cancer immunotherapy. type of tumor: -non-invasive (benign) - invasive (malignant)
TRANSCRIPT
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:
Gene HLA T.tissue N.tissue
MUC1 A11 Breast & Ovarian
None
HPV-E7 DR*0401 Cervical carcinoma
none
AFP A2 Hepatocellular carcinoma
Fetal liver
GnT-v A2 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
Antibody Trade name Target antigen Indication
Rituximab Mabthera® CD20 Treatment of relapsed or refractory low-malignancy non-Hodgkin lymphoma
Trastuzumab Herceptin® HER-2 Treatment of chemotherapy refractory breast cancer
Gemtuzumab MylotargTM 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
Product Basic description Primary indication Status
Cytotherapeutic agents
Therapeutic vaccines
OsidemTM Macrophages + anti-Her2/neu bispecific antibody
Ovarian cancer Phase III
ElademTM
(IDD-1)
Dendritic cells + PSA Prostate cancer Phase II
BexidemTM
(IDM-2)
Macrophages Bladder cancer Phase II
IDM-4 Macrophages + monoclonal anti-CD20
Chronic lymphocytic leukemia
Phase II
UvidemTM
(IDD-3)
Dendritic cells + melanoma tumor cell lysate
Melanoma Phase II
CollidemTM
(IDD-5)
Dendritic cells + peptides
DC + tumor cell lysate
DC fused with autologous cancer cells
Colorectal cancer
Renal cell carcinoma
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