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"Currently things progress in major steps"

Personalised Cancer Therapies: "Currently things progress in major steps"


Photo: Ulrike Köhl

Assistant professor Ulrike Köhl; © private

The goal of personalised medicine is to be able to provide an individual disease forecast and to implement an accurate and fast treatment. Today new genetic and molecular findings, as well as the analysis of individual patient characteristics, already make first conclusions on the individual course of disease possible.

In the future thanks to biomarkers, cancer treatments could be almost exactly tailored to the needs of the individual patient to find a balance to the desired and damaging effects of a therapy.

But how far has research already progressed, and what milestones are still in store for personalized cancer therapy, especially for high risk patients? asked PD Dr. Ulrike Köhl, who researches new cancer treatments at the Pediatric Oncology Hematology and Hemostaseology Laboratory for Stem Cell Transplantation and Immunotherapy at the Clinical Center of the Goethe University in Frankfurt am Main, Germany Many cell-based therapies are already performed in clinical research. Of late, which of them have turned out to be especially reliable in the fight against cancer in high risk patients, for instance in leukemia therapy?

Ulrike Köhl: Particularly allogeneic stem cell transplantation should be mentioned here, where for example leukemia patients after high-dose chemotherapy receive stem cells from a family member or a so-called foreign donor. These stem cells have two functions: On the one hand they are responsible for regeneration, meaning the regeneration of the immune system through the stem cells of the donor and on the other hand they are in charge of the so-called graft-versus-leukemia effect (GvL effect). In the process lymphocytes form from the transplanted stem cells which are able to recognize and destroy remaining malignant cells in the patient’s body. For this reason, this is a classic cell and immunotherapy. Similarly for several years through additional donation of immune cells by the donor in the form of cell therapy, one tries to boost this GvL effect even more. How do you accomplish this?

Köhl: By especially purifying the cells of donors. This is called immunomagnetic purification. This procedure works under clean room conditions like in an operating room. In closed systems, specific cells with monoclonal antibodies coupled to magnetic beads can be marked. These are then separated in a sterile, closed system via a magnetic field from the unmarked cells. You can purify the specific immune cells, for example T cells or natural killer cells, and then expand them in culture. We administer this as cell therapy to patients with high-risk leukemia or tumors. Biomarkers assist in finding out what therapy is best for which patient. They open up new perspectives for diagnosis options. How far has research progressed here in terms of individualized medicine?

Köhl: Currently things progress in major steps. However, you need to clearly distinguish between studies that succeed with the aid of biomarkers to differentiate between high risk and low risk patients. This is important for developing a therapy compared to for instance using biomarkers for individualized therapy or personalized medicine. So far only a few patients are benefitting from the latter, but the topic certainly has a very promising future. However, we are still in the beginning stage.

Photo: An image of a DNA structure

For stem cell transplantation, the stem cells can come from a so-called matching foreign or family donor. In addition, there is the possibility for instance for children with high risk leukemia to transplant stem cells of their parents;
© Pargeter How do biomarkers manage to convey a recommendation for a personalized therapy and to reliably diagnose cancers?

Köhl: For several years now in breast cancer diagnostics, one succeeds very well in distinguishing women with so-called HER2-positive breast cancer - this is about a receptor for breast cancer cells - from female patients who for example have breast cancer without exhibiting this tumor antigen. Here the first group has a particularly highly malignant type of breast cancer. By using a specific antibody, Trastuzumab, women with HER2-positive breast cancer can be considerably helped. This example of personalized medicine thus pertains to clinical diagnostics as well as the therapeutic application. Of late, highly purified hematopoietic stem cells are being transferred to leukemia patients. How does this therapy work and for which of these patients is it interesting?

Köhl: For stem cell transplantation, the stem cells can come from a so-called matching foreign or family donor. In addition, there is the possibility for instance for children with high risk leukemia to transplant stem cells of their parents. The donor in this case is only haploidentical , so just half matching. Since during transplantation an immunological barrier is overcome for this, these stem cells have to be immunomagnetically purified to rid them of the aggressive immune cells of the donor. These aggressive immune cells can perform the positive graft-versus-leukemia effect very well, but it is also possible that these immune cells unfortunately can also attack healthy organs in the patient. This is called graft-versus-host disease. This reaction can run a very dangerous course in the patient. The larger the differences between donor and recipient are, the more intensively a stem cell transplant has to be purified. What is the current status on this?

Köhl: It already works very well, but it is dependent on the type of disease. Initially for patients with a medium or also low risk of leukemia, the matching foreign or family donor is preferred. The same goes for certain types of the disease, if a matching foreign donor is available anyway. For a particularly aggressive type of leukemia, for multiple relapses of the disease or if a matching foreign donor is unavailable, the haploidentical transplantation from parent to child, from child to parent or even from a non-matching foreign donor is the method of choice. In such cases the well-established process of specific purification is being used. How exactly are you using this method?

Köhl: Currently we are using two different procedures. On the one hand there is the so-called CD34 selection. CD34 is a marker on the surface of stem cells. By marking these stem cells with a subsequent purification via a magnetic column, high purity CD34-positive stem cells can be obtained. In doing so, you reach a purity grade of 97 to 98 percent. With this procedure you get high purity stem cells with few accompanying immune cells, so that the risk to trigger the dangerous graft-versus-host disease is very small. In the graft-versus-host disease the T lymphocytes that are enclosed in the graft of the donor attack the recipient’s organism. However, a graft without accompanying immune cells can slow down the engraftment of the transplant and the immune system regeneration. That’s why some of these accompanying immune cells should be available in the transplant.

Now we have optimized a second procedure that has been successfully used for several years. This is the so-called CD3/CD19 depletion. Here cells that are not desired are being marked. Those are for one the CD3+ T cells that are marked with immunomagnetic antibodies directed against CD3 and also the B cells that are labeled with anti-CD19 antibodies. Both cell types are extracted from the graft. The graft for the patient is made up of stem cells, of the so-called natural killer cells and also of monocytes and dendritic cells which are immunologically very important, since they can trigger an antitumor immune response. Such a graft is very attractive in regard to combating the remaining leukemia cells. This type of purification involves a larger amount of aggressive T cells than with the CD34-selection, therefore the patient needs high-dose immunosuppressive therapy. Both procedures thus are equal concerning the effectiveness for the patient. Oftentimes we opt for a mix of both procedures for our patients, since in many cases it is the optimal therapy. How many stem cells need to be engrafted in the patient to promise a possible cure or improvement?

Köhl: There is a kind of rule of thumb: At least two million stem cells per kilogram of body weight of the recipient for a matching foreign or family donor transplant. In haploidentical stem cell transplantation you overcome an immunological barrier. That’s why at a minimum you need seven million stem cells, preferably even ten or 15 million stem cells per kilogram of the patient’s body weight. Does this also apply to high risk patients?

Köhl: Initially this is the minimum limit for all patients who need an allogeneic stem cell transplant. Needless to say, if we are provided with five or six million stem cells per kilogram of body weight from a matching foreign donor, we love to give more since a larger number or stem cells for the most part leads to a faster cell recovery. The fast recovery of the immune system is particularly important to guard against a new disease outbreak and infections. In pediatric patients with high risk leukemia or tumors more and more often the haploidentical stem cell transplantation is also being used where we administer the previously mentioned larger number of stem cells. The activation of cytotoxic T cells is presently often discussed. What pros and cons in a nutshell result from this type of cellular immunotherapy?

Köhl: The cytotoxic T cells are a part of the so-called acquired immune system and are extremely important for recognizing and destroying leukemia and tumor cells. That’s why T cell therapies have already been used for several years now at the onset of a relapsing disease as a so-called donor lymphocyte infusion. However, they can also lead to the life-threatening graft-versus–host reaction and procure it. Here healthy tissue of the patient, for instance in the colon, is being attacked. The T cell therapies are therefore very carefully being used and as a general rule one starts with a small amount of donor T cells to achieve an effect and avoid side effects.

Photo: Man in laboratory

Mesenchymal stem cells can also currently be used to treat the dangerous graft-versus-host disease. This type of therapy however was only just tested in small beginning studies; © walter zerla What other personalized types of therapy would have the potential in the future to successfully combat against cancer?

Köhl: This is a difficult question, because we are still in the beginning stage. There is the possibility to create specific T cell therapies, so that the T cells are aimed at very specific infections, for instance against cytomegalovirus infection or mycosis fungoides. These antigen-specific T cells are immunomagnetically purified and are very effective against these pathogens. Due to the fact that the cells are highly purified, other T cells are missing. This way you avoid the dangerous graft-versus-host disease.

Another example are the natural killer cells which are a part of the inherent immune system and very early and effectively cause the destruction of cancer cells. Fortunately, these only rarely trigger the graft-versus-host disease. I would like to give you three more examples: The vaccination with dendritic cells which generally help to boost an antitumor or leukemia response. This type is also already being used in studies. Mesenchymal stem cells can also currently be used to treat the dangerous graft-versus-host disease. This type of therapy however was only just tested in small beginning studies. And then there is the combination of cell therapy and targeted therapies, the combination of Trastuzumab and NK cells for breast cancer patients. Trastuzumab can recruit NK cells which then very effectively lead to the destruction of breast cancer cells – and this is a typical example of a targeted therapy. To what extent are these new types more effective than the classic types of therapies like surgery, chemo therapy or radiation therapy?

Köhl: Generally I would not be so quick to talk about being “more effective“, since it always depends on the patient’s situation. For patients with low, sometimes also medium risk for disease, the classic type is still the most suited therapy. For example on the pediatric side we can classically heal more than 85 percent of children with acute lymphoblastic leukemia. With regard to the new therapy types it is in fact more about improving the chances of high risk patients who were severely pre-damaged due to chemotherapy and can barely tolerate it any longer. For these patients, I really see a big potential by means of new types of therapies to achieve a better healing process, particularly in combination with targeted therapy and cell therapy. What challenges will come your way in the development of personalized medicine?

Köhl: There are many. Immunology is very complex and particularly aggressive cancer cells can protect themselves well against immune cells and a directed attack. Currently, in Basel and Frankfurt a study on the effectiveness of natural killer cells in patients with high risk leukemia and tumors is being conducted. It is all about administering additional natural killer cells from their donors to patients after a haploidentical stem cell transplant. Even though we see positive effects from the natural killer cells, like for instance the destruction of cancer cells, we also notice resistance of cancer cells against this attack. In the serum of several patients we were able to provide evidence for a tumor marker, soluble MICA which massively blocks NK cell activity. This way actually a very effective therapy is almost disabled. That’s why we currently are developing a new therapy to neutralize this tumor marker or remove it from the bloodstream. In addition, we have run another path to specifically tie up the natural killer cells to the cancer cells, so they can effectively destroy the cancer cells. This sounds easy, but it is very complicated and complex. There still is a long and bumpy road ahead of us, but it is important for the patients to follow this path. This is a challenge in terms of personalized medicine. Many of these types of therapies are, as you mention, in their infancy, but they are already being used. How well do we already know the precise mechanisms of this cell therapy?

Köhl: By now we know a lot about the mechanisms of individual cells, the T cells, the natural killer cells, the dendritic cells, how they act and how they attack and in parts we also comprehend the interactions between cells. However, you have to realize that the human immune system is very complex and that’s why we don’t exactly know many of these cell interactions. That’s why it is hard to assess, what different interactions for individual cell therapies take place in a patient. Only the future will show us, in controlled Phase I/II clinical trials. How many patients are actually already being treated with this therapy?

Köhl: This is quite palpable for allogeneic stem cell transplantation. Right before the turn of the century there were just 1200 stem cell transplants each year in Germany. The number has doubled within the span of ten years, which is mainly due to the effectiveness of this type of therapy. Today we are clearly at over 2200 stem cell transplantations per year and approximately 10 percent of them are performed in children. Initially we start with Phase I clinical trials for new cell therapies and check for side effects that are supposed to clarify whether the therapy is actually applicable. Generally this is about a number of patients of 20 participants. If you register few side effects here and already gather some experiences in preclinical trials in terms of effectiveness, you then continue on with a follow-up study and a larger number of patients after the completion of the first survey to be able to specifically evaluate the effectiveness. What differences can you detect in leukemia cases of children and grown-ups?

Köhl: There are many differences but also many similarities. If you just look at the large group of leukemia diseases, there are significant differences between childhood and adulthood. This means the type of leukemia is a different one. In childhood for example acute lymphoblastic leukemia is more at the forefront and in adulthood acute myeloid leukemia occurs more often. The type of leukemic blasts is different in childhood and adulthood, so that also different therapy schemes have to be applied. If in contrast one considers the immunological side, then the mode of action of cells opposite cancer cells is very similar. That’s why a development of cell therapies also takes place relatively parallel and comprehensively with research groups from the internal medicine and pediatrics disciplines. For instance, we are conducting the NK cell clinical trials in Frankfurt with children and simultaneously there is a clinical trial with adult patients in Basel. But there are also differences between children and adults from an immunological perspective. Immune reconstruction, the cell regeneration after stem cell transplantation proceeds significantly faster in children than in adult patients. This is due to the so-called thymus, which still completely exists in small children and can barely be found in an old person. Are these therapies paid for by the health insurance companies or are they only paid for within the scope of clinical trials?

Köhl: Health insurance companies in Germany pay for the therapies, if in controlled studies the effectiveness and if applicable also the advantage of one type of therapy compared to classic therapy was proven. Currently for instance this applies to several types of stem cell transplantations. For new developments in the scope of stem cell transplantation or cell therapies, the researcher first - by for instance making an application and spending a lot of time and effort – has to obtain the significant financial means and total costs for such a therapy. That’s the current status.

The interview was conducted by Diana Posth and translated by Elena O’Meara.


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