Leukemic cell vaccinations in relapsed patients with CML after allogenic blood stem cell transplantation

Um eine anhaltende Remission bei Patienten mit chronischer myeloischer Leukämie nach allogener Stammzelltransplanation zu erreichen, werden heutzutage verschiedene Therapien angewendet. Unter anderem appliziert man diesen Patienten je nach Remissionsstatus Donor-Lymphozyteninfusionen oder orale Thyrosinkinaseinhibitoren.Diese Arbeit berichtet über Vakzinierungsversuche mit lysierten Leukämiezellen, um einen Graft-versus-Leukämieeffekt (GvL)induzieren zu können, und somit bestimmte Immunzellen (T-Lymphozyten)zu stimulieren. Das Leukämievakzin bestand aus lysierten CML-Zellen des Empfängers und angezüchteten Dendriten des Spenders, als sogenannten Antigenpräsentierende Zellen (APC). Die Vakzinierungen fanden insgesamt 3-mal statt, in 3-wöchigen Abständen.Die Patienten befanden sich in einem weit fortgeschrittenem Stadium ihrer Erkrankung nach Zweittransplantation. Die Krankheitsstadien der Patienten unterschieden sich jeweils. Ein Patient befand sich in einem hämatologischen Rezidiv,der andere Patient hatte ein extramedulläres Rezidiv. Beide Patienten wurden zuvor durch HLA-idente Spender transplantiert. Ein Patient zeigte eine chronische Graft-versus-Host-Reaktion (GvHD). Um den zu erwartenden Immuneffekt des subkutan applizierten Vakzins sichtbar machen zu können, wurde jeweils vor und nach den Vakzinierungen die mRNA-Expression von INf-y und der CD8+ T-Zellen durch eine Real-time PCR gemessen.Parallel dazu wurde die Expression des Gens bcr-abl gemessen, um einen Hinweis auf einen GvL-Effekt zu bekommen. Bei beiden Patienten konnte ein zweifacher Anstieg der INF-y mRNA- Expressionen gemessen werden, wobei sich der Zeitpunkt des Anstieg bei beiden Patienten jeweils unterschied. Interessanterweise konnte bei einem Patienten ein paralleler Abfall der bcr-abl Expression gemessen werden.Dies kann ein Hinweis für die Induktion eines GvL-Effektes sein. Bei beiden Patienten war die Immunantwort allerdings zu schwach, um einen anhaltenden klinischen Erfolg zu erzielen. Zusammenfassend konnte gezeigt werden, dass durch diesen Vakzinierungsansatz eine messbare Immunstimulation zu induzieren ist, welche aber für diese Patienten keine langanhaltende Remission erbrachte.To keep patients with CML in remission after hematopoietic stem cell transplantation (HSCT) several options of therapies like donor cell lymphocytes infusion (DLI) or thyrosinekinase inhibitors (TKI) are appointed for several years. Here we report about the use of leukemic cell vaccination to induce a graft-versus-leukemia (GvL) effect after HSCT for two patients with CML. Leukemic cell vaccinations were applied three times in 3-week intervals to two patients with relapse of CML after allogeneic peripheral blood stem cell transplantation (PBSCT). One of these two study patients was transplanted for CML in 1st chronic phase (CP) and relapsed in a stable phase of CML after transplant, whereas the other study patient was transplanted for CML in lymphatic blast crises, and suffered from an extramedullary relapse of CML after transplant. Leukemic cell vaccination was performed two weeks after applying an unfractioned donor leukocyte infusions (DLI) in the first patient with relapse of CML. In the second study patient, leukemic cell vaccination was applied after achieving a complete remission of CML again using a combination of radiochemotherapy and DLI in order to keep the patient in remission. The vaccine was generated by culturing monocyte-derived donor-cell derived antigen presenting cells (APCs) which were pulsed with patient-derived CML cell lysates. To assess an immune reaction to the vaccination the expression of interferon-gamma (INF-γ) mRNA in relation to the expression of CD8 cells mRNA in mononuclear cells of peripheral blood by quantitative real-time RT-PCR assay was also measured. Simultaneously we measured the bcr-abl expression in order to evaluate a possible induce GvL effect by the vaccination. In both patients we could detect a twofold increase in the INF-γ expression after vaccination, which we considered as a hint for a specific immune response to the vaccination. Interestingly, we observed a transient decrease of bcr-abl expression simultaneously in the first patient, which might be a hint for induction of a transient GvL effect. But in contrast to earlier reports about vaccination both patients did not profit clinically from the leukemic cell vaccination. Nor did the first patient achieved a remission of CML, neither was the second patient pretended from relapsing again after completing the 3rd vaccination. So, we concluded that leukemic cell vaccination may induce measurable immune responses, which are not strong enough to produce clinical relevant antileukemic effects

Colorectal cancer

$\textit {Background:}$ Colorec tal cancer (CRC ) is the second most common t ype of cancer in the Western world. The treatment of this disease has evolved greatly, particularly for patients with metastatic disease. The advent of combination chemotherapy plus targeted agents has led to more curative resections and improved survival rates in these patients. A deeper understanding of the mechanisms of tumorigenesis has facilitated tumor characterization, prognosis and patient stratification, bringing us one step closer towards personalized medicine. $\textit {Summary:}$ There are two main pathways of CRC development: (1) chromosomal instability, also known as the classical adenoma-carcinoma sequence, and (2) microsatellite instability, caused by a defective mismatch repair (dMMR) system. Analysis of these pathways has uncovered key prognostic and predictive biomarkers to guide patient selection and treatment strategy. This review summarizes the current treatment regimens and recent advances in the personalized therapy of CRC. $\textit {Key Message:}$ Understanding of the mechanisms of CRC pathogenesis has led to new developments in tumor characterization, patient stratification, prognosis and treatment, bringing us closer to personalized therapy. $\textit {Practical Implications:}$ In the adjuvant setting, the treatment decision is driven by clinical and histopathological factors. dMMR status is one of the most robust positive prognostic factors in resected colon cancer. More and more guidelines recommend refraining from adjuvant chemotherapy in patients with dMMR. In the metastatic setting, the introduction of effective compounds, including agents that target the epidermal growth factor receptor and vascular endothelial growth factor pathways, has significantly improved survival. The presence of wild-type KRAS and NRAS (all RAS) is a positive predictive factor for epidermal growth factor receptor antibody treatment. Therefore, analysis of all RAS status is recommended for all patients with metastatic disease prior to the initiation of first-line chemotherapy