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Tumor Immunology Xue-Feng Bai, MD, Ph.D. Division of Cancer Immunology Department of Pathology The Ohio State University Email:

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

Important features of the immune system • Innate immunity & adaptive immunity • Response to foreign antigens • Self tolerance • Immunological memory

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 molecules 4. Effector molecules

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 tumor targets (antigens) available? 3. Can immune system be utilized to attack cancer? 4. What are the obstacles for effective cancer immunotherapy?

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.

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 molecules and then do peptide sequencing 3. SEREX: serological analysis of recombinant complementary DNA (cDNA) expression library 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 (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)

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, 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 anti-tumor effects Activation of complement


Blocking growth factor

Induction of apoptosis

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 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

Dudley ME, et al: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850-854.

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 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.

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

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)

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)

Questions related to this talk 1.

What are the current themes of cancer immunotherapy?


What are the current obstacles for developing cancer immunotherapy?


What methods are being used for monitoring anti-cancer T cell responses?

Tumorimm224 (bai)