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1.
Br J Haematol ; 189(3): 475-488, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32057093

RESUMEN

Chronic lymphocytic leukaemia (CLL) cells are strongly influenced by microenvironmental signals through the activation of distinct membrane receptors including the B-cell receptor and toll-like receptors (TLR). Recapitulating TLR stimulation in vitro by treating CLL cells with the TLR9 ligand CpG can induce metabolic activation and protection from apoptosis. We hypothesized that interfering with TLR signalling may be beneficial for treating CLL, and we tested in preclinical studies the effect of a specific interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitory small molecule on primary leukaemic cells isolated from the peripheral blood of patients. We observed that IRAK4, an upstream kinase of the TLR pathway, is expressed in patients with CLL, and lower IRAK4 mRNA levels associate with a better outcome. The specific IRAK4 inhibitor disrupted TLR signalling as assessed by reduction of the specific biomarkers NFKBIZ and interleukin-6 mRNAs, and restrained the protective effect of in vitro TLR stimulation on cell viability. To note, IRAK4 inhibitor induced p53 and triggered apoptosis. Co-treatment of CLL cells with increasing concentrations of IRAK4i and the Bruton tyrosine kinase inhibitor ibrutinib demonstrated a synergistic effect. Our results suggest that targetting IRAK4 may represent a novel approach in CLL and may be combined with other signalling inhibitors.


Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Receptores Toll-Like/efectos de los fármacos , Apoptosis , Femenino , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/farmacología , Masculino , Transducción de Señal
4.
Clin Cancer Res ; 27(3): 729-739, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33051305

RESUMEN

PURPOSE: Approximately 30% of patients with chronic lymphocytic leukemia (CLL) can be grouped into subsets with stereotyped B-cell receptor immunoglobulin (BcR IG) displaying remarkable similarity in the heavy complementarity-determining region 3 (VH CDR3). Here, we investigated whether the consensus VH CDR3 sequences from CLL stereotyped subsets can be exploited for immunotherapy approaches. EXPERIMENTAL DESIGN: Immunogenic epitopes from the consensus VH CDR3 sequence of the clinically aggressive subsets #1 and #2 and from Eµ-TCL1 mice, which spontaneously develop CLL with BcR IG stereotypy, were identified and used to generate specific HLA class I- and II-restricted T cells in vitro. T-cell reactivity was assayed in vitro as IFNγ production. Bone marrow-derived dendritic cells loaded with the peptides were used as vaccination strategy to restrain leukemia development in the Eµ-TCL1 mouse model. RESULTS: These stereotyped epitopes were naturally processed and presented by CLL cells to the VH CDR3-specific T cells. Furthermore, we validated the efficacy of VH CDR3 peptide-based immunotherapy in the Eµ-TCL1 transplantable mouse model. Immunization of mice against defined VH CDR3 peptide epitopes, prior to the challenge with the corresponding leukemia cells, resulted in the control of CLL development in a significant fraction of mice, and increased overall survival. CONCLUSIONS: Our data highlight the immunogenicity of stereotyped VH CDR3 sequences and support the feasibility and efficacy of their use for novel cancer vaccine in CLL. Such approach has the advantage to generate "off-the-shelf" therapeutic vaccines for relevant groups of patients belonging to stereotyped subsets.See related commentary by Seiffert, p. 659.


Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/uso terapéutico , Epítopos de Linfocito T/inmunología , Leucemia Linfocítica Crónica de Células B/terapia , Receptores de Antígenos de Linfocitos B/inmunología , Anciano , Anciano de 80 o más Años , Animales , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/inmunología , Regiones Determinantes de Complementariedad/genética , Regiones Determinantes de Complementariedad/inmunología , Regiones Determinantes de Complementariedad/metabolismo , Modelos Animales de Enfermedad , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/metabolismo , Femenino , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/inmunología , Cadenas Pesadas de Inmunoglobulina/metabolismo , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Cultivo Primario de Células , Proteínas Proto-Oncogénicas/genética , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Vacunas de Subunidad/genética , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/uso terapéutico
5.
Blood Adv ; 5(14): 2817-2828, 2021 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-34269799

RESUMEN

Chronic lymphocytic leukemia (CLL) is caused by the progressive accumulation of mature CD5+ B cells in secondary lymphoid organs. In vitro data suggest that CD4+ T lymphocytes also sustain survival and proliferation of CLL clones through CD40L/CD40 interactions. In vivo data in animal models are conflicting. To clarify this clinically relevant biological issue, we generated genetically modified Eµ-TCL1 mice lacking CD4+ T cells (TCL1+/+AB0), CD40 (TCL1+/+CD40-/-), or CD8+ T cells (TCL1+/+TAP-/-), and we monitored the appearance and progression of a disease that mimics aggressive human CLL by flow cytometry and immunohistochemical analyses. Findings were confirmed by adoptive transfer of leukemic cells into mice lacking CD4+ T cells or CD40L or mice treated with antibodies depleting CD4 T cells or blocking CD40L/CD40 interactions. CLL clones did not proliferate in mice lacking or depleted of CD4+ T cells, thus confirming that CD4+ T cells are essential for CLL development. By contrast, CD8+ T cells exerted an antitumor activity, as indicated by the accelerated disease progression in TCL1+/+TAP-/- mice. Antigen specificity of CD4+ T cells was marginal for CLL development, because CLL clones efficiently proliferated in transgenic mice whose CD4 T cells had a T-cell receptor with CLL-unrelated specificities. Leukemic clones also proliferated when transferred into wild-type mice treated with monoclonal antibodies blocking CD40 or into CD40L-/- mice, and TCL1+/+CD40-/- mice developed frank CLL. Our data demonstrate that CD8+ T cells restrain CLL progression, whereas CD4+ T cells support the growth of leukemic clones in TCL1 mice through CD40-independent and apparently noncognate mechanisms.


Asunto(s)
Dromaiidae , Leucemia Linfocítica Crónica de Células B , Animales , Linfocitos T CD4-Positivos , Ligando de CD40/genética , Leucemia Linfocítica Crónica de Células B/genética , Ratones , Ratones Transgénicos , Proteínas Proto-Oncogénicas
6.
Oncotarget ; 6(5): 3043-54, 2015 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-25460504

RESUMEN

Tyrosine kinase inhibitors, affecting angiogenesis, have shown therapeutic efficacy in renal cell carcinoma (RCC). The increased overall survival is not fully explained by their anti-tumor activity, since these drugs frequently induce disease stabilization rather than regression. RCC patients frequently develop cachectic syndrome. We used the RXF393 human renal carcinoma xenograft that recapitulates the characteristics of the disease, including the growth in the mouse kidney (orthotopic implantation), and the induction of cachexia with subsequent premature death. Sunitinib prevents body weight loss and muscle wasting and significantly improves the survival of RXF393-bearing nude mice. The anti-cachectic effect was not associated to direct anti-tumor activity of the drug. Most relevant is the ability of sunitinib to reverse the cachectic phenotype and rescue the animals from the loss of fat tissue. Body weight loss is prevented also in mice bearing the C26 colon carcinoma, classically reported to induce cachexia in immunocompetent mice. Among the mechanisms, we herein show that sunitinib is able to restrain the overactivation of STAT3 and MuRF-1 pathways, involved in enhanced muscle protein catabolism during cancer cachexia. We suggest that off-target effects of angiogenesis inhibitors targeting STAT3 are worth considering as a therapeutic option for patients who develop cachexia, independently of their anti-tumor activity.


Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Caquexia/prevención & control , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/farmacología , Neoplasias Renales/tratamiento farmacológico , Proteínas Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Factor de Transcripción STAT3/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Caquexia/diagnóstico por imagen , Caquexia/metabolismo , Caquexia/patología , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Ratones Endogámicos C57BL , Ratones Desnudos , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestructura , Transducción de Señal/efectos de los fármacos , Sunitinib , Factores de Tiempo , Proteínas de Motivos Tripartitos , Carga Tumoral/efectos de los fármacos , Pérdida de Peso/efectos de los fármacos , Microtomografía por Rayos X , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Blood Adv ; 3(12): 1891-1896, 2019 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-31227476
8.
Mol Cancer Ther ; 12(10): 2237-47, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23918831

RESUMEN

The development of resistance and progressive disease after treatment with angiogenesis inhibitors is becoming a controversial issue. We investigated the experimental conditions that cause multireceptor tyrosine kinase inhibitors (RTKI) to augment metastasis and whether opportune combinations with chemotherapy could counteract this effect. The renal Renca-luc tumor was transplanted orthotopically in the kidney of Balb/c mice, which then were or were not nephrectomized. The Lewis Lung carcinoma (LLC) was transplanted in the tibial muscle of C57/Bl6 mice. Treatment with the RTKI sunitinib started at different stages of tumor progression, mimicking neoadjuvant or adjuvant settings. Combination studies with paclitaxel, doxorubicin, cisplatin, gemcitabine, and topotecan were done on the LLC model, using opportune regimens. In a neoadjuvant setting, sunitinib inhibited Renca-luc tumor growth, prolonging survival despite an increase in lung metastasis; treatment after primary tumor surgery (adjuvant setting) or on established metastasis prolonged survival and decreased metastasis. Sunitinib increased lung metastasis from mice bearing early-stage LLC, but did not affect established metastases (no acceleration) from advanced tumors. Combinations with doxorubicin, topotecan, gemcitabine, but not cisplatin and paclitaxel, counteracted the increase in metastasis from LLC, partly reflecting their antitumor activity. Histology analysis after sunitinib confirmed tumor vascular changes and increased hypoxia. Topotecan at suboptimal daily doses reduced sunitinib-related metastasis, reducing tumor hypoxia. Tyrosine kinase inhibitors, as sunitinib, can have adverse malignant effects mainly in the neoadjuvant setting. The addition of chemotherapy might influence metastasis, depending on each drug mechanism of action and its regimen of administration.


Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Metástasis de la Neoplasia , Animales , Carcinoma Pulmonar de Lewis/patología , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Doxorrubicina/administración & dosificación , Humanos , Indoles/administración & dosificación , Ratones , Invasividad Neoplásica/patología , Paclitaxel/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirroles/administración & dosificación , Sunitinib , Topotecan/administración & dosificación , Gemcitabina
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