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