 melanoma using autologous DC. </li></ul><ul><li>Patients were immunized with 1x10 6 DC by direct injection into an uninvolved lymph node qweek x6. </li></ul><ul><li>5 objective responses were recorded (2CR, 3PR) by week 10. Immunological reactivity to melanoma antigens was documented in 11 patients. </li></ul><ul><li>Treatment was safe, well-tolerated and feasible. </li></ul>
  31. 31. Clinical Trials for Melanoma: First Generation Dendritic Cell Vaccines
  32. 32. Idiotype serves as a tumor antigen
  33. 33. Complete molecular remissions induced by patient-specific vaccination plus GM-CSF against lymphoma M Bendandi et al. Nature Med 5:1171, 1999 <ul><li>Phase I/II clinical trial (n=20) in low-grade, stage III/IV NHL who achieved CR after combination chemotherapy. </li></ul><ul><li>Patients were immunized with Ig protein conjugated to KLH (beginning at 6 mo) q mo x 4 </li></ul><ul><li>Immunological reactivity was seen in 19/20 patients. </li></ul><ul><li>18/20 patients remain in first CR (median 42 mo; range 28-53+). </li></ul>
  34. 34. 8 (of 11) patients had a molecular CR after vaccination
  35. 35. Summary <ul><li>Antigen identification and new vaccination strategies have been instrumental in advancing our knowledge of cancer vaccines. </li></ul><ul><li>Vaccines for melanoma and lymphoma show encouraging results. </li></ul><ul><li>Vaccines for other malignancies such as breast, colon, lung, and prostate carcinoma are in early stage clinical trials. </li></ul>
  36. 36. Summary <ul><li>Past: cancer vaccine clinical trials have been conducted in patients with advanced (metastatic) disease. </li></ul><ul><li>Future: cancer vaccines will most likely be used as adjuvant therapy for patients with minimal or no measurable disease. </li></ul>
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