Cancer Immunotherapy

Type of tumor: -Non-invasive (benign) - Invasive (malignant)

Tumor antigens: 1)Tumor-specific transplantation antigens(TSTAs) 2)Tumor-associated transplantation antigens(TATAs)

TSTAs & TATAs: GeneHLAT.tissueN.tissue MUC1A11Breast & Ovarian None HPV-E7DR*0401Cervical carcinoma none AFPA2 Hepatocellular carcinoma Fetal liver GnT-vA2 Melanoma & Brain tumor Breast & Brain(low exp.)

Tumor evasion of the immune system: Immunosupression Modulation of tumor antigens Reduction in class I MHC molecules Lack of co-stimulatory signal

Cancer treatment options ► Surgical excision ● Only valuable in early stages ● Restricted to solid tumor ► Radiotherapy ● Only feasible in localized and non-metastatic cases ► Chemotherapy ● Last option in advanced cases ● Unique approach in heamatologic malignancies ● Non-specific cytotoxicity with unbearable side effects

Cancer Immunotherapy: Manipulation of co-stimulatory signal(B7) Enhancement of APC activity(GM-CSF, TNFα, IL4 & BCG) Cytokine therapy INFs: HLA, proliferation & Tc act. TNF : Reducing in tumor proliferation & angio. IL2 : T cell & NK cell activity Monoclonal Ab. T-cell based vaccines

Monoclonal Antibodies A) Mouse B) Human  Diagnostic Viral and bacterial antigens and antibodies Tissue typing (HLA and Rh,…) Imaging or localization of tumors  Treatment and Prophylaxis Tumors (as therapeutic agents) Infectious diseases (Hepatitis B,…) Other diseases (HDN)  Investigating the immune system in health and disease B/T cell repertoire Red cell antigens Tumor antigens

Mouse Monoclonal Antibody Mouse + Ag Spleen Cells fusion Mouse Myelomas HAT selection Fused Clones screening and limiting dilution Monoclonal Antibody

Human Monoclonal Antibody Human + Ag PBMC immortalization with EBV Screening Specific BLCL + heterohybridomas (mouse x human) HAT + Ouabain Fused Clones Screening and Limiting Dilution Monoclonal Hybrid

Recombinant Antibodies

AntibodyTrade nameTarget antigenIndication RituximabMabthera ® CD20 Treatment of relapsed or refractory low-malignancy non-Hodgkin lymphoma TrastuzumabHerceptin ® HER-2 Treatment of chemotherapy refractory breast cancer GemtuzumabMylotarg TM CD33 Treatment of relapsed acute myeloid leukemia in eldery patients Monoclonal antibodies approved for clinical use

Problems and possible solutions to Mab immunotherapy of cancer in humans: Tumors not antigenic in mice Use of Adj. Tumor antigens present in normal tissue Selec. of mAb Presence of circulating free tumor antigen Inc. doses of Ab Modulation of tumor antigen Use of mixtures or diff. Ab Immune response to foreign mAb Use of M-H chimeric Ab Low effection to solid tumor Use of bifunctional Ab

T cell-based therapies ► Donor lymphocyte infusion ●Protection against leukemia relapse after bone marrow transplantation ► Mini-transplants ● Allogenic T cell instead of whole bone marrow ● Used in elderly patients ● Also valuable in patients with transplant contra-indications ►Tumor vaccines

Principle of cancer vaccination

Dendritic cell-based strategies: DC + tumor lysate DC + purified peptide Transfection of DC with tumor gene DC + Tumor cell fusion

Clinical trials: Dose toxicity titration studies to determine maximum safely tolerated dose phase I Determination of most effect antitumor activity at doses chosen from phase I … phase II Comparison of treatment protocols with new agent … phase III Application of effective new therapy protocol into general oncology practice … phase IV

ProductBasic descriptionPrimary indicationStatus Cytotherapeutic agents Therapeutic vaccines Osidem TM Macrophages + anti-Her2/neu bispecific antibody Ovarian cancerPhase III Eladem TM (IDD-1) Dendritic cells + PSAProstate cancerPhase II Bexidem TM (IDM-2) MacrophagesBladder cancerPhase II IDM-4Macrophages + monoclonal anti-CD20 Chronic lymphocytic leukemia Phase II Uvidem TM (IDD-3) Dendritic cells + melanoma tumor cell lysate MelanomaPhase II Collidem TM (IDD-5) Dendritic cells + peptides DC + tumor cell lysate DC fused with autologous cancer cells Colorectal cancer Renal cell carcinoma Pre-clinical Phase II Phase III Products in Clinical Development

Clinical response to DC vaccination Tumor regression of the left chest wall tumor and improvement of the left lung after the fourth vaccination