The NCT Clinical Immunotherapy Cross-Section Program (CIP, D. Jäger, P. Krammer) has been recently initiated based on the particularly strong research activities among the Heidelberg scientific community regarding cancer immunology (SFB938, KFO 227, Helmholtz Alliance Immunotherapy).
Research in this field has not only resulted in a fundamentally improved understanding of the role of the immune system in the development and progression of cancer, but also in concepts for re-inducing host immunosurveillance in tumors by modulating tumor-host immune interactions. Immune-modulating reagents can interfere with critical checkpoints of the immune system. Several new reagents are in phase II and III clinical trials, and ipilimumab (anti-CTLA4 mAb) was recently approved as a first-in-class compound for the treatment of stage IV melanoma. NCT CIP develops clinical protocol designs for immune-modulating compounds, based on cutting-edge immune monitoring technology (e.g. measurements of pre-existing T-cell and antibody responses against defined tumor antigens or infiltration of tumor tissue by T-cells). CIP is strongly interconnected with the Early Clinical Development Program (ECDP).
In the last two years, NCT CIP has conducted several immunotherapy first-in-man studies with extensive correlative research projects (Klug Cancer Cell 2013; Gnjatic PNAS 2010; Witzens-Harig Blood 2013). Preclinical research showed that a chemokine receptor is key in generating a tumor-supressive micromilieu in colon cancer, and blocking this receptor by a commercially available drug results in restoration of tumor immunosurveillance.
Based on these results, the first NCT investigator-initiated phase I immunotherapy trial (NCT IIT-CIS00001) has been initiated in colon cancer patients who are refractory to standard treatment. Interim data indicate excellent tolerability and, in some patients, objective responses associated with immune milieu modulations (manuscript submitted; patent pending). This IIT is a blueprint study for several other phase I studies (both IIT and IST) with correlative research programs employing vaccines, immune-modulating antibodies, cancer antigen-targeting antibodies, bispecific T-cell-activating antibody fragments (‘BiTe’), and chimeric antigen receptor (CAR)-modified T-cells. Most recently, the EU-FP7 program awarded €5.9 m to a large immunotherapy consortium coordinated by R. Offringa for the clinical development of immunostimulatory agonist antibodies for cancer therapy (IACT). Furthermore, within SFB 938, P. Beckhove’s group has advanced a personalized vaccine program to its late preclinical stage. Recently established technologies of NCT CIP include whole-slide imaging of histological sections coupled with automatic image processing, laser microdissection, and multiplex protein quantification technologies (Halama Cancer Res 2011), multiplex serological assays and generation of the NCT Liquid Biobank currently comprising more than 4,000 serum samples from 400 patients being utilized in ongoing and collaboration projects (e.g., L. Zitvogel, Institut Gustave Roussy). New targets like NY-BR-1 in breast cancer are attacked by a NY-BR-1-specific CAR (chimeric antigen receptor) in collaboration with S. Feldman/S. Rosenberg (National Cancer Institute). CIP has also integrated technologies for the development of novel proprietary immunotherapeutic agents (vaccines, modified effector cells, fully humanized immune-modulating antibodies; Krawczyk PNAS 2013).
Recent examples include the development of the proprietary vaccine VXM01 for pancreatic cancer (Schmitz-Winnenthal) and generation of the largest known collection of cancer patient-specific antibody phage display libraries (Krauss). The program was recently elected as a new Clinical Cooperation Unit (Klinische Kooperationseinheit) of the DKFZ with additional intramural funding of €400,000/year.
- Development of sophisticated early clinical trial protocols (IIT and IST) with systematic integration of cutting-edge correlative research programs.
- Implementation of personalized immunotherapy concepts using vaccines, antibodies, and genetically modified T-cells (collaboration with Sahin, Mainz and Rosenberg, NCI).
- Development and expansion of novel technologies for in-depth analysis of personalized tumor-host interactions for patient-specific clinical decision-making.
- Discovery and clinical development of proprietary immune-modulating reagents for cancer therapy.