Introducing Apceden™

Topics

• IMMUNITY AND CANCER• DENDRITIC CELL BIOLOGY

– Development of Dendritic Cells– Why Dendritic Cells– Mechanism of Action

• CLINICAL TRIALS• APCEDEN™

– Preparation– Associated Logistics

IMMUNITY AND CANCER

IMMUNITY AND CANCER• Clinical trials with vaccination of ex-vivo generated dendritic cells

(DCs) pulsed with tumor antigens have provided a proof-of-principle that therapeutic immunity can be elicited in cancers

• However Clinical benefit has been observed in only a fraction of cases when measured by regression of tumors in stage IV cancer

• The next generation of DC vaccines are expected to generate large numbers of high avidity effector CD8+ T cells to overcome regulatory T cells and the suppressive environment established by tumors

• Therapeutic vaccination protocols with improved DC vaccines in combination with chemotherapy is expected to exploit immunogenic chemotherapy regimens

IMMUNOTHERAPY

DC can activate Almost

all Immune

cells

DENDRITIC CELL BIOLOGY

Dendritic Cell Therapy in Cancer

DEVELOPMENT OF DENDRITIC CELLS

Our cells of Interest

WHY DENDRITIC CELLS?

There ability to migrate through tissue and act on tumors

There capacity to activate naïve T cells

Antigen Presenting cell

Tumor Antigen

Expanding T-Cells

Tumor Killing

MoA OF DENDRITIC CELLS ASSOCIATED TUMOR KILLING

CLINICAL TRIALS WITH DENDRITIC CELL THERAPY

Companies conducting Clinical Trials with Dendritic Cell Therapy

Name of the Company Country

Immunocellular Therapeutics

California (USA)

Prima Biomed Sydney (Australia

Geron and Merix US

Aastrom Bioscience Michigan (USA)

Northwest USA

DCPrime Amsterdam (Netherland)

Dandrit Biotech Denmark

Creagene Korea

Dendreon Washington (USA)

FEW CLINICAL TRIALS WITH DCS No. Trials Country Type of Cancer Phase No. of

Patients

1 BAYLOR RESEARCH INSTITUTE

USA Melanoma, neoplasm Metastasis

I & II 30

2 SAMSUNG MEDICAL CENTER

KOREA Prostatic cancer I & II 12

3 NATIONAL CANCER INSTITUTE

USA Melanoma I 20

4 HOAG MEMORIAL HOSPITAL

PRESBYTERIAN Metastatic Melanoma

I & II 80

5 HERLEV HOSPITAL DENMARK Advanced Melanoma I & II 25

6 STANFORD UNIVERSITY USA Multiple Myloma I & II 30

INTERPRETING CLINICAL EFFICACY FOR DC CTs • Pre-mature dismissal of therapy is not suggested if ORR is not high for such a therapy• Unrealistic to expect efficient immune responses to eliminate the total tumor burden in a patient with advanced cancer• Analysis of improved survival benefits in randomized studies and long-term follow-up is suggested• Molecular pathways or chemotherapeutics now considered active based not on only ORR but improved survival and/or

time to disease progression• A phase III study comparing DC Therapy with standard chemotherapy (DTIC) in melanoma patients showed insignificant

ORR in DC arm but post-hoc analysis demonstrated improved survival and performance status in specific phenotype• Clinical Trials results suggest that DC vaccination therapy needs to be tailored for pre-identified cohorts of patients.• Prolonged survival and good quality of life might be considered a therapeutic success

SOME CONCLUSIONS FROM DC CTs• DCs are the critical decision-making cells in the immune response and an attractive target for therapeutic manipulation to enhance otherwise insufficient immune responses to tumor

antigens • Complexity of the DC system requires rational manipulation to achieve protective or

therapeutic immunity• Further research needed to analyze the immune responses induced in patients by distinct ex

vivo generated DC subsets activated via different pathways• Progresses made in the knowledge of DC biology as well as effector/regulatory T cell biology

clearly open the avenues for development of considerably improved clinical protocols • Possibility of including therapeutic vaccination of metastatic disease and preventive

vaccination in patients with resected tumors• The ultimate ex vivo-generated therapeutic DC vaccine will be heterogeneous and composed

of several subsets, each of which will target a specific immune effector. • These ex vivo strategies should help to identify the parameters for DC targeting in vivo, which

lead to the next step

APCEDEN™

WHAT IS Apceden™

• Apceden™ is an autologous (self) monocyte derived Dendritic Cell immunotherapy which nurtures the patient’s own mononuclear cells against cancer specific cells

• Patients undergo apheresis for collection of blood monocytes. These cells are cultured and processed for the production of mature dendritic cells (DC) against the specific tumor cell type, which are harvested on Day 8.

• Each dose of APCEDEN™ consists of dendritic cells (CD 80+, 83+, 86+,CD14-) more than 1 million in 15ml

• 6 doses are given every 2 weeks for first 3 cycles and next 3 cycles are given every 3 weeks.

Buffy Coat

Incubate for 4-6 Hrs

Adherent cells

Incubate for 48 Hrs

Wash with PBS thrice

Incubate for 6 Days

Preparation of Apceden™ from Monocytes (1)

Patient

Isolation of Monocytes from peripheral blood

Generation of Immature Dendritic Cells

Isolation of Tumor cells

Lysate Preparation Loading of Dendritic cells with whole cell

Tumor Lysate

The APCEDENTM is to be administered to the patient

intravenously

Mature antigen presenting Dendritic

Cells

Preparation of Apceden™ from Monocytes (2)

NutriprepTM

Registration

8 Days

Associated Logistics

APCEDEN™