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Tumor Immunology

Xue-Feng Bai, MD, Ph.D.

Division of Cancer Immunology

Department of PathologyThe Ohio State University

Email: [email protected]


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Reference

The basic science of oncologyChapter 20: Cancer and immune system

Chapter 21: Biological therapy of cancer

Science, 2002, 298:850

J Clin. Invest. 2003, 111: 1487


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Important features of the immune system

Innate immunity & adaptive immunity

Response to foreign antigens

Self tolerance

Immunological memory


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Players of the Immune system

-Cells that mediate innateimmunity
http://www.sciencemag.org.proxy.lib.ohio-state.edu/content/vol305/issue5681/images/large/zse0270426710001.jpeghttp://www.sciencemag.org.proxy.lib.ohio-state.edu/content/vol305/issue5681/images/large/zse0270426710001.jpeghttp://www.sciencemag.org.proxy.lib.ohio-state.edu/content/vol305/issue5681/images/large/zse0270426710001.jpeghttp://www.sciencemag.org.proxy.lib.ohio-state.edu/content/vol305/issue5681/images/large/zse0270426710001.jpeg


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Players of the immune system

-Cells that mediate adaptive immunity


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Key molecules involved in immune response

1. T cell receptor

2. MHC molecules

3. Co-stimulatory molecules

4. Effector molecules


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T cell receptor (TCR)


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MHC molecules


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Figure 5-11


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Figure 5-13

MHC polymorphism


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The Function of MHC-Antigen Presentation


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Figure 5-17


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T cell activation-Two signals required


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T cell development in the Thymus


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Positive & Negative selection of T cells

-Central tolerance


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Peripheral T cell tolerance


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Questions in tumor

immunology1. Does immune system play a role in

the control of cancer?2. Are sufficient tumor targets

(antigens) available?

3. Can immune system be utilized toattack cancer?

4. What are the obstacles for effectivecancer immunotherapy?


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Does immune system play a role in the

control of cancer?

Increased cancer incidence inimmuno-compromised patients.

Occasional spontaneous regressionsof cancers in immunocompetent

hosts.

D i t l l i th


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Does immune system play a role in the

control of cancer?

Schreiber et al: Nature 2001, 410: 1107


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Low affinity T cells can be activated

to reject tumor


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Are sufficient tumor targets (antigens) available?


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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


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cancerimmunity.org

Human tumor antigen data base

Human Tumor Antigens


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Figure 14-11 part 1 of 2

Human Tumor Antigens


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Figure 14-11 part 2 of 2


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Can immune system be util ized to attack cancer?


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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)


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Production of mAb-hybridoma technique

Production of humanized mAb


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Production of humanized mAb


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Antibody therapy of cancer

1. Rituximab (anti-CD20)-B-cell non-Hodgkins 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

Mechanisms of antibody-mediated


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anti-tumor effects

Activation of complement

ADCC

Blocking growth factor

Induction of apoptosis

Other developments for Ab-therapy of cancer


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Other developments for Ab therapy of cancer

Adoptive T cell therapy of cancer
http://www.jem.org/content/vol200/issue12/images/large/20042004f1.jpeghttp://www.jem.org/content/vol200/issue12/images/large/20042004f1.jpeg


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p py

Riddell SR. 2004. J Exp Med 200: 1533-1537

Adoptive T cell therapy of cancer
http://www.jem.org/content/vol200/issue12/images/large/20042004f1.jpeghttp://www.jem.org/content/vol200/issue12/images/large/20042004f1.jpeghttp://www.jem.org/content/vol200/issue12/images/large/20042004f1.jpeg


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Adoptive cell therapy of cancerThe most promising immunotherapy for solid tumors. >50% of patientswith metastatic melanoma refractory to other therapies obtainedobjective 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


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Dudley ME, et al: Cancer regression

and autoimmunity in patients after

clonal repopulation with antitumor

lymphocytes.Science 298:850-854.


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Cytokine therapy of cancer

IFN-alpha: 90% hairy cell leukemia

IL-2: Renal cell carcinoma, melanoma

IL-15: ?

Cancer vaccination


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Cancer vaccination

DNA vaccination


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DNA vaccination

Tumor cell vaccine


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Tumor cell vaccine

Dendritic cell vaccine


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Dendritic cell vaccine

Monitoring T cell response-Tetramer


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Functional evaluation of T cell response

-ELISAspot assay


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-ELISAspot assay

Nat re Medicine 10 909 915 (2004)


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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 tumorimmunology in the past decade, but optimism about theclinical application of currently available cancer vaccineapproaches is based more on surrogate endpoints than

on clinical tumor regression. In our cancer vaccine trialsof 440 patients, the objective response rate was low(2.6%), and comparable to the results obtained byothers. We consider here results in cancer vaccine trials

and highlight alternate strategies that mediate cancerregression in preclinical and clinical models.


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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-restrictedTr1: TGF- producer (class II-restricted)Th3: IL-10 producer (class II-restricted)NKT: (CD1d-restricted) IL-13 producer

3. Immune evasion

How cancer cells evade CTL responses in vivo?


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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 Med157, 1040-52, 1983)

5. Loss of co-stimulation molecules (Zheng et al, Cancer Res

59, 3461-67, 1999)


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6. Tumors and/or their surrounding stroma mayproduce immunosuppressive factors such as

TGF- (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 (OConnell 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)


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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?

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