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Introduction
Additional affiliations
June 2006 - present
January 2000 - April 2006
CureVac GmbH
Position
- Immunotherapy using RNA
May 1998 - April 2006
Education
January 2007 - December 2012
Publications
Publications (155)
Cancer-associated immune dysfunction is a major challenge for effective therapies. The emergence of antibodies targeting tumor cell-surface antigens led to advancements in the treatment of hematopoietic malignancies, particularly blood cancers. Yet their impact is constrained against tumors of hematopoietic origin manifesting in the skin. In this s...
Adoptive transfer of engineered immune cells expressing chimeric antigen receptors (CAR) is an emerging cancer immunotherapy that is also being investigated for glioblastoma. Many separate studies focus on either CAR T or CAR NK cells, and CAR macrophages are in early stages of development. However, a systemic cross-comparison of engineered immune...
[This corrects the article DOI: 10.1016/j.omto.2023.07.003.].
Background
Extracorporeal photopheresis (ECP) has emerged as a systemic first-line immunomodulatory therapy in leukaemic cutaneous T-cell lymphoma (L-CTCL) and now beginning to be utilized in other T-cell-mediated diseases. Although ECP has been used for nearly 30 years, its mechanisms of action are not sufficiently understood, and biomarkers for r...
Discrimination between hematopoietic stem cells and leukemic stem cells remains a major challenge for acute myeloid leukemia immunotherapy. CAR T cells specific for the CD117 antigen can deplete malignant and healthy hematopoietic stem cells before consolidation with allogeneic hematopoietic stem cell transplantation in absence of cytotoxic conditi...
Acute Myeloid Leukemia originates from the accumulation of mutations in hematopoietic stem and progenitor cells, leading to the emergence of leukemia-initiating cells, which sustain blast formation. CAR T cells specific for the CD117 antigen can deplete malignant and healthy hematopoietic stem cells. Here we exploit non-viral technology to achieve...
The first worldwide article reporting that injections of synthetic non-replicating mRNA could be used as a vaccine, originated from a French team located in Paris was published in the European Journal of Immunology (EJI) in 1993. It relied on work conducted by several research groups in a handful of countries in the 1960s, who put forward the preci...
Nanoparticles of different sizes formulated with unmodified RNA and Protamine differentially engage Toll-like Receptors (TLRs) and activate innate immune responses in vitro. Here, we report that similar differential immunostimulation that depends on the nanoparticle sizes is induced in vivo in wild type as well as in humanized mice. In addition, we...
Cancer treatment with immune checkpoint blockade (ICB) often induces immune-related adverse events (irAEs). We hypothesized that proteins coexpressed in tumors and normal cells could be antigenic targets in irAEs and herein described DITAS (discovery of tumor-associated self-antigens) for their identification. DITAS computed transcriptional similar...
Purpose:
Most chimeric antigen receptor (CAR)-T cell strategies against glioblastoma have demonstrated only modest therapeutic activity and are based on persistent gene modification strategies that have limited transgene capacity, long manufacturing processes and the risk for uncontrollable off-tumor toxicities. mRNA-based T cell modifications are...
RNA editing refers to non-transient RNA modifications that occur after transcription and prior to translation by the ribosomes. RNA editing is more widespread in cancer cells than in non-transformed cells and is associated with tumorigenesis of various cancer tissues. However, RNA editing can also generate neo-antigens that expose tumour cells to h...
Introduction
Acute Myeloid Leukemia (AML) arises from the accumulation of mutations within the hematopoietic stem and progenitor cells (HSPC), leading to the emergence of a population of malignant leukemia-initiating cells (LIC). AML-LICs maintain high phenotypic similarity with their cells-of-origin and can cause post-treatment relapse. Immunother...
Mycosis fungoides (MF) is a type of cutaneous T cell lymphoma (CTCL). Chlormethine (CL) is recommended as first-line therapy for MF with a major purpose to kill tumor cells via deoxyribonucleic acid (DNA) alkylation. To study the extent of treatment susceptibility and tumor specificity, we investigated the gene expression of different DNA-repair pa...
As of September 2021, twenty-one anti-COVID-19 vaccines have been approved in the world. Their utilization will expedite an end to the current pandemic. Besides the usual vaccine formats that include inactivated viruses (eight approved vaccines) and protein-based vaccines (four approved vaccines), three new formats have been validated: recombinant...
Background
In cancer, the lack of early diagnostic biomarkers is a challenge, results in delayed diagnosis, and can seriously affect treatment and prognosis. Therefore, defining accurate methods for early identification of rare malignant cells is of pivotal importance. We explore the potential of artificial intelligence (AI) to uncover tumor-defini...
Background
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of extranodal non-Hodgkin’s lymphoma. Mycosis fungoides (MF) is the most common types of CTCL and considered as a malignancy of skin-resident T cells. Chlormethine (CL), also known as mechlorethamine or nitrogen mustard, is a synthetic agent with well-known alkylating capacity. It...
Sézary syndrome (SS) is a rare, leukemic type of cutaneous T-cell lymphoma (CTCL), for which extracorporeal photopheresis (ECP) is a first-line therapy. Reliable biomarkers to objectively monitor the response to ECP in patients with SS are missing. We examined the quantitative and qualitative impact of ECP on natural killer (NK) cell activity in SS...
Extracorporeal photopheresis (ECP) emerged as a systemic first-line therapy in leukemic cutaneous T-cell lymphoma (L-CTCL) and is now being implemented in a variety of T-cell-mediated diseases. Although ECP has been used for nearly 30 years, the mechanisms of its efficacy are not sufficiently understood and biomarkers for response are lacking. We a...
The adenosine deaminase inhibitor 2'-deoxycoformycin (Pentostatin, Nipent®) has been used since 1982 to treat leukaemia and lymphoma but its mode of action is still unknown. Pentostatin was reported to decrease methylation of cellular RNA. We discovered that RNA extracted from Pentostatin-treated cells or mice has enhanced immunostimulating capacit...
Efficient vaccination can be achieved by injections of in vitro transcribed mRNA (ivt mRNA) coding for antigens. This vaccine format is particularly versatile and allows the production of individualised vaccines conferring, T-cell immunity against specific cancer mutations. The CDR3 hypervariable regions of immune receptors (T-cell receptor, TCR or...
The quantification of T-cell immune responses is crucial for the monitoring of natural and treatment-induced immunity, as well as for the validation of new immunotherapeutic approaches. The present study presents a simple method based on lipofection of synthetic mRNA in mononuclear cells as a method to determine in vitro T-cell responses. We compar...
Protamine is a natural cationic peptide mixture mostly known as a drug for the neutralization of heparin and as a compound in formulations of slow-release insulin. Protamine is also used for cellular delivery of nucleic acids due to opposite charge-driven coupling. This year marks 60 years since the first use of Protamine as a transfection enhancem...
SARS-CoV-2 infection and the resulting COVID-19 have afflicted millions of people in an ongoing worldwide pandemic. Safe and effective vaccination is needed urgently to protect not only the general population but also vulnerable subjects such as patients with cancer. Currently approved mRNA-based SARS-CoV-2 vaccines seem suitable for patients with...
Protamine is a natural cationic peptide mixture mostly known as a drug for the neutralization of heparin and as a compound in formulations of slow-release insulin. Protamine is also used for cellular delivery of nucleic acids due to opposite charge-driven coupling. This year marks60 years since the first use of Protamine as a transfection enhanceme...
In the race for a vaccine against SARS-CoV-2, the synthetic mRNA format has been shown to be the fastest one and proved to be safe and highly efficient, even at the very low dose of a few µg per injection. The mRNA vaccines are not new: vaccines that are based on attenuated mRNA viruses, such as Mumps, Measles, and Rubella, immunize by delivering t...
Sézary syndrome (SS) is a rare, leukemic type of cutaneous T-cell lymphoma (CTCL), for which extracorporeal photopheresis (ECP) is a first-line therapy. Reliable biomarkers to objectively monitor the response to ECP in patients with SS are missing. We examined the quantitative and qualitative impact of ECP on natural killer (NK) cell activity in SS...
Background:
RNA editing is a highly conserved posttranscriptional mechanism that contributes to transcriptome diversity. In mammals, it includes nucleobase deaminations that convert cytidine (C) into uridine (U) and adenosine (A) into inosine (I). Evidence from cancer studies indicates that RNA-editing enzymes promote certain mechanisms of tumorig...
Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (L-CTCL) that arises from malignant clonally derived skin-homing CD4⁺ T cells. Based on advancements in our understanding of the mechanisms underlying L-CTCL, boosting the suppressed immune response emerges as a promising strategy in SS management. Immune checkpoint...
Background:
Early and precise diagnosis of cutaneous T-cell lymphomas (CTCL) is challenging. Currently, polymerase chain reaction (PCR)-based clonality assessment of the T-cell receptor (TCR) is a helpful tool for this diagnosis.
Objectives:
In this retrospective study, we aimed to assess the sensitivity and specificity of this method for the di...
Protamine is a natural cationic peptide mixture used as a drug for the neutralization of heparin and in formulations of slow-release insulin. In addition, Protamine can be used for the stabilization and delivery of nucleic acids (antisense, small interfering RNA (siRNA), immunostimulatory nucleic acids, plasmid DNA, or messenger RNA) and is therefo...
Background: Treatment of triple negative breast cancer (TNBC) is hampered by lack of established therapeutic targets like hormone receptors or HER-2. Surgery, chemotherapy and radiotherapy are the standard of care yet cure rates in patients with TNBC remain inferior compared to other BC subtypes. Approaches tailored to the patient’s individual tumo...
Background: Treatment of triple negative breast cancer (TNBC) is hampered by lack of established therapeutic targets like hormone receptors or HER-2. Surgery, chemotherapy and radiotherapy are the standard of care yet cure rates in patients with TNBC remain inferior compared to other BC subtypes. Approaches tailored to the patient’s individual tumo...
The use of in vitro transcribed messenger RNA (ivt mRNA) for vaccination, gene therapy and cell reprograming has become increasingly popular in research and medicine. This method can be used in vitro (transfected in cells) or administered naked or formulated (lipoplexes,
polyplexes, and lipopolyplexes that deliver the RNA to specific organs, such a...
The non-canonical initiation factor DENR promotes translation reinitiation on mRNAs harbouring upstream open reading frames (uORFs). Moreover, DENR depletion shortens circadian period in mouse fibroblasts, suggesting involvement of uORF usage and reinitiation in clock regulation. To identify DENR-regulated translation events transcriptome-wide and,...
In Sézary syndrome (SS) impaired T-cell function and cytokine profile lead to immune evasion. Immune checkpoints non-redundantly regulate immune responses and targeting them is promising. We evaluated the expression of BTLA, CTLA-4, FCRL3, LAG-3, and TIGIT in tumor and non-tumor SS T-cells.Compared to CD4+ T helper cells from ten healthy individual...
Background: in vitro-transcribed messenger RNA (ivt mRNA) is a safe genetic vector that can be used for vaccination and gene therapy. We investigated the impact of the 3’ untranslated region (UTR) and of modified nucleotides on the functionality of ivt mRNA in vitro as well as in vivo. We confirmed that a 3’ UTR consisting of a tandem repeat of bet...
The transient expression of a protein in vitro or in vivo can be obtained by transfection of the in vitro transcribed messenger RNA (ivt mRNA). Delivery of ivt mRNA for therapies is typically based on liposomal formulations. The trapping and possible metabolic degradation of the liposome's payload within acidic/digestive compartments can limit the...
Background: As a versatile and safe vector, in vitro transcribed messenger RNA (ivt mRNA) is currently being intensively evaluated as an active pharmaceutical ingredient. Its therapeutic uses encompass vaccination, cell reprogramming, genome engineering, gene complementation and the expression of protein drugs (e.g., growth factors or antibodies)....
The functional impact of modifications of cellular RNAs, including mRNAs, miRNAs and lncRNAs, is a field of intense study. The role of such modifications in cancer has started to be elucidated. Diverse and sometimes opposite effects of RNA modifications have been reported. Some RNA modifications promote, while others decrease the growth and invasiv...
Nanoparticles of defined size can be easily obtained by simply mixing Protamine, a pharmaceutical drug that is used to neutralize heparin after surgery, and RNA in the form of oligonucleotides or messenger RNA. Depending on the concentrations of the two reagents and their salt contents, homogenous nanoparticles with a mean diameter of 50 to more th...
PurposeFollowing a previously published pre-clinical validation, this phase I study evaluated the safety, maximum tolerated dose, anti-tumour activity and immune status of a gemcitabine–chloroquine combination as a first- or late-line treatment in patients with metastatic or unresectable pancreatic cancer. Methods
In this 3 + 3 dose escalation stud...
In contrast to the prejudices plaguing the use of mRNA as a drug, we now know that the large scale production of mRNA under GMP conditions is in reality relatively easy and robust, and therefore inexpensive, when compared to the production of other biopharmaceutics such as peptides, proteins, modified microorganisms (i.e., bacteria or viruses), and...
MHC-multimers are essential tools in T cell immunomonitoring which are employed both in basic and clinical research, as well as for assessing clinical samples during therapy. The generation of MHC monomers loaded with synthetic peptides is an elaborate and time-consuming process. It would be beneficial to assess the quality of these monomers prior...
The majority of metastatic cancers remain incurable since the current methods of treatment often fail to target the heterogeneous nature of each individual patient's tumor. Personalized approaches targeting each individual patient's tumor may therefore bring significant improvements. The Mutanome Engineered RNA Immuno-Therapy (MERIT) consortium wil...
Although it is a very safe compound, the antimalarial drug chloroquine raises the endosomal pH in all cells of an organism, thereby modifying fundamental cell functions and physiological systems. This impact may promote or antagonize the activity of other drugs such as anti-cancer chemotherapeutics. One published placebo-controlled clinical study i...
Renal cell carcinoma (RCC) is an immunogenic tumor for which immunotherapeutic approaches could be associated with clinically relevant responses. It was recently shown, that induction of T-cell responses against multiple tumor-associated antigen (TAA) epitopes results in prolonged overall survival in RCC patients. In 2003–2005 we performed a phase...
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have a key role in immune responses because they bridge the innate and adaptive arms of the immune system. They mature upon recognition of pathogens and upregulate MHC molecules and costimulatory receptors to activate antigen-specific CD4(+) and CD8(+) T cells. It is now wel...
Small interfering RNA (siRNA)-based therapies allow targeted correction of molecular defects in distinct cell populations. Although efficient in multiple cell populations, dendritic cells (DCs) seem to resist siRNA delivery. Using fluorescence labeling and radiolabeling, we show that cholesterol modification enables siRNA uptake by DCs in vitro and...
The Mutanome Engineered RNA Immuno-Therapy (MERIT) consortium will clinically and industrially validate a pioneering RNA-based immunotherapy concept that targets individual tumor antigens and tumor-specific mutations in triple negative breast cancer (TNBC) patients. This biomarker-guided, personalized therapy is a collaborative effort of five partn...
Poly ribonucleic acid (RNA) is the only polymer capable to recapitulate all processes of life: containment of genetic information, enzymatic activities and capacity to create defined 3D structures. Since it has a remarkable chemical stability (at neutral or acidic pH) and can be modified to enhance/reduce particular features (e.g., stability in bio...
Abstract is missing (Short communication).
Introduction
Recently Walter et al. (Nature med 2012) demonstrated that induction of T cell responses to tumor-associated antigens (TAA) after peptide vaccination (IMA901) is associated with significantly prolonged overall survival in patients with advanced renal cell carcinoma (RCC). Between August 2003 and November 2005 we performed a phase I/II...
Lactoferrin, a key component of innate immunity, is a cationic monomeric 80-kDa glycoprotein of the transferrin superfamily. Recombinant human lactoferrin, known as talactoferrin (TLF), induces a distinct functional maturation program in human dendritic cells (DCs) derived from peripheral blood monocytes. However, the receptors and molecular mechan...
Because they specifically kill dividing cells, untargeted chemotherapeutic drugs such as platin derivatives, antimetabolites or topoisomerase inhibitors for example impact the immune system resulting in more or less profound transient lympho- and/or myelo-ablations in treated patients. Although this side effect of chemotherapeutic regimens could be...
Functional differences between human dendritic cell (DC) subsets and the potential benefits of targeting them with vaccines remain poorly defined. Here we describe that mice with reconstituted human immune system components (huNSG mice) develop all human conventional and plasmacytoid DC compartments in lymphoid organs. Testing different Toll-like r...
CD4(+) T cells have been shown to be crucial for the induction and maintenance of cytotoxic T cell responses and to be also capable of mediating direct tumor rejection. Therefore, the anticancer therapeutic efficacy of peptide-based vaccines may be improved by addition of HLA class II epitopes to stimulate T helper cells. Survivin is an apoptosis i...
At the forefront of medicine, Gene Therapy brings you the latest research into genetic and cell-based technologies to treat disease. It also publishes Progress & Prospects reviews and News and Commentary articles, which highlight the cutting edge of the field.
Particle-mediated epidermal delivery (PMED) is a potent genetic vaccination method. However, a recent report found PMED only poorly and infrequently triggered antigen-specific cytotoxic T-cells in cancer patients. Here, we show that injection of the chemotherapeutic drug Gemcitabine in mice results in improvement of the efficacy of subsequent PMED...
The aim of this phase I/II nonrandomized trial was to assess feasibility, safety as well as immunological and clinical responses of a mRNA-based vaccination in patients with stage IV renal cell cancer using granulocyte-macrophage colony stimulating factor (GM-CSF) as adjuvant. Intradermal injections of in vitro transcribed naked mRNA, which was gen...
Most diseases with unmet medical needs can be addressed by one or several therapies based on RNA. Cancer-related diseases, for example, may be treated by one or a combination of RNA therapies. Similarly, the spread of infectious diseases such as AIDS or malaria may be prevented or treated with RNA-based therapeutics. This article discusses potentia...
Previous studies have shown that single-stranded RNA (ssRNA) mixed with protamine forms particles and activates immune cells through Toll-like receptors (TLRs). We have found that the size of protamine-RNA particles generated depends on the electrolyte content when mixing the 2 components. Moreover, we have evidenced that (1) nanometric particles i...
In mice, injection of messenger RNA (mRNA) coding for tumor-associated antigens can induce antitumor immune responses and therefore offers a broadly applicable immunotherapy approach. We injected intradermally protamine-stabilized mRNAs coding for Melan-A, Tyrosinase, gp100, Mage-A1, Mage-A3, and Survivin in 21 metastatic melanoma patients. In 10 p...
A phase I/II trial was conducted to assess feasibility and tolerability of tumor associated antigen peptide vaccination in hormone sensitive prostate carcinoma (PC) patients with biochemical recurrence after primary surgical treatment.
Nineteen HLA-A2 positive patients with rising PSA without detectable metastatic disease or local recurrence receiv...
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Background: We conduct a phase I/II monocenter clinical trial using multi peptide vaccination in patients with hormone naive, biochemically relapsed prostate cancer. The synthetic peptides applied are MHC-class I (HLA-A2) and -class II binders for activating CD4+ and CD8+ T- effector cells in vivo. Study endpoints are side effects as well as P...
