Researchers at Heidelberg University Hospital (UKHD), the German Cancer Research Center (DKFZ), and the National Center for Tumor Diseases (NCT) Heidelberg have treated adults who have acute lymphoblastic leukemia (ALL) with third-generation CAR T cells. Their study found high efficacy with comparatively mild side effects, opening up new therapeutic perspectives for patients with ALL.
The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center (DKFZ) and Heidelberg University Hospital (UKHD).
Acute lymphoblastic leukemia is difficult to treat in adult patients and is associated with a poor prognosis. Researchers at the UKHD, DKFZ, and NCT Heidelberg took a new approach in a study: They treated 13 adult patients with ALL who had not responded to the standard treatment or had suffered a relapse of the disease (refractory/relapsed; r/r ALL) with third-generation CAR T cells. CAR means chimeric antigen receptor.
Third-generation CAR T cells contain two specific components (called costimulatory domains) within their CAR construct that are present only once in second-generation CAR T cells. Preclinical and clinical studies have proved that third-generation CAR T cells have higher clinical efficacy and longevity. However, so far, there has been very little clinical data evaluating only third-generation CAR T cells available.
The Heidelberg CAR Number 1 (HD-CAR-1) study aimed to provide new insights here. In the study, all treatment steps were performed in Heidelberg, including the separation of the white blood cells from the other blood components, the production and administration of the CAR T cells, patient monitoring, and patient follow-up.
Maria-Luisa Schubert, Department of Hematology, Oncology and Rheumatology at UKHD, is first author of the publication. She says, "Commercially available and approved products use second-generation CAR T cells. Our study distinguishes itself because we treat adult ALL patients with third-generation CAR T cells of our own manufacture according to the quality-assurance guidelines of Good Manufacturing Practice." The study was realized in collaboration with the DKFZ.
The 13 study participants received increasing doses of CAR T cells directed against the B lymphocyte antigen CD19. 90 days after the CAR T cell treatment, ten patients had a response. Eight patients achieved complete remission, and their disease was no longer detectable by standard methods. In addition, even the minimal residual disease (MRD) was undetectable in five patients. After one year of observation, more than half of the study participants were alive, and the progression-free survival (PFS) was 38 percent.
Michael Schmitt, Head of Cell and Immunotherapy at the Department of Hematology, Oncology and Rheumatology of the UKHD, led the study and is one of the leading authors. He says, "The high efficacy of treatment with third-generation CAR T cells is a very gratifying result. And the fact that we observed only comparatively weak side effects makes the result all the more valuable." In the trial, no patient developed the dreaded neurological symptoms known as immune effector cell-associated neurotoxicity syndrome or higher-grade cytokine release syndrome.
Carsten Müller-Tidow, Medical Director of the Department of Hematology, Oncology and Rheumatology at the UKHD, says, "We are very pleased to have achieved such a promising result with our study, which opens up new perspectives for patients severely affected by ALL. I want to thank all those involved in the study for their commitment."
The publication:
Maria-Luisa Schubert, Anita Schmitt, Angela Hückelhoven-Krauss, Brigitte Neuber, Alexander Kunz, Philip Waldhoff, Dominik Vonficht, Schayan Yousefian, Lea Jopp-Saile, Lei Wang, Felix Korell, Anna Keib, Birgit Michels, Dominik Haas, Tim Sauer, Patrick Derigs, Andreas Kulozik, Joachim Kunz, Petra Pavel, Sascha Laier, Patrick Wuchter, Johann Schmier, Gesine Bug, Fabian Lang, Nicola Gökbuget, Jochen Casper, Martin Görner, Jürgen Finke, Andreas Neubauer, Mark Ringhoffer, Denise Wolleschak, Monika Brüggemann, Simon Haas, Anthony D. Ho, Carsten Müller-Tidow, Peter Dreger & Michael Schmitt: Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial; Journal of Hematology & Oncology (2023) 16:79, https://doi.org/10.1186/s13045-023-01470-0
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The National Center for Tumor Diseases (NCT) Heidelberg
The National Center for Tumor Diseases (NCT) Heidelberg is a joint institution of the German Cancer Research Center, Heidelberg University Hospital and German Cancer Aid. The NCT's goal is to link promising approaches from cancer research with patient care from diagnosis to treatment, aftercare and prevention. The interdisciplinary tumor outpatient clinic is the central element of the NCT. Here the patients benefit from an individual treatment plan prepared in a timely manner in interdisciplinary expert rounds, the so-called tumor boards. Participation in clinical studies provides access to innovative therapies. The NCT thereby acts as a pioneering platform that translates novel research results from the laboratory into clinical practice. The NCT cooperates with self-help groups and supports them in their work. Since 2015, a second site for the NCT beside Heidelberg has been under development in Dresden.
German Cancer Research Center (DKFZ)
With more than 3,000 employees, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is Germany’s largest biomedical research institute. DKFZ scientists identify cancer risk factors, investigate how cancer progresses and develop new cancer prevention strategies. They are also developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to questions relating to cancer.
To transfer promising approaches from cancer research to the clinic and thus improve the prognosis of cancer patients, the DKFZ cooperates with excellent research institutions and university hospitals throughout Germany:
- National Center for Tumor Diseases (NCT, 6 sites)
- German Cancer Consortium (DKTK, 8 sites)
- Hopp Children's Cancer Center (KiTZ) Heidelberg
- Helmholtz Institute for Translational Oncology (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim
- National Cancer Prevention Center (jointly with German Cancer Aid)
The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.
Heidelberg University Hospital and Faculty of Medicine: Internationally Renowned Patient Care, Research and Teaching
Heidelberg University Hospital (Universitätsklinikum Heidelberg, UKHD) is one of the largest and most prestigious medical centers in Germany. The Medical Faculty of Heidelberg University (Medizinische Fakultät Heidelberg, MFHD) belongs to the internationally renowned biomedical research institutions in Europe. Both institutions have the common goal of developing new therapies and implementing them rapidly for patients. Heidelberg University Hospital and the Medical Faculty of Heidelberg University employs around 14.500 employees and is committed to providing trainings and qualifications. Every year, around 86,000 patients and more than 1.100.000 outpatient cases are treated in more than 50 clinical departments with almost 2.500 beds. Together with the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and the German Cancer Aid, the UKHD established the first National Center for Tumor Diseases (NCT) in Heidelberg. The goal is to provide care at the highest level as an oncology center of excellence and to rapidly transfer promising approaches from cancer research to the hospital. In addition, the UKHD operates in partnership with the DKFZ and the University of Heidelberg the Hopp Children’s Cancer center Heidelberg (KiTZ), a unique and nationally known therapy and research center for oncological and hematological diseases in children and adolescents. The Heidelberg Curriculum Medicinale (HeiCuMed) is one of the top medical training programs in Germany. Currently, there are about 4.000 future physicians studying in Heidelberg.