Immune therapies are based on the ability of the immune system to differentiate between normal and malignant cells. During malignant transformation of cancer cells mutations occur in the genes which in turn influence the protein synthesis. As a consequence, cancer cells express tumour-associated antigens on the cell surface. These antigens are degraded and presented on the cell surface by binding to tissue type molecules (HLA). Tumour-specific T-cells can recognize and bind to the tumour antigens presented as peptides bound to the HLA molecules on the surface of the cancer cells. The interaction between the cancer cell and the tumour-specific T-cell initiates tumour cell lyses and killing. Immunization with tumour antigens can thus induce an immune response that causes specific killing of those cancer cells that express the antigens used for immunization. Several phase I/II clinical trials are conducted at CCIT where we have a close collaboration between the laboratory and the clinic. The different types of immunotherapies used in the clinic are prepared in a certified clinical grade laboratory and all immune monitoring from the clinical trials takes place in the laboratory of CCIT.
Patients are treated at the Department of Oncology at Copenhagen University Hospital Herlev.
In the clinic we treat patients with several types of cancer, including metastatic malignant melanoma, lung, breast and prostate cancer. The therapies include adoptive cell therapy, dendritic cell vaccinations and peptide vaccinations. More recently we have also included combination therapies with immunotherapy and chemotherapy.
All clinical trials at CCIT are approved by the Danish Medicines Agency, the Danish Ethics Committee for the Capital Region of Denmark and by the Danish Data Protection. The studies are monitored according to Good Clinical Practice by the GCP Unit and are registered at Clinicaltrials.gov.
Below is a short introduction to the different immunotherapies that we are working with at CCIT and also, you will find a link for more information about currently ongoing trials.
Adoptive cell therapy is based on the isolation of tumour-specific T cells from biopsies, i.e. autologous tumour infiltrating lymphocytes (TIL). These cells can be obtained by a surgical resection of a metastasis from the patient. The tumour tissue is then prepared and cultured in the laboratory in order to isolate and activate the lymphocytes. These activated lymphocytes can then be expanded to a large number of cells before they are re-infused into patients upon chemotherapy induced lymphodepletion. This therapy is then followed by intravenous infusion of Interleukin-2 in order to further stimulate the proliferation of the T-cells in vivo.
Dendritic cell (DC) vaccines can be used to induce a T cell response directed against a specific antigen expressed by tumor cells. DC vaccinations consist of autologous monocytes that are harvested by a leucapheresis procedure and then matured into DCs in vitro. DCs are then transfected with the antigens of choice (depending on the cancer type) before they are re-injected into the patient as an intradermal injection in the thigh. The DCs will then present the tumour antigens to the T-cells and thereby activate T cells that are capable of recognizing tumor cells.
Peptide vaccination is an immunotherapeutic strategy aiming at activating tumour specific T-cells in vivo. The peptide (given subcutaneously) is taken up by antigen presenting cells and is presented to the T-cells - these T cells are activated an can subsequently recognize cancer cells. The peptide sequence chosen for vaccination can be short or longer peptide sequences and can be used as ´single peptide´ as well as ´multi-peptide´ vaccine strategies. The peptide is mixed with different adjuvants of choice. At CCIT we have experience with ISA-51 Montanide, Aldara (Imiquimod) ointment and GM-CSF (Leukine) as vaccine adjuvants.
Combination trials have recently been started at CCIT combining immunotherapy with conventional chemotherapy for cancer patients. During the last years it has been proposed that chemotherapy can support immunotherapeutic strategies by inducing favourable changes in the signalling pathways of the immune system, i.e. diminish the number of regulatory T cells and optimize the conditions for tumour cell killing.
At CCIT we have recently started a new randomised phase II trial combining standard chemotherapy (Docetaxel) with a dendritic cell vaccine for metastatic prostate cancer patients and yet another phase II trial combining standard chemotherapy (Temozolomide) with a peptide vaccine for metastatic melanoma patients.
Blood sample protocols
At CCIT we are assessing changes in T-cell lymphocyte subsets during anticancer treatment, aiming at monitoring the influence on the immune system of different types of anticancer treatment, ie treatment with Temozolomide or Interleukin 2/Interferon for melanoma patients and treatment with Sunitinib for renal cell carcinoma patients.
The protocols are approved by the Danish Ethics Committee for the capital region of Denmark, and can be looked up in their register.