Cancer cells are tricky opponents: To avoid being recognized by the immune system, they usually disguise themselves, by reducing certain molecules on their surface. CAR-T cells expose this disguise. “With the CAR-T cells, cells from the patient’s own immune defense are changed genetically, so that they recognize the surface structures typical for certain cancer cells. They bind to the cancer cells and then destroy them”, says Prof. Michael Schmitt, holder of the Chair for Cellular Immunotherapy endowed by the Siebeneicher Stiftung and Head of the Good Manufacturing Practice Facility (GMP Facility), where the CAR-T cells are developed and manufactured. “CAR” stands for “Chimeric Antigen Receptor” – a type of “gripper”, with which the T-cells are equipped in order to find and destroy the cancer cells.
CAR T Cells Actively Attack Tumors
Impulses for immunotherapies for cancer
CAR T cells actively attack tumors
CAR-T cells are completely new players in the field of immune cell therapy: The patient’s own immune cells are changed using a gene-technology process so that they can recognize and fight certain forms of leukemia and lymph node cancer (lymphoma).
The Department for Hematology, Oncology and Rheumatology at the Heidelberg University Hospital is one of the first facilities in Germany to manufacture these genetic medications and to be allowed to use them as part of a clinical trial.
Small cells – large hopes: CAR-T cells mature and reproduce in the incubator.
Prof. Michael Schmitt, Head of the Good Manufacturing Practice Facility (GMP Facility) and Prof Carsten Müller-Tidow, Medical Director of the Department of Internal Medicine V in the lab.
CAR T-Cell Therapeutic Procedure
As part of a CAR-T treatment, white blood cells (T cells) are first removed from the patient during dialysis (1). They are incubated, activated, and genetically altered for 14 days. Subsequently they develop a molecule – the “gripper” on their surface – that binds to the CD19 antigen (2). CD19 is found on over 95 percent of the cancer cells of patients with acute lymphatic leukemia, chronic lymphatic leukemia, or B-cell lymphoma. The altered cells are tested for sterility for another two weeks and the patient undergoes chemotherapy before receiving the CAR-T cells. Then the cells are returned to the patient through a vein (3). They bind with and destroy the cancer cells (4).
Overall 22 patients (as of October 2020) to date have been admitted to clinical trials and treated with products that we manufactured. The initial results have been encouraging: “We saw a response in half of the patients, in some even a complete response to this therapy” summarizes Prof. Carsten Müller-Tidow, Medical Director of the Department for Hematology, Oncology and Rheumatology. “However, it remains to be seen how the patients will develop in the first year after the treatment. Sometimes a complete success only emerges after a few months.”
“There was no alternative” – How one of the first Heidelberg patients experienced the CAR-T therapy
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On Feb. 28, 2007 at 6:15 a.m.: Martin Schmidt (*) climbs out of the cockpit for the last time, after 34 years as a pilot for Lufthansa. He has seen many countries, met many people, mastered many difficult situations – now it is time to retire associated with a mild regret, but with nice plans for the future. What Schmidt does not suspect: His largest challenge is just ahead. About one year after his last flight, shortly before his 60th birthday, he receives the serious diagnosis: He is suffering from mantle cell lymphoma, a malignant disease of the lymphatic system, which leads to a disruption of blood formation and adversely affects the immune system. Once you have the diagnosis, there is no time to loose, because the disease progresses rapidly, if left untreated.
CAR-T cells as the last chance
For Martin Schmidt, a struggle begins which has lasted for eleven years meanwhile. Three stem cell transplantations help at first, but relapses occur again and again. He does not have many possibilities anymore and he is doing poorly, when Prof. Dr. Peter Dreger, Head of the Heidelberg Stem Cell Transplantation Unit and his attending physician, tells him in the summer of 2018: “There is a new therapeutic approach. HUK has the approval to develop and use its own CAR-T cells.”
The patient must decide quickly: Does he want to take the risk and undergo a comparatively new form of treatment? The battle between CAR-T and cancer cells can be severe. One possible risk is that the newly developed “killer cells” trigger a particularly violent, life-threatening inflammatory reaction – a so-called cytokine storm. Schmidt considers this and discusses the situation with his wife Marianne. However, it is quickly clear to both that “there is no alternative.” He agrees, relies on his physicians and on his optimism, which has accompanied and protected him for many years during flights around the globe.
The tumor shrinks
At the beginning of the CAR-T treatment, Martin Schmidt first receives the lowest possible dose of genetically modified cells, the blood values improve for a short time, but then get worse again. This is a blow, but the patient and the physicians do not give up. A second attempt is made with a twenty-fold dose of genetically changed CAR-T cells, preceded by a renewed, preparatory chemotherapy and light radiation of the eye. “Nothing happened at first,” he recalls. “But after three days, the tumor behind the eye melted like snow in the sun.” The swelling in the eye and the other detectable tumors have receded, as have the tumor cells circulating in the blood.
Martin Schmidt is home again in the meantime. It would be an exaggeration to say that he does not have any complaints – he has to take multiple medicines and be on his guard against infections. His immune defense is weak and minor infections can have major impacts. But he feels no pain; on the contrary, he is fully of zest for life. He and his wife are making travel plans. “Tegernsee is beautiful”, she suggests. He says: “California, at least four weeks”.
(* The name has been changed.)
Prospects for other types of cancer
Other patients received commercial products for the use of which Heidelberg University Hospital, as one of the first facilities in Germany to do so, qualified in 2019. The approval of the preparations is currently restricted to diffuse large B-cell lymphoma (DLBCL) and – only for patients under 25 years of age – to acute lymphatic leukemia (ALL), if the standard treatments have failed.
But why does the University Hospital develop its own applications if there are already commercial suppliers on the market? “In this way, we can help people who do not fall under the strict terms of the authorization requirements for the commercial products”, says Prof. Carsten Müller-Tidow. “Moreover, with approximately 300,000 euros per treatment, the costs for the already authorized products are very high”, adds Carsten Müller-Tidow. “Our own products can be made available more affordably and more quickly.” Furthermore, this makes additional research possible, in order to develop new and even better treatments.
In the mid-term it is hoped that this form of gene therapy will partly replace stem cell transplants and can be expanded to other types of blood cancer on the basis of the accompanying research work. Until now, treatment with CAR-T cells manufactured at the University Hospital is only possible within the framework of clinical trials. The Heidelberg researchers would like to take the next step and request a so-called hospital exception approval after the completion of the current trial with the Paul-Ehrlich-Institute as the authority responsible. If this is granted, the statutory health insurance providers would reimburse the costs of the treatment. “With an exception for the hospital, we could treat many more people on our own”, says Müller-Tidow. “We have a service obligation which we would like to fulfill in the best possible way while saving resources.”
Impulses from strong teams
When cancer tears their world apart, cancer patients fight not only the disease, but always with many everyday challenges. Elena Hemlein and Matthias Hoffmann are jointly available as a team of consulting services experts in order to comprehensively support, accompany patients, and help them in crisis situations during their illness. They organize, for example, a suitable rehabilitation facility or coordinate comprehensive home care – depending in what is required.