High–tech immunotherapy is the new hope of oncohematology
Currently, many patients with newly diagnosed blood diseases, ranging from oncological to rare hereditary diseases, respond well to modern therapeutic protocols. However, in more than 50% of cases, therapy eventually loses its effectiveness or the patient develops a relapse, which can significantly worsen the prognosis of the course of the disease.
Improving the effectiveness of treatment by influencing specific targets responsible for the development of diseases is the task of a new actively developing direction, called precision ("high-precision") medicine". One example of the application of the principles of precision medicine is the use of modified patient's own cells to fight the disease.
At the 55th Annual Congress of the American Society of Hematology, held on December 7-10 in New Orleans, several research groups presented preliminary results of the application of a method of cellular engineering known as chimeric antigen receptor technology, or CAR-technology (from the English chimeric antigen receptor). This technology consists in isolating T-lymphocytes from the patient's blood and their two-component modification: attaching to their surface a receptor that recognizes CD19 protein expressed by most leukemic cells, and introducing a powerful intracellular mechanism that triggers active cell growth and division in response to their interaction with the target protein. Such modified T-lymphocytes are injected back into the patient's bloodstream, where they begin hunting for malignant cells.
Preliminary research results indicate that this approach can give good results in 2/3 of patients who have not responded to all traditional methods of treatment. Moreover, the introduction of the patient's own cells is associated with a minimal risk of developing a graft-versus-host reaction, in which the transplanted immune cells attack the recipient's tissues.
Another achievement of cellular engineering, which was reported at the congress, is the use of gene therapy using a new generation of viral vectors that self-destruct after delivering therapeutic genes to patients' cells. This solves the problem of the appearance of an excessively large number of T-lymphocytes, identified during earlier studies.
Finally, selective removal of certain cell subtypes from haploidentical (50% identical) transplants before their introduction may significantly expand the possibilities of using such transplants for the treatment of patients who do not have fully compatible donors in the coming years.
According to Dr. Laurence Cooper from the University of Texas, the initial results obtained to date from the use of modified immune cells look very encouraging. Especially impressive are the long periods of remission in patients with aggressive forms of diseases that have recurred after the use of standard therapy protocols. However, there are still several tasks to be solved in the future. It is necessary to find out the reason why some patients show improvement, while others react worse to therapy. Is it worth developing universal protocols in this case, or does T-cell therapy require an individual approach? Moreover, it is necessary to check the feasibility of applying the developed approaches to other diseases, especially solid tumors.
The following are abbreviated translations of the most interesting reports on this topic.
Bertaina et al. [157]
The removal of alpha/beta+ T and CD19+ B cells from the transplant ensures rapid engraftment, the absence of a graft-versus-host reaction affecting internal organs, and low mortality due to transplantation in children with acute leukemia who underwent transplantation of hematopoietic stem cells haploidentical in the HLA system
Transplantation of haploidentical (half-compatible) hematopoietic cells can be an effective way out for patients who do not have a fully compatible donor. However, until now, compared with the use of a transplant from a fully compatible donor, this method has been associated with an increased risk of infections and disease recurrence. As part of this study, Italian scientists analyzed the effectiveness of manipulations on haploidentical donor stem cells carried out in the laboratory.
The authors selectively removed alpha/beta+ T and CD19+ B cells from the donor graft, since they most often trigger the process of destruction of the recipient's tissues by donor immune cells, leading to a life-threatening complication known as the "graft versus host reaction" (GVHD). At the same time, this manipulation preserves healthy mature immune cells in the transplant: natural killer cells and gamma/delta+ T lymphocytes, which prevent the recurrence of the disease and the development of infections.
In total, 45 children with acute leukemia participated in the study, who received haploidentical transplants from one of their parents. In 44 out of 45 patients, graft engraftment occurred, while in only 29% of cases there were manifestations of moderate GVHD. None of the patients developed hepatic or acute forms of GVHD. A month after transplantation, the examination showed that the transplanted cells were preserved in the recipients' body and showed pronounced antileukemic activity, increasing over time.
According to one of the authors, Alice Bertaina from the Bambino Gesu Children's Clinic in Rome, the data obtained demonstrating the equivalence of the results of transplantation of selectively modified haploidentical donor stem cells to the results of using completely identical transplants are an additional confirmation of the feasibility of using this approach for the treatment of patients who do not have a fully compatible donor.
Hacein-Bey-Abina et al. [715]
Immune recovery and preliminary safety analysis with the participation of 9 patients who underwent somatic gene therapy as part of the treatment of X-linked severe combined immunodeficiency (TCID-X1) using a self-inactivating gamma retroviral vector
Previously, experts have already studied the possibility of using gene therapy using a retroviral vector for the treatment of children with a lethal hereditary disease – X-linked severe immunodeficiency (TKID-X1). Such a vector attaches to the surface of T-lymphocytes and injects into the cells the genetic material necessary for the formation of full-fledged immune cells. This approach proved to be quite successful, but some patients subsequently developed leukemia. The reason for this was the embedding of therapeutic genes into the so-called trigger regions of patients' DNA, triggering the malignancy of T-lymphocytes.
To overcome this problem, researchers have developed a new modified self-inactivating adenovirus vector. In a clinical study conducted in clinics in France, Germany, the UK and the USA, 9 boys with TKID-X1 took part. CD34+ hematopoietic stem cells were isolated from the patients' bone marrow, modified with a new vector, and injected into the patients' bloodstream.
1 out of 9 patients subsequently died from an active adenovirus infection diagnosed in him before the therapy. Another patient who did not respond to treatment was transplanted with incompatible donor cord blood. Examination of the remaining 7 patients demonstrated the formation of almost normal immunity and the absence of infections that usually affect patients with TKID. Analysis of the nature of the insertion of the therapeutic gene showed a significantly lower probability of involvement of trigger regions of DNA compared to that observed in earlier studies.
According to one of the authors, Sung-Yun Pai from the Boston Center for Pediatric Oncology and Blood Diseases, preliminary evidence has been obtained that the use of a new vector is as effective as the traditional approach, but can eliminate the risk of developing leukemia in the future. The researchers plan to closely monitor patients to assess long-term risks, but at the current stage, the excellent results obtained give them great hopes.
Kalos et al. [163]
Long-term preservation of functions, efficacy against B-cell aplasia and leukemia in the treatment of resistant malignant diseases affecting B-lymphocytes after T-cell immunotherapy with CAR-modified CD19-specific T cells
Researchers at the University of Pennsylvania and the Children's Clinic of Philadelphia analyzed the reactions of patients who participated in clinical trials of experimental methods of treating adults and children with leukemia using genetically modified CAR-technology T-lymphocytes. The analysis included different cohorts of patients, including children and adults with severe treatment-resistant acute lymphocytic leukemia and adult patients with severe relapses and/or treatment-resistant chronic lymphocytic leukemia. The purpose of this work was to clarify the patterns of behavior of modified T-lymphocytes in patients after treatment, as well as the relationship of these patterns with the antileukemic activity of transplanted cells. To accurately assess the quality, life expectancy and activity of modified cells in the patient's body, researchers have developed a set of special tests. Their use showed that patients with the most pronounced proliferation of T-lymphocytes (the number of modified cells reached 5% or more of all the patient's T-cells) were highly likely to develop a complete response to therapy. In patients with less pronounced but significant cell proliferation, a partial response to therapy was recorded, while the absence of detectable T-cell proliferation corresponded to a lack of response to treatment. In patients with a complete response to therapy, modified T cells were usually detected many months after administration, while they demonstrated full functional activity.
Grupp et al. [67]
T cells modified with a chimeric antigen receptor (CAR) specific to CD19 (CTL019) demonstrate pronounced proliferation in vivo, as well as provide a complete response to therapy and long-term functioning in the body without the development of GVHD in children and adults with recurrent acute lymphocytic leukemia
As part of this study, scientists from the University of Pennsylvania and the Children's Clinic of Philadelphia processed the results selected according to special criteria obtained during a number of clinical studies using CAR-modified proprietary T-lymphocytes of patients specific to the CD19 antigen expressed by tumor cells in the treatment of 16 children and 4 adults with relapsed treatment-resistant acute lymphocytic leukemia.
A complete response to therapy was registered in 14 patients, 3 patients did not respond to treatment. Information about the 3 remaining patients was not available at the time of the analysis. In three patients who responded to treatment, the disease subsequently relapsed again, while the remaining 11 patients were in remission at the time of examination (1.2-15 months after therapy).
None of the patients had any manifestations of toxicity and GVHD associated with the introduction of cells. The most serious side effect diagnosed in each of the patients was a complication known as delayed cytokine release syndrome, manifested by fever, muscle pain and nausea. The cause of these symptoms is the active proliferation of modified T-lymphocytes, triggered by their interaction with malignant cells.
According to one of the authors, Dr. Stephan Grupp, based on the data obtained as a result of relatively short-term monitoring of the condition of patients, there is every reason to assume that over time this therapy may become a worthy option for patients with recurrent forms of lymphocytic leukemia resistant to traditional methods of treatment.
Kochenderfer et al. [168]
Effective treatment of chemotherapy-resistant diffuse large-cell B-cell lymphoma with autologous genetically modified T cells expressing the anti-CD19 chimeric antigen receptor
Within the framework of this study, 15 patients with late-stage malignant diseases of B-lymphocytes underwent therapy with modified T-lymphocytes specific to the CD19 antigen using CAR technology. As a result, 6 patients went into full remission and 6 into partial remission. At the same time, all acute side effects of therapy, such as fever, low blood pressure, focal neurological disorders and delirium resolved within less than three weeks.
According to one of the authors, Dr. James Kochenderfer from the US National Institute for Cancer Research, this study provides the first evidence of the possibility of using this approach to treat aggressive bodices that have not actually succumbed to therapy until now. Moreover, patients with chemoresistant large-cell B-cell lymphomas are usually not recommended for hematopoietic stem cell transplantation, so immunotherapy with genetically modified T-lymphocytes gives them new hope for a cure. Of course, today the therapy is in the early stages of development, but researchers will continue to work on improving the protocol.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Medical Xpress materials:
High-tech gene-therapy advances offer hope for patients with hard-to-treat blood disorders.
13.12.2013