Dendritic cell vaccines

Medigene’s new generation of dendritic cell (DC) vaccines have optimal immunotherapeutic potential to activate potent anti-tumor immune responses

Medigene has established a DC vaccine platform for the generation of antigen-tailored DC vaccines prepared from patients’ own blood cells.

Medigene’s has developed new, fast, and efficient methods for generating autologous (patient-derived) mature DCs with the ability to activate patients’ lymphocytes (both T cells and natural killer cells). For a given type of tumor, several antigens are introduced into mature patient-derived DCs, which are subsequently applied as vaccines. With this modular antigen approach Medigene can develop vaccines for a wide variety of different tumor types.

The DC vaccines can interact with T cells and induce antigen-specific T cells to proliferate and gain functions that allow them to attack tumor cells. Vaccine-activated T cells can thereby specifically recognize and eliminate antigen-expressing tumor cells. They can also induce natural killer cells to become active and attack tumor cells. The Medigene approach also allows DC vaccines to be developed using neoantigens identified in the tumors of individual patients.

Presently, DC vaccines have worked best in patients with low numbers of tumor cells, such as the minimal residual disease that is often left after surgery, radiation, or chemotherapy. The advantageous safety profile of DC vaccines in general, as observed in numerous clinical trials in the past, is not detrimental to the patients’ quality of life during DC vaccine immunotherapy.

Medigene’s DC vaccine platform offers unique advantages:

  • Young and potent DCs can be manufactured in just three days.
  • High quantity yields of DC vaccines for up to two years or longer.
  • Cells stored frozen and administered through simple injections under the skin.
  • Collection of antigens as off-the-shelf reagents to tailor DC vaccines according to medical need.

Medigene holds a patent in the US, Australia and Europe for the manufacturing of mature dendritic cells. The patent protects our process to generate polarized mature dendritic cells using our unique maturation cocktail.

Specific characteristics of Medigene’s new generation DC vaccines:

  • Medigene’s DCs display a surface profile composed of high levels of molecules needed for co-stimulation of T cells, leading to optimal activation.
  • DCs manufactured following Medigene’s protocol produce bioactive IL-12, a critical cytokine that is needed for effective activation of anti-tumor immunity.
  • Medigene’s DCs can also activate natural killer cells of the innate immune system to provide immune synergy of the innate and adaptive immune systems.

Personalized cancer treatment with DC vaccines

Isolation of DC precursor cells from patient's blood.
Tumor
Generation of dendritic cells and loading with tumor-associated antigens.
MHC complex
Tumor-associated antigen
New generation of DC vaccines loaded with tumor-associated antigens.
MHC complex
Freezing of vaccine cells in multiple aliquots.
Batch quality testing and vaccination according to protocol over defined time period.
Activation of tumor-specific patient-T cells by DCs. T cells seek and attack tumor cells.
Tumor
T cell
DC vaccine

Profile and function of dendritic cells

In 1973, Prof. Dr. Zanvil Cohn and Prof. Dr. Ralph Steinman discovered the DC, a new immune cell that plays a crucial role in bridging innate and adaptive immunity, and further characterized it over the next several decades. Prof. Dr. Steinman was awarded with the Nobel Prize in Physiology or Medicine in 2011 for his pioneer work on the discovery of DCs. They are the most potent antigen-presenting cells that hold the task in our body to take up, process and present peptide fragments of on their cell surface in conjunction with MHC molecules. This display of MHC-peptide complexes on DCs leads to activation of either CD4+ or CD8+ T cells, dependent upon the display of the peptide fragments by MHC class II or MHC class I molecules respectively. 

Medigene’s new generation DC vaccines deliver three signals to T cells to activate optimal responses. First, controlled expression of MHC-peptide ligands is achieved using RNA as the source of antigen that is processed into appropriate fragments that are presented by MHC class I and class II molecules of the DC. The surface display of MHC-peptide ligands allows T cells to bind to the DCs via their TCRs and this interaction delivers an activation signal to the T cells. The second signal contributes to the survival of the T cells. At day three, mature DCs display a strong positive co-stimulatory profile through high expression of several stimulatory molecules of the B7 family, among others. The third signal delivered by the DCs to the T cells is provided by secreted bioactive IL-12 that binds to the IL-12 receptors on the T cells and contributes to their differentiation into potent effector cells.

Medigene’s dendritic cell vaccines deliver three signals to activate optimal anti-tumor immune responses

Activation of the T cell via peptide-MHC TCR interaction.
DC vaccine
T cell
MHC class I plus peptide
At day three, mature DCs display strong co-stimulatory profile, which contributes to T cell survival.
DC vaccine
T cell
MHC class I plus peptide
PD-1 (B7.1) and PD-L2 (B7.2)
Secretion of IL-12 by DCs binds to IL-12 receptor on the T cells, contributes to the differentiation into potent effector cells.
DC vaccine
T cell
MHC class I plus peptide
PD-1 (B7.1) and PD-L2 (B7.2)
IL-12 receptor

Click on the picture to see a short video of Medigene's DC vaccine technology

Clinical status of Medigene’s DC vaccines

March 2015, Medigene started a clinical phase I/II trial with its DC vaccine for the treatment of acute myeloid leukemia (AML) at Oslo University Hospital (NCT02405338). This trial will treat 20 patients with AML positive for the vaccine-specific antigens. In the first half of 2016, the Phase II part of this trial was started after a positive recommendation of the Data and Safety Monitoring Board (DSMB).

This is an open-label trial for patients who have completed intensive induction chemotherapy and if possible consolidation therapy that brings them into remission. Patients will then be vaccinated for two years or until progression.

The primary objective is to test feasibility and safety. Secondary objectives are overall survival, relapse rate, time to progression and induction of immune responses. Because these trial patients are at high risk, we hope to hinder or delay disease relapse through T cell responses induced by DC vaccination.

Further studies utilizing Medigene’s DC vaccine technology include two ongoing clinical investigator-initiated trials: a clinical Phase I/II trial in AML at the Ludwigs-Maximilians-University Hospital of Munich Großhadern and a clinical Phase II trial in prostate cancer at Oslo University Hospital. Moreover, a compassionate use program is being conducted at the Department of Cellular Therapy at Oslo University Hospital. Medigene is concentrating on the further development of the DC vaccines in hematological malignancies.

Key indication: Acute myeloid leukemia

Acute myeloid leukemia (AML), the most common form of acute leukemia, is a heterogeneous type of cancer affecting patients’ blood and bone marrow. It is characterized by an overproduction of myeloid progenitor cells named myeloblasts or leukemic blasts. Myeloid leukemia starts from immature forms of cells derived from the myeloid lineage of bone marrow cells.

The American Cancer Society’s estimates about 60,140 new cases of leukemia (all kinds) and 24,400 deaths from leukemia (all kinds) are recorded annually. Of these, about 19,950 new cases are AML. GLOBOCAN projected the worldwide total leukemia incidence of AML for 2012 to be 351,965 with an age-standardized rate of 4.7 per 100,000. For Europe the estimated annual incidence rate of AML ranges between 1/33,000-1/25,000 (Source: orphanet).

AML is typically treated initially with intensive induction chemotherapy in order to achieve remission. Some patients are eligible to receive additional chemotherapy or a hematopoietic stem cell transplant (HSCT), which increases the potential for eradication of residual tumor cells. However, HSCT induces high morbidity and mortality and less than half of the AML patients can be treated with HSCT.

Elderly patients may be unable to complete the full regimen of intensive chemotherapy due to its high toxic side effects. Thus, the majority of elderly patients remain undertreated and continue to experience minimal residual disease (MRD) burden that sooner or later will lead to leukemia relapse. We are developing our new generation DC vaccine formulation for post-remission therapy of patients with AML who cannot undergo HSCT and carry risk for disease relapse.