Jonas Mattsson's Group
Research at the Centre for allogeneic stem cell transplantation (CAST), Karolinska University Hospital, Sweden
The bone marrow produces white blood cells that build up our immune system, red blood cells that carry oxygen to all body cells and platelets that enable the blood to efficiently clot. Hematopoietic stem cell transplantation (HSCT), or bone marrow transplantation which it was called earlier, is nowadays an established treatment for a range of diseases that affect the body's blood stem cells such as leukemia, severe anemia, immune defects, and some more unusual enzyme deficiency diseases. These illnesses often leads to that the patient needs to have his bone marrow replaced by new, healthy blood cells.
Allogeneic stem cell transplantation means that the patient receives stem cells from another individual, either a sibling or unrelated, volunteer donor. Today is estimated that about 30% of patients in need of HSCT have access to a sibling whose tissue type is suitable. The other 70 percent must rely on the existence of an unrelated, volunteer donor that fit. Today there are more than 20 million volunteer donors in registries around the world. It is important that donor and patient cell characteristics are comparable. On the surface of a person's cells are tissue markers that are specific for each individual. These are called MHC molecules and help the white blood cells to recognize what is "own" and "not own". Cells with 'non-own' MHC are perceived as alien and are killed.
Before the transplant, all patients are treated with chemotherapy and / or radiation. The purpose of this pre-treatment is to remove as many cancer cells in the body as possible and to remove their own immune system so that the new, healthy marrow is not rejected. Donor's healthy stem cells are then given to the patient as a blood transfusion. Although the donor and the patient's cells appear to be equal in terms of tissue type, i.e. the MHC molecules are matched; there are still minor differences between these individuals that immune cells can perceive as dangerous. This means that the new immune system (white blood cells from the new stem cells) perceive the new body as "foreign", which provokes an immune attack. This reaction, called graft-versus-host disease (GVHD), affects primarily the remaining blood cells from the patient's "old" marrow and kills them. The type of white blood cells that is responsible for this attack (which also affects the cancer cells) is called T cells. For leukemia patients, this is a very desirable response, because it helps to destroy residual cancer cells that survived the pre-treatment. Unfortunately, GVHD reaction can also affect other body parts and if the reaction becomes excessive it can become life threatening for the patient. GVHD is therefore both good and evil. A certain reaction from the donor cells against the patient is wanted, while not too powerful. The ideal would be to find a way to get rid of the GVHD while the so-called graft-versus-leukemia effect (GVL) is maintained. In more severe GVHD, there is no effective treatment today. It is also well known that it is easier to prevent than treat GVHD. It is therefore of great importance to develop new, sensitive methods so patients at risk of severe GVHD can be identified early.
All patients after HSCT have an increased risk of infections due to absence of white blood cells before the new marrow begins to function. This period can in some cases last for many weeks until the new immune system have matured. Some of these opportunistic infections after HSCT may be life threatening
The most common and threatening complication in patients with malignant disease after HSCT, is relapse. Today, we have developed methods for early detection to see which patients are at increased risk. In these patients, we can enhance anti-cancer effect after HSCT by additional new immune cells from the original donor. However, this is also associated with an increased risk of severe GVHD. In addition, cancer cells although there are several ways to avoid being attacked. The most serious complications after HSCT are therefore GVHD, infections and relapse of the malignancy.
Early detection of GVHD
In our group we are studying three different possible methods which will enable early detection of GVHD after HSCT.
To reduce the risk of GVHD in SCT from unrelated donors we routinely give anti-thymocyte globulin (ATG). In a pilot study we found that patients with low serum levels of ATG, on the day of transplantation, are at increased risk of developing severe acute GVHD.
In another prospective study, we have also seen that low levels of certain cytokines (a cytokine = "immune hormone") on the day of transplantation was correlated with higher risk of GVHD after HSCT.
We are also collecting sample of sibling pairs before HSCT. These cells are used against each other in different immunological tests and the results correlates with certain important parameters, such as GVHD, after transplantation. The objective is to seek out a prediction marker already before transplantation which may enable us to predict GVHD or even choose donor.
Treatment of opportunistic infections
Several viral infections e.g. CMV, EBV and adenovirus can be life threatening after HSCT. EBV can even in some cases cause cancer, EBV lymphoma, which is a very severe complication and associated with a high rate of mortality. T cells specific for the EBV virus from the original donor is often an effective treatment of EBV lymphoma. This is though very laborious and time-consuming (at least 6 weeks).
We have developed a novel method for efficiently separating out specific T cells that only kill EBV-infected cells. We recently treated a patient with life-threatening EBV lymphoma after transplantation by selecting EBV-specific cells from the patient's mother which were infused into the patient. The patient responded and is now cured from this life-threatening complication. Similarly, we have treated three patients with severe CMV infection not responding to conventional therapy. All three responded to the treatment without complications.
We are now isolating EBV-specific T cells from patient's parents or siblings of a patient developing EBV lymphoma after transplantation. We now produce these cells within one day. We will also produce T cells that can kill CMV virus, either from the original donor or relatives, and treat patients who do not respond to usual treatment or where the situation is life threatening. Treatment may be by extension also be used to treat severe viral diseases in other patients.
Treatment of cancer – Cord blood
Umbilical cord blood (CB) transplantation is used increasingly as therapy for both children and adults. Patients in risk of relapse of the underlying malignant disease or if the CB stem cells are being rejected there is no alternative for further treatment. After HSCT with a sibling or unrelated donor, we give T cells as an additional treatment from the original donor. This is not possible after CB SCT.
We have now in our lab developed a protocol to grow T cells from the umbilical cord blood, which can be used to treat patients if the leukemia comes back or if the patient's immune system starts rejecting the transplanted cells. We will evaluate how the cultured T cells from cord blood immune function and treat children and adults who may be threatening rejection or relapse.
Treatment with CD19 chimeric antigen receptors transduced cells
B-cell malignancies consist of a heterogeneous group of leukemias and lymphomas and despite improvements in treatment strategies many patients, both children and adults, still succumb to the diseases.
In patients with the most common lymphoma, diffuse large B-cell lymphoma (DLBCL), 30-50% of the patients are not cured by standard treatment today. The same holds true for patients with B-cell chronic lymphocytic leukemia (CLL) and mantle-cell lymphoma (MCL) who generally cannot be cured by current treatment modalities. Therefore new treatment options are clearly needed for these diseases.
Leukemia is the most common pediatric malignancy, accounting for 30% of all pediatric cancers. Improvement in treatment of pediatric acute lymphoblastic leukemia (ALL) have achieved cure rates of over 80%, but still relapsed leukemia remains the commonest cause of pediatric cancer death. To address the problem of limited success with today’s available treatment for these patients novel cellular therapies using genetically modified, tumor specific T cells have gained interest.
It is now possible to efficiently introduce genes encoding chimeric antigen receptors (CARs) into immune effector cells. In most clinical applications, a patient’s own T cells are reprogrammed to express these tumor-specific receptors. To this end, most clinical trials in the field of CAR technology for leukemia have targeted CD19 since it is expressed on most B-cell malignancies. In spite of extremely encouraging results there is only today one multi-centre study in Europe recruiting patients.
This project will increase the chance of cure in patients with otherwise dismal prognosis.
Jonas Mattsson, Chief physician, Associate Professor, Group leader
Mats Remberger, Professor
Brigitta Omazic, Chief physician, PhD
Melissa Norström, Postdoc
Ola Blennow, MD, PhD
Berit Sundberg, Laboratory technician
Mats Engström, MD, PhD student
Sofia Berglund, MD, PhD student
Gustaf Fjärtoft, MD, PhD
Eva Martell, Research nurse
T-cell receptor excision circle levels after allogeneic stem cell transplantation are predictive of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome.
Stem Cells Dev. 2014 Jul;23(14):1559-67
Cord blood T cells cultured with IL-7 in addition to IL-2 exhibit a higher degree of polyfunctionality and superior proliferation potential.
J. Immunother. 2013 Oct;36(8):432-41
Factors with an impact on chimerism development and long-term survival after umbilical cord blood transplantation.
Transplantation 2012 Nov;94(10):1066-74
Rapid salvage treatment with virus-specific T cells for therapy-resistant disease.
Clin. Infect. Dis. 2012 Oct;55(8):1064-73
Effects of different serum-levels of ATG after unrelated donor umbilical cord blood transplantation.
Transpl. Immunol. 2012 Aug;27(1):59-62
Expansion of T-cells from the cord blood graft as a predictive tool for complications and outcome of cord blood transplantation.
Clin. Immunol. 2012 May;143(2):134-44
Thymic function after allogeneic stem cell transplantation is dependent on graft source and predictive of long term survival.
Clin. Immunol. 2012 Mar;142(3):343-50
Clinical expansion of cord blood-derived T cells for use as donor lymphocyte infusion after cord blood transplantation.
J. Immunother. 2010 Jan;33(1):96-105
A novel haplo-identical adoptive CTL therapy as a treatment for EBV-associated lymphoma after stem cell transplantation.
Cancer Immunol. Immunother. 2010 Mar;59(3):473-7