Based on a deep understanding of tumor-host immune interactions and the mechanisms tumors use to evade immunity, both sites develop strategies to re-induce tumor immunity. This includes strategies to modulate the tumor environment, strategies to actively guide T cells to the tumor cell and strategies to enhance host immunity by vaccination, or by reinfusion of potent effectors such as autologous antigen-specific T cells, chimeric antigen receptor transduced (CAR) T cells, or T cell receptors (TCR) transduced T cells. Fully human, fully immunocompetent tumor models have been developed that help to test such strategies preclinically and to identify potential mechanisms of resistance.
Joint Aims, Strategy and Perspectives
A number of concepts have been developed for personalized immunooncology approaches and validating response prediction algorithms for defined therapeutic interventions in prospective clinical trials. Several bispecific antibody constructs and formats are being tested preclinically and some will be translated in early phase clinical testing. Novel CAR constructs have been developed at both sites and novel technologies are ready to be tested in phase I settings (Uni-CAR platform). A platform that allows the identification and isolation of mutation specific T cells in patients has been set up and the first patients are currently being screened. Target antigens are validated for expression, processing and presentation in every patient. Mutation specific T cells are being tested and the inhibitory effects in the context of T cell transfer are being studied carefully in explant model systems. The strength of both centers is the ability to assess mechanisms of action and mechanisms of resistance in the fields of immunomodulation, antibody formats and cell-based strategies with unmodified and modified cells.
Research Profile NCT Heidelberg
In 2019, the NCT immunotherapy program was restructured with the main focus on enhancing tumor immunity including the following units: (1) development of bispecific antibodies for tumor immunotherapy, (2) applied tumor immunity and combination strategies (validation of immunotherapeutic antibody constructs, immunomodulators and gene-transduced autologous T cells on patient material), (3) analysis of the tumor microenvironment, (4) computer-based algorithms and integrated data analysis in tumor immunology, (5) expansion of the GMP unit (production unit for the manufacture of peptide vaccines, support of regulatory processes to obtain manufacturing authorization for cellular products), (6) expansion of the unit “DNA vectors for cancer therapy”, (7) expansion of the mass spectrometry unit to identify target structures for tumor immunotherapy and (8) the program “Genetically modified cells as cancer immunotherapy” for solid tumors. The overall aim is to develop novel immunotherapeutic constructs, evaluate them immediately in a preclinical setting and transfer them into clinical trials. The medium-term goal is to further strengthen the networking of the different units for the development of active substance/target structures in cancer immunotherapy.
Immuntherapy NCT Heidelberg - Selected Activities
TCR proof of concept program: neoepitope-specific T cell receptors
This interdisciplinary project aims at identifying and cloning neoepitope-specific T cell receptors from tumor patients for the development of individual TCR T cell therapies by applying and comparing different TCR identification approaches. Apart from varying methodologies, the protocols also differ regarding the need for biomaterials, such as significant amounts of fresh tumor tissue and high blood volumes. If applicable, epitopes will also be analyzed by mass spectrometry. Once identified, TCRs will be cloned into DNA vectors. Then, autologous T cells are electroporated and TCR transgenic T cells are validated (e.g. in xenograft or explant models, cell lines, etc.). Next, validated TCRs are selected for the generation of “clinical grade” TCR T cell products in a CliniMACS Prodigy Pro (Miltenyi Biotec GmbH). Three cases have been selected for the program so far and several TCs could be cloned.
Green et al., Methods Enzymol. 2019; Bunse et al., Methods Enzymol. 2019
Resolving immunity to target brain tumors (RE-IGNITE)
Previously, it was possible to identify and clone tumor-reactive TCRs from patient material, however translating these TCRs into personalized therapeutics as part of an adoptive cell immunotherapy will require dramatic increases in throughput and turnaround time. The Baden-Württemberg Stiftung is supporting these efforts by combining existing expertise in the field of high-throughput single cell analysis and TCR cloning, with the internationally recognized bioinformatics excellence of researchers at UCSC. The aim is to develop a gene expression “signature” that identifies tumor-reactive T cells, significantly shortening the time required to develop personalized immunotherapeutics. Initially focusing on Glioma patients, the plan is to roll out this signature to other cancer modalities and autoimmune disorders, through a publicly available cell signature analysis server.
Hilf et al., Nature 2019; Green et al., Methods Enzymol 2019
CD19 third generation CAR T cell trial HD-CAR-1
CAR T cell therapy has sparked new hope for patients with CD19+ B cell neoplasias, like acute lymphoblastic leukemia (ALL) or non-Hodgkin’s lymphoma. The University Hospital of Heidelberg is the first institution to run an investigator initiated CAR T cell trial (HD-CAR-1) in Germany with in-house production of CD19-directed CAR T cells. Adult patients with lymphoblastic leukemia and non-Hodgkin’s lymphoma including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma or mantle cell lymphoma are treated with autologous T-lymphocytes transduced by a third-generation (CD28 and 4-1BB) retroviral vector. The safety and feasibility of escalated CD19.CAR T cell doses after lymphodepletion is evaluated. Furthermore, an assessment of frequency, immunophenotype and functionality of CD19.CAR T cells is performed and correlated to the clinical outcome of the patients. So far, 15 patients have been treated with an overall response rate of 72% since 09/2018.
Schubert et al., BMJ Open 2019; Kunz et al., Mol Ther Methods Clin Dev 2020