0
Tumor Immunology

     Xue-Feng Bai, MD, Ph.D.
  Division of Cancer Immunology
     Department of Pathology
     The Ohio ...
Reference
• The basic science of oncology
  Chapter 20: Cancer and immune system
  Chapter 21: Biological therapy of cance...
Important features of the immune system


• Innate immunity & adaptive immunity

• Response to foreign antigens

• Self to...
Players of the Immune system
  -Cells that mediate innate
           immunity
Players of the immune system
-Cells that mediate adaptive immunity
Key molecules involved in immune response


     1. T cell receptor

     2. MHC molecules

     3. Co-stimulatory molecul...
T cell receptor (TCR)
MHC molecules
Figure 5-11
MHC polymorphism
   Figure 5-13
The Function of MHC-Antigen Presentation
Figure 5-17
T cell activation-Two signals required
T cell development in the Thymus
Positive & Negative selection of T cells
-Central tolerance
Peripheral T cell tolerance
Questions in tumor
        immunology
1. Does immune system play a role in
    the control of cancer?
2. Are sufficient tu...
Does immune system play a role in the
control of cancer?

• Increased cancer incidence in
  immuno-compromised patients.

...
Does immune system play a role in the
control of cancer?




               Schreiber et al: Nature 2001, 410: 1107
Low affinity T cells can be activated
to reject tumor
Are sufficient tumor targets (antigens) available?
Identification of cancer antigen

1. Use T cells to screen cDNA library

2. Use acid to elute peptides from MHC
   molecul...
cancerimmunity.org

Human tumor antigen data base
Human Tumor Antigens

Figure 14-11 part 1 of 2
Figure 14-11 part 2 of 2
Can immune system be utilized to attack cancer?
Immunotherapy of cancer


Passive immunotherapy:

       Antibodies (standard therapy in certain cancer)
       cytokines ...
Production of mAb-hybridoma technique
Production of humanized mAb
Antibody therapy of cancer

1. Rituximab (anti-CD20)-B-cell non-Hodgkin’s lymphoma

2. CAMPATH 1H (CDw52)-CLL, Prolymphocy...
Mechanisms of antibody-mediated
anti-tumor effects

                            Activation of complement




             ...
Other developments for Ab-therapy of cancer
Adoptive T cell therapy of cancer




            Riddell SR. 2004. J Exp Med 200: 1533-1537
Adoptive T cell therapy of cancer
The most promising immunotherapy for solid tumors. >50% of patients
with metastatic mela...
Dudley ME, et al: Cancer regression
 and autoimmunity in patients after
 clonal repopulation with antitumor
 lymphocytes.
...
Cytokine therapy of cancer



IFN-alpha: 90% hairy cell leukemia

IL-2: Renal cell carcinoma, melanoma

IL-15: ?
Cancer vaccination
DNA vaccination
Tumor cell vaccine
Dendritic cell vaccine
Monitoring T cell response-Tetramer
Functional evaluation of T cell response
  -ELISAspot assay
Nature Medicine 10, 909 - 915 (2004)
 Cancer immunotherapy: moving beyond current vaccines
  Steven A Rosenberg, James C Y...
Obstacles of current T cell-based therapy of cancer


     1. Self-tolerance

     2. Suppressor cells

            Myeloi...
How cancer cells evade CTL responses in vivo?

1. Immune ignorance (Wick et al, J EXP Med 186, 229-38, 1997;
   Ochsenbein...
How cancer cells evade CTL responses in vivo?



6. Tumors and/or their surrounding stroma may
   produce immunosuppressiv...
Questions related to this talk
1.   What are the current themes of cancer immunotherapy?

2.   What are the current obstac...
Tumor Immunology
Upcoming SlideShare
Loading in...5
×

Tumor Immunology

2,240

Published on

0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
2,240
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
142
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide

Transcript of "Tumor Immunology"

  1. 1. Tumor Immunology Xue-Feng Bai, MD, Ph.D. Division of Cancer Immunology Department of Pathology The Ohio State University Email: Xue-Feng.Bai@osumc.edu
  2. 2. Reference • The basic science of oncology Chapter 20: Cancer and immune system Chapter 21: Biological therapy of cancer • Science, 2002, 298:850 • J Clin. Invest. 2003, 111: 1487
  3. 3. Important features of the immune system • Innate immunity & adaptive immunity • Response to foreign antigens • Self tolerance • Immunological memory
  4. 4. Players of the Immune system -Cells that mediate innate immunity
  5. 5. Players of the immune system -Cells that mediate adaptive immunity
  6. 6. Key molecules involved in immune response 1. T cell receptor 2. MHC molecules 3. Co-stimulatory molecules 4. Effector molecules
  7. 7. T cell receptor (TCR)
  8. 8. MHC molecules
  9. 9. Figure 5-11
  10. 10. MHC polymorphism Figure 5-13
  11. 11. The Function of MHC-Antigen Presentation
  12. 12. Figure 5-17
  13. 13. T cell activation-Two signals required
  14. 14. T cell development in the Thymus
  15. 15. Positive & Negative selection of T cells -Central tolerance
  16. 16. Peripheral T cell tolerance
  17. 17. Questions in tumor immunology 1. Does immune system play a role in the control of cancer? 2. Are sufficient tumor targets (antigens) available? 3. Can immune system be utilized to attack cancer? 4. What are the obstacles for effective cancer immunotherapy?
  18. 18. Does immune system play a role in the control of cancer? • Increased cancer incidence in immuno-compromised patients. • Occasional spontaneous regressions of cancers in immunocompetent hosts.
  19. 19. Does immune system play a role in the control of cancer? Schreiber et al: Nature 2001, 410: 1107
  20. 20. Low affinity T cells can be activated to reject tumor
  21. 21. Are sufficient tumor targets (antigens) available?
  22. 22. Identification of cancer antigen 1. Use T cells to screen cDNA library 2. Use acid to elute peptides from MHC molecules and then do peptide sequencing 3. SEREX: serological analysis of recombinant complementary DNA (cDNA) expression library
  23. 23. cancerimmunity.org Human tumor antigen data base
  24. 24. Human Tumor Antigens Figure 14-11 part 1 of 2
  25. 25. Figure 14-11 part 2 of 2
  26. 26. Can immune system be utilized to attack cancer?
  27. 27. Immunotherapy of cancer Passive immunotherapy: Antibodies (standard therapy in certain cancer) cytokines (e.g. IL2/IL15, IFN-alpha) Cells (Adoptive transfer of autologous T cells) Active immunotherapy: Allogeneic bone marrow transplantation (GVH) Specific tumor vaccines (i.e. peptides, idiotype vaccine etc) Assisted antigen presentation (DC)
  28. 28. Production of mAb-hybridoma technique
  29. 29. Production of humanized mAb
  30. 30. Antibody therapy of cancer 1. Rituximab (anti-CD20)-B-cell non-Hodgkin’s lymphoma 2. CAMPATH 1H (CDw52)-CLL, Prolymphocytic leukemia 3. Bevacizumab (VEGF)-metastatic colorectal cancer 4. Trastuzumab (HER2/NEU)-breast cancer 5. Edrecdomab (EPCAM-1, KSA)-Colon cancer
  31. 31. Mechanisms of antibody-mediated anti-tumor effects Activation of complement ADCC Blocking growth factor Induction of apoptosis
  32. 32. Other developments for Ab-therapy of cancer
  33. 33. Adoptive T cell therapy of cancer Riddell SR. 2004. J Exp Med 200: 1533-1537
  34. 34. Adoptive T cell therapy of cancer The most promising immunotherapy for solid tumors. >50% of patients with metastatic melanoma refractory to other therapies obtained objective responses. Rosenberg SA et al. Nature Med 2004, 10:909 Advantages •High numbers of T cells can be generated in vitro •T cells are activated in vitro, therefore bypass immune tolerance •Select high avidity, antigen specific T cells •Manipulate the host Problems •Labor intensive, technically demanding and expensive •Adoptively transferred T cells fail to persist •Tumor evasion
  35. 35. Dudley ME, et al: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850-854.
  36. 36. Cytokine therapy of cancer IFN-alpha: 90% hairy cell leukemia IL-2: Renal cell carcinoma, melanoma IL-15: ?
  37. 37. Cancer vaccination
  38. 38. DNA vaccination
  39. 39. Tumor cell vaccine
  40. 40. Dendritic cell vaccine
  41. 41. Monitoring T cell response-Tetramer
  42. 42. Functional evaluation of T cell response -ELISAspot assay
  43. 43. Nature Medicine 10, 909 - 915 (2004) Cancer immunotherapy: moving beyond current vaccines Steven A Rosenberg, James C Yang & Nicholas P Restifo Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.
  44. 44. Obstacles of current T cell-based therapy of cancer 1. Self-tolerance 2. Suppressor cells Myeloid suppressor cells (MSC) Granulocyte suppressors (GS) TR (CD4+CD25+) Ts: Qa-1-restricted Tr1: TGF-β producer (class II-restricted) Th3: IL-10 producer (class II-restricted) NKT: (CD1d-restricted) IL-13 producer 3. Immune evasion
  45. 45. How cancer cells evade CTL responses in vivo? 1. Immune ignorance (Wick et al, J EXP Med 186, 229-38, 1997; Ochsenbein et al, Proc Natl Acad Sci USA 96, 2233-8, 1999) 2. Induce clonal anergy of tumor-specific T cells (Shrikant et al, Immunity 11, 483-93, 1999) 3. Down-regulation of antigen presentation (Zheng et al, Nature 396, 373-376, 1998; Seliger et al, Immunol Today 18, 292-9, 1997) 4. Loss of tumor antigen expression (Uyttenhove et al, J Exp Med 157, 1040-52, 1983) 5. Loss of co-stimulation molecules (Zheng et al, Cancer Res 59, 3461-67, 1999)
  46. 46. How cancer cells evade CTL responses in vivo? 6. Tumors and/or their surrounding stroma may produce immunosuppressive factors such as TGF-β (Singh et al, J Exp Med 175:139-146, 1992) 7. Expression of FasL on tumor cells can induce apoptosis of T cells entering the site of tumor growth (O’Connell et al, J Exp Med 184:1075-82, 1996; Strand et al, Nature Med 2:1361-70, 1996; Hahne et al, Science 274:1363-1366, 1996; Andreola et al, J Exp Med 195:1303-1316, 2002)
  47. 47. Questions related to this talk 1. What are the current themes of cancer immunotherapy? 2. What are the current obstacles for developing cancer immunotherapy? 3. What methods are being used for monitoring anti-cancer T cell responses?
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×