Trabectedin Reveals a Strategy of Immunomodulation in Chronic Lymphocytic Leukemia .
Aquí, Demostramos que la Trabectedina Induce la Apoptosis de las Células Leucémicas Primarias Humanas y también las Células Inmunosupresoras Mieloides y Linfoides seleccionadas, Principalmente a través de la Vía TRAIL / TNF.
Yondelis® Bloquea el eje PD-1 / PD-L1 Dirigiéndose a las Células PD-L1 + CLL, los Monocitos / Macrófagos PD-L1 + y las Células T PD-1 + .
Por lo tanto, la Trabectedin se Comporta como un Fármaco Inmunomodulador con un Valor Terapéutico Potencialmente Atractivo en la Subversión del Microambiente del Tumor y en la Superación de la Resistencia Quimioinmune.
©2019 American Association for Cancer Research.
Priyanka Banerjee, Ronghua Zhang, Cristina Ivan, Giovanni Galletti, Karen Clise-Dwyer, Federica Barbaglio, Lydia Scarfò, Miguel Aracil, Christian Klein, William Wierda, William Plunkett, Federico Caligaris-Cappio, Varsha Gandhi, Michael J. Keating and Maria Teresa S. Bertilaccio
Published December 2019 .
Abstract:
Chronic Lymphocytic Leukemia (CLL) is a B-Cell Neoplasia Characterized by protumor Immune Fysregulation involving nonmalignant cells of the Microenvironment, including T lymphocytes and Tumor-associated Myeloid cells.
Ather Therapeutic Agents have Improved Treatment Options for CLL, many Patients still Fail to Respond. Some Patients also show Immunosuppression. We have investigated Trabectedin, a marine-derived compound with Cytotoxic Activity on Macrophages in solid tumors. Here, we demonstrate that Trabectedin induces Apoptosis of human primary Leukemic cells and also selected Myeloid and Lymphoid Immunosuppressive cells, mainly through the TRAIL/TNF pathway.
Trabectedin Modulates transcription and translation of IL6, CCL2, and IFNα in myeloid cells and FOXP3 in regulatory T cells. Human memory CD8+ T cells downregulate PD-1 and, along with monocytes, exert in vivo antitumor function. In xenograft and immunocompetent CLL mouse models, Trabectedin has Antileukemic effects and antitumor impact on the Myeloid and Lymphoid cells compartment. It depletes myeloid-derived suppressor cells and tumor-associated Macrophages and increases memory T cells. T
Trabectedin Also blocks the PD-1/PD-L1 axis by targeting PD-L1+ CLL cells, PD-L1+ Monocytes/Macrophages, and PD-1+ T cells.
Thus Trabectedin behaves as an Immunomodulatory Drug with Potentially attractive therapeutic value in the subversion of the Protumor Microenvironment and in Overcoming Chemoimmune Resistance.
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De Hecho ya existe esta Nueva Expectativa para Yondelis Gracias a su Manera de Actuar de la mano del M.D. Anderson Cancer Center y el NCI :
MD Anderson Cancer Center como Patrocinador en Colaboración con el Instituto Nacional del Cáncer US ( NCI ) Llevarán a Cabo un Ensayo Clínico con Yondelis en Combinación con Venclexta™ en el Tratamiento de Pacientes con Leucemia Linfocítica Crónica o Linfoma Linfocítico Pequeño Resistente o Intolerante a un Inhibidor de BTK .
Official Title : A Phase I/Ib Pilot Study of Combined Trabectedin and Venetoclax in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Resistant or Intolerant to a BTK Inhibitor .
Study Status :
Overall Status : Recruiting .
Study Start : June 18, 2019 .
Primary Completion : April 9, 2020
Sposor/Collaborators :
Sponsor : M.D. Anderson Cancer Center .
Responsible Party : Sponsor .
Collaborators : National Cancer Institute (NCI) .
La Generación de Estrés del Retículo Endoplásmico y la Inhibición de la Autofagia por Plitidepsina Induce la Apoptosis Proteotóxica en las Células Cancerosas .
Generation of Endoplasmic Reticulum Stress and Inhibition of Autophagy by Plitidepsin Induces Proteotoxic Apoptosis in Cancer Cells .
Alejandro Losada , Juan Fernando Martínez-Leala .
Plitidepsin (PLD, Aplidin®), a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans, has been recently approved by Australian regulatory authorities for the treatment of multiple myeloma patients. Plitidepsin binds to eEF1A2 and induces oxidative stress, Rac1 activation and JNK1 phosphorylation, triggering a rapid apoptotic program in tumor cells. Since oxidative stress is one of the known sources of endoplasmic reticulum stress, we investigated whether PLD was inducing a bona fide ER stress in HeLa cells and whether this process was essential in the mechanism of action of the compound. Indeed, PLD activated an ER stress-induced unfolded protein response (UPR), including the alternative splicing of XBP1, the proteolytic processing of ATF6 and the phosphorylation of eIF2α and JNK. Interestingly, though PLD induced a strong phosphorylation of eIF2α in all the analyzed cell lines, it did not elicit an increased expression of ATF4 and CHOP, a transcription factor involved in launching UPR-mediated apoptosis. On the contrary, a clear reduction of CHOP protein levels was observed after PLD treatment, most probably due to both the lack of transactivation by ATF4 and its rapid degradation by the ubiquitin/proteasome machinery. Using fibroblasts devoid of each one of the four possible kinases involved in eIF2α phosphorylation, we observed that only PKR was involved in the response to PLD treatment and, accordingly, PKR-/- fibroblasts are shown to be resistant to the apoptogenic activity of the compound. Furthermore, eIF2α phosphorylation itself was shown to be irrelevant for the induction of cell death by PLD. Instead, we reveal that PLD induces an increase in the levels of misfolded proteins while simultaneously inhibiting the autophagic flux. These two effects combined prevent PLD-treated cells from reducing proteotoxic stress and lead to apoptosis. Other anti-myeloma drugs like bortezomib, which target the proteasome, also inhibit the degradation of misfolded proteins through alternate pathways and a synergistic anticancer effect of the PLD plus bortezomib combination has been previously disclosed. The present results extend this synergy to in vivo experiments and provide a mechanistic rationale for this synergy.
Efficacy and Safety of Trabectedin for Patients With Unresectable and Relapsed Soft-Tissue Sarcoma in Japan: A Japanese Musculoskeletal Oncology Group Study.
Hiroshi Kobayashi et al. Cancer. 2019
Background:
Although initial trabectedin (1.2 mg/m2 ) is safe and effective for patients with translocation-related sarcoma (TRS) in Japan, its efficacy in other types of soft-tissue sarcomas (STSs) remains unknown. This study retrospectively investigated its efficacy and safety through postmarketing surveillance of trabectedin in patients with unresectable and relapsed STS.
Methods:
One hundred forty patients received intravenous trabectedin (1.2 mg/m2 on day 1 every 21 days) over the course of 24 hours. The primary endpoint was the efficacy and safety of trabectedin.
Results:
Grade 3 or higher adverse events occurred in 100 patients (71%) and included hepatotoxicity (37.8%), neutropenia (32.8%), and rhabdomyolysis (3.6%). Patients at high risk for grade 3 or higher rhabdomyolysis (36%) were classified by height (≥170.3 cm) and age (≤32 years) through a classification and regression tree model (area under the curve, 0.9). The overall median progression-free survival (PFS) was 3.7 months; with respect to the histological type, the median PFS was 17.4 months for myxoid liposarcoma, 4.9 months for leiomyosarcoma, 5.6 months for synovial sarcoma, and 3.7 months for dedifferentiated liposarcoma. Histological type (liposarcoma/leiomyosarcoma [L-sarcoma] and TRS) and grade 3 neutropenia (but not grade 4) were associated with significantly improved PFS after trabectedin treatment (P = .003, P = .04, and P = .001). The median growth modulation index (GMI) was 0.91; 37 patients (36.7%) experienced a GMI > 1.33, and among patients with solitary fibrous tumors and undifferentiated pleomorphic sarcoma, 60% and 42.9%, respectively, had a GMI > 1.33. The median overall survival (OS) was 16.4 months. A GMI > 1.33 was associated with significantly improved OS (P = .0006).
Conclusions:
Initial trabectedin at 1.2 mg/m2 has clinically meaningful benefits for patients with L-sarcoma and certain histological subtypes of TRS.
MD Anderson Cancer Center como Patrocinador en Colaboración con el Instituto Nacional del Cáncer US ( NCI ) Llevarán a Cabo un Ensayo Clínico con Yondelis en Combinación con Venclexta™ en el Tratamiento de Pacientes con Leucemia Linfocítica Crónica o Linfoma Linfocítico Pequeño Resistente o Intolerante a un Inhibidor de BTK .
