Research Program "Cancer Immunotherapy (CI)"
The overall long-term aim of this Program is to cure cancer by immune reactions. After a century of visionary concepts on cancer elimination by the patient's immune system a breakthrough was achieved only a few years ago with the introduction of checkpoint-inhibitory antibodies. These unblock therapeutic T cell responses against neoantigens such as Human Leukocyte Antigens (HLA). HLA-presented mutations are recognizable by T cells that arise due to neoantigen encoding mutations in the tumor.
Based on the analysis of now thousands of treated patients, the clinical response has been positively correlated with the number of mutations in tumors. The presently emerging view - both from clinical observations, in particular T cell specificity analysis, and from HLA ligandomics - is that neoantigens are rather rare, which explains why even melanoma patients with hundreds of exome mutations in their tumors can be clinical nonresponders to checkpoint inhibition, possibly due to a lack of suitable neoantigens. According to this view, the majority of cancer patients will not benefit from checkpoint inhibition alone.
The investigators of the DKTK Cancer Immunotherapy Program, with their combined expertise, are ideally suited to build on these newly established fundaments. The four pillars of the Program, Advanced Tumor Vaccines, New Therapeutic Antibodies, Advanced Cellular Therapeutics, and Combinatorial Immunomodulation, are based on the now accepted fact that the immune system of patients is able to destroy tumors. If one or more neoantigens are found in a tumor of a given patient, individualized vaccination with peptides or RNAs representing the neoantigens is a promising strategy for achieving therapeutic efficiency similar to that of checkpoint blockade but without off-target toxicity. For those patients, and these will be many, whose tumors lack neoantigens, there is still a large selection of reasonably tumor-specific antigenic germline epitopes that are suitable for vaccination in particular in the minimal residual disease (MRD) setting. In patients with more advanced disease, these tumor antigens are suitable targets for adoptive transfer strate¬gies with T cell receptor (TCR)- or chimeric antigen receptor (CAR)-modified T cells, or with new generation antibodies against tumor-associated cell surface antigens. Combinations of these strategies, in particular combining immunovirotherapy or other non-antigen-specific perturbation of the tumor microenvironment, or antigen-specific vaccination or cell transfer, with checkpoint inhibition or other recently developed immunomodulations are especially promising.
Selected major translational highlights
1. Identification of immunogenic neo-epitopes in melanoma by mass spectrometry (Bassani-Sternberg et al., Nature Commun 2016).
2. Demonstration that melanomas and other cancers frequently show CDKN2A and JAK2 co-deletion, enhancing susceptibility to IFNγ resistance and possibly resulting in a tendency to immunotherapy resistance (Horn et al., J Natl Cancer Inst 2018).
3. Development of XS15 (a TLR2/1 ligand) as a promising adjuvant candidate for tumor peptide vaccination (Rammensee et al., J Immunother Cancer 2019).
4. Investigation of a peptide vaccine targeting mutant IDH1 in patients with newly diagnosed glioma (NCT02454634; Platten et al., Nature 2021).
5. DKTK researchers contributed to the study on a personalized peptide-based vaccine, based both on MS-defined HLA tumor ligands and on predicted neo-epitopes for newly diagnosed glioblastoma, performed by an international, EU-funded consortium (GAPVAC) (NCT02149225; Hilf et al., Nature 2019).
6. 1st patient dosed with TCR gene-modified autologous T cells in a first-in-human phase I clinical trial in relapsed/refractory multiple myeloma.
7. Approval of the first-in-human phase I clinical trial in AML patients with a UniCAR T cell product in combination with a CD123-specific targeting module (NCT04230265).
8. The IMMUNED trial demonstrated that the combined blockade of PD-1 and CTLA-4 is superior to PD-1 blockade alone as adjuvant treatment in stage IV melanoma without evidence of disease (NCT02523313; Zimmer et al., Lancet 2020) – the translational work-up of this study is funded as a DKTK Joint Funding UPGRADE project.
9. Publication of first results of the prospective, multicenter, observational ALLogeneic Iron inVEstigators (ALLIVE) trial, showing that enhanced labile plasma iron (eLPI) is a possible biological mediator of iron-related toxicity in AML and MDS patients after allogeneic haemopoietic cell transplantation (NCT01746147; Wermke et al., Lancet Haematol 2018).
10. Phase I trial evaluating an optimized bispecific PSMAxCD3 antibody, termed CC-1, which was developed and GMP-produced entirely on an academic level with contributions from the Helmholtz Validation Fund (HVF), DKFZ and DKTK. The first clinical trial (NCT04104607) evaluating this antibody after preemptive application of tocilizumab for IL-6 receptor blockade, to prevent the undesired sequelae of cytokine release syndrome (CRS), is presently recruiting for prostate cancer.
11. The iVAC-XS15-CLL01 study, combining a patient-individualized peptide vaccine with a new adjuvant in CLL patients under ibrutinib treatment, started in December 2020. In parallel, a first-in-human study with XS15 to prevent COVID-19 infection in adults started in November 2020 (pVAC, NCT04546841).