This document discusses tumor immunity and immunotherapy approaches for cancer. It covers: - Tumor antigens that can be recognized by the immune system, including tumor-specific antigens from mutations and tumor-associated antigens normally expressed. - Components of the innate and adaptive immune response against tumors, like T cells, macrophages, and cytokines. - Mechanisms of "tumor escape" from immune recognition like downregulating MHC proteins. - Immunotherapy approaches including vaccines targeting tumor antigens, immune modulation using cytokines or other agents, oncolytic viruses, and passive transfer of immune cells like antibodies or T cells.

1. Tumor immunity
Immunopatology of autoimmune
diseases

4. • Neoplastic transformations are genetic
alterations.
• Expression of cell surface antigens – both self
and non-self - seen by immune system.
• Ehrlich – positive mechanism eliminating
transformed cells.
• L.Thomas, McFarlane – immune surveillance -
recognition and destruction of non-self tumor
cells on their appearance.
• Tumor occurrence: immune surveillance is
imperfect.

8. Tumor Specific Antigen
•TSA – mutations of somatic cells induced by
chemical carcinogenesis or x-rays
•Each carcinogenic factor induces a unique and
specific class of antigens.
•TSA is the result of somatic mutations which is
recognized (according to the individual MHC
haplotype) by the immune system.

9. Tumor Associated Antigen
Products (e.g. hormones, growth factors, cell
surface receptors, differentiation molecules
etc.) of both normal and altered cells during
their differentiation.
Production of TAAs is not related with
tumorous transformation exclusively, but
expression profile of TAAs could be
characteristic in some tumours, and useful
as „tumor markers” in differential diagnosis
or in the monitoring of therapeutic efficiency.

10. Naspin A in bone metastasis of lung adenocarcinoma.

12. AFP Alpha (a)-fetoprotein
AIM-2 Interferon-inducible protein absent in
melanoma 2
ALL Acute lymphoblastic leukemia
AML Acute myeloid leukemia
707-AP 707 alanine proline
APL Acute promyelocytic leukemia
ART-4 Adenocarcinoma antigen recognized byT
cells 4
BAGE B antigen
bcr-abl Breakpoint cluster region- Abelson
CAMEL CTL-recognized antigen on melanoma
CAP-1 Carcinoembryonic antigen peptide-1
CASP-8 Caspase 8
CDC27 Cell division cycle 27
CDK4 Cyclin-dependent kinase 4
CEA Carcinoembryonic antigen
CLCA2 Calcium-activated chloride channel 2
CML Chronic myelogenous leukemia
CT Cancer-testis (antigen)
CTL Cytotoxic T lymphocytes
Cyp-B Cyclophilin B
DAM Differentiation antigen melanoma (the
epitopes of DAM-6 and DAM-10 are equivalent,
but the gene sequences are different. DAM-6 is
also called MAGE-B2 and DAM-10 is also called
MAGE-B1)
ELF2 Elongation factor 2
Ep-CAM Epithelial cell adhesion molecule
EphA2, 3 Ephrin type-A receptor 2,3
Ets E-26 transforming specific (family of
transcription factors)
ETV6-AML1 Ets variant gene 6 / acute myeloid
leukemia 1 gene ETS
FGF-5 Fibroblast growth factor 5
FN Fibronectin
G250 Glycoprotein 250
GAGE G antigen
GnT-V N-Acetyl glucosaminyl transferase
Gp100 Glycoprotein 100 kDa
HAGE Helicase antigen
HER-2/neu Human epidermal receptor
2/neurological
HLA-A*0201-R170I Arginine (R) to isoleucine (I)
exchange at residue 170 of the a-helix of the a2-
domain in the HLA-A2 gene
H/N Head and neck
HSP70-2 M Heat shock protein 70-2 mutated
HST-2 Human signet-ring tumor 2
hTERT Human telomerase reverse transcriptase
iCE Intestinal carboxyl esterase
IL-13Ra2 Interleukin 13 receptor a2 chain
KIAA0205 Name of the gene as it appears in
databases
LAGE L antigen
LDLR/FUT Low density lipid receptor /
GDP-L-fucose:b-D-galactosidase
2-a-L-fucosyltransferase
MAGE Melanoma antigen
MART-1/Melan-A Melanoma antigen recognized
by T cells-1 / melanoma antigen A
MART-2 Melanoma Ag recognized by T cells-2
MC1R Melanocortin 1 receptor
M-CSF Macrophage colony-stimulating factor
gene
MHC Major histocompatibility complex
MSI Microsatellite instability
MUC1, 2 Mucin 1, 2
MUM-1, -2, -3 Melanoma ubiquitous mutated 1,
2, 3
NA88-A NA cDNA clone of patient M88
Neo-PAP Neo-poly(A) polymerase
NPM/ALK Nucleophosmin/anaplastic lymphoma
kinase fusion protein
NSCLC Non–small cell lung carcinoma
NY-ESO-1 New York esophageous1
OA1 Ocular albinism type 1 protein
OGT O-Linked N-acetylglucosamine transferase
gene
ORF Open reading frame
OS-9 Name of the gene as it appears in
databases
P15 Protein 15
p190 minor bcr-abl Protein of 190-kDa bcr-abl
Pml/RARa Promyelocytic leukemia / retinoic acid
receptor a
PRAME Preferentially expressed antigen of
melanoma
PSA Prostate-specific antigen
PSMA Prostate-specific membrane antigen
PTPRK Receptor-type protein-tyrosine
phosphatase kappa
RAGE Renal antigen
RCC Renal cell carcinoma
RU1, 2 Renal ubiquitous 1, 2
SAGE Sarcoma antigen
SART-1, -2, -3 Squamous antigen rejecting
tumor 1, 2, 3
SCC Squamous cell carcinoma
SSX-2 Synovial sarcoma, X breakpoint 2
Survivin-2B Intron 2-retaining survivin
SYT/SSX Synaptotagmin I /synovial sarcoma, X
fusion protein
TAA Tumor-associated antigen
TEL/AML1 Translocation Etsfamily
leukemia/acute myeloid leukemia 1
TGFbRII Transforming growth factor b receptor 2
TPI Triosephosphate isomerase
TRAG-3 Taxol resistant associated protein 3
TRG Testin-related gene
TRP-1 Tyrosinase-related protein 1, or gp75
TRP-2 Tyrosinase-related protein 2
TRP-2/INT2 TRP-2/intron 2
TRP-2/6b TRP-2/novel exon 6b
TSTA Tumor-specific transplantation antigens
WT1

16. Immune response against tumors
• Component s of both innate and adaptive
immunity (iNKT, MAIT, iγδT cells)
• T cell mediated immune response (CD8+,
CD4+Th1, γδT cells, NK, NK T cells)
• Macrophage mediated immune response
• immunoglobulin mediated (ADCC)
• Network of citotoxic cytokines

19. Innate and adaptive immune cell mediated tumoricidal activities.
-GalCer, -galactosylceramide; DC, dendritic cell; TAA, tumor-associated antigen.

20. „Tumor escape”
• Downregulation or owerexpression of MHC class I.
• Owerexpression of FcRs.
• Failed cytokine receptors.
• Masking and blocking glykoproteines.
• Production of tumor associated cytokines.
• Blocking cytokines produced by macrophages or
dendritic cells.

22. Tumor-associated cytokines inhibit anti-tumor immunity. IL10, TGFß, and vascular
endothelial growth factor (VEGF), can inhibit the maturation and activation of antigen-
presenting dendritic cells (DC) as well as regulate the generation of effector and/or
regulatory T cells.

24. TIMs present MHC class II:tumor peptide ligands to specific Th1 cells and induce them to produce IFN-γ. In
addition, by upregulating CD40 ligand, these activated Th1 cells ligate CD40 receptors on TIMs and induce
them to secrete IL-12; IL-12 then triggers IFN-γ production by NKs. Low MHC class I–expressing tumor cells
also activate high-avidity tumor-specific CTLs and NKs (unengaged iNKRs + activated aNKRs) to produce IFN-γ.
By upregulating classical and nonclassical MHC class I expression by tumor cells, IFN-γ, promotes activation of
iNKRs on NKs and anti-tumor CTLs and turns off their cytotoxic effector function.

26. Immunotherapeutic possibilities
• immunotargeting against TAAs
• Immunomodulation
• Tumour vaccines
• Oncolythic viruses

27. Incidence and mortality of cancer types in Europe. Data from GLOBOCAN 2008
[WHO Europe Region], International Agency for Research on Cancer, WHO.

28. Immunotherapy of tumors
a c t i v e
non-specific
BCG, Propionibacterium
acnes, levamisole,
cytokine genes, etc.
specific
killed tumor cells or their
extract, recombinant
antigens, idiotype, co-
stimulatory molecule
genes, etc.
p a s s i v e
nonspecific LAK cells, cytokines
specific
antibodies alone or
coupled to drugs, pro-
drug toxins or
radioisotope; bispecific
antibodies; T-cells
combined
LAK cells and bispecific
antibody
* BCG: Bacillus Calmette Geurin is a bovine strain of Mycobacterium tuberculosis.

29. Non-specific active immunotherapy:
biological response modifiers (BRMs)
type of BRM examples major effect
bacterial product
BCG, P. acnes,
muramyl di-peptide,
trehalose dimycolate
activate macrophages
and NK cells (via
cytokines)
synthetic molecules
pyran, poly I:C,
pyrimidines
induce interferon
production
cytokines
interferon-alpha, -beta, -
gamma, IL-2, TNF
activate macrophages
and NK cells

30. Cytokine therapy of tumors
cytokine tumor type and result antitumor mechanism(s)
IFN-alpha, beta
remission of hairy cell
leukemia, weak effect on
some carcinomas
increased expression of class
I MHC, possible cytostatic
anti-tumor effect,
IFN-gamma
remission of peritoneal
carcinoma of ovary:
ineffective systemically
increased MHC antigens;
macrophage, Tc and NK cell
activation
IL-2
remission in renal
carcinoma and
melanoma
T-cell proliferation and
activation, NK cells activation
TNF-alpha
can reduce malignant
ascites
macrophage and lymphocyte
activation

31. Mistletoe lectin
Two chains of the Viscum
Album Agglutinin-I (VAA-I) :
• „A chain” (29 kD) strong
ribosoma inactivator by the
N-glikosidase activity.
• Sugar binding „B cahian”
(34 kD) is responsible for the
imunomodulant activity.

32. Opportunities for adaptive immunotherapy and cancer vaccines.
Tg, transgenic; TH cell, T helper cell.

34. Recruitment of dendritic cells by DNA vaccine of
GM-CSF

36. Immunotoxin therapy

37. Immunotoxin Therapy of Hairy Cell Leukemia
with BL22

38. HER-2/neu