The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma

Witzig, Thomas E.; Reeder, Craig B.; Han, Jing; LaPlant, Betsy; Stenson, Mary; Tun, Han W.; Macon, William R.; Ansell, Stephen M.; Habermann, Thomas M.; Inwards, David J.; Micallef, Ivana N.; Johnston, Patrick B.; Porrata, Luis F.; Colgan, Joseph P.; Markovic, Svetomir N.; Nowakowski, Grzegorz S.; Gupta, Mamta

doi:10.1182/blood-2015-02-629543

Cited by 101 publications

(89 citation statements)

References 37 publications

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“…Of interest, rapamycin analogues, which disrupt the mTORC signaling cascade have shown promise in early phase clinical trials of PTCL patients. [49–51]…”

Section: Discussionmentioning

confidence: 99%

Genetic landscape of T- and NK-cell post-transplant lymphoproliferative disorders

et al. 2016

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Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/or deletion(n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development.

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“…Of interest, rapamycin analogues, which disrupt the mTORC signaling cascade have shown promise in early phase clinical trials of PTCL patients. [49–51]…”

Section: Discussionmentioning

confidence: 99%

Genetic landscape of T- and NK-cell post-transplant lymphoproliferative disorders

et al. 2016

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“…6 We have demonstrated that the PI3K/mTOR pathway is activated in NHL cells 10,11 and that mTORC1 inhibitors have single-agent activity in relapsed B-cell 12 and T-cell NHL. 13 Everolimus has also been shown to be safe and effective when combined with rituximab in relapsed DLBCL patients. 14 Inhibition of the pathway at the PI3K level is effective and idelalisib is now approved for relapsed CLL and indolent B-cell NHL.…”

Section: Introductionmentioning

confidence: 99%

Everolimus combined with R-CHOP-21 for new, untreated, diffuse large B-cell lymphoma (NCCTG 1085 [Alliance]): safety and efficacy results of a phase 1 and feasibility trial

Johnston

LaPlant

McPhail

et al. 2016

The Lancet Haematology

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Background The PI3K/mTORC pathway is upregulated in diffuse large B-cell lymphoma (DLBCL) and can be targeted with the mTORC1 inhibitor everolimus. Everolimus has activity in relapsed DLBCL. These data provide the rationale to combine everolimus with standard R-CHOP-21. Methods The primary endpoint of this study was to determine the maximum tolerated dose of everolimus 10 mg days 1-10 or 1-14 in combination with R-CHOP-21 for 6 cycles along with a feasibility cohort for response assessment in patients with new, untreated DLBCL. Secondary endpoints were the rate of event-free survival 12 months from registration and overall survival. Patients were considered evaluable for the primary endpoint in the phase I portion if they completed the first cycle as planned. In the feasibility portion all patients who received at least one dose of everolimus were included. This completed trial is registered with ClinicalTrials.gov as NCT01334502. Findings Nine patients were enrolled into the phase I trial without dose-limiting toxicities; therefore, everolimus 10 mg days 1-14 with standard R-CHOP-21 was tested in 15 additional patients for a total of 24 patients. The median age was 58.5 years (IQR, 49.5-71.5); 18 (75%) stages III/IV; 13 (54%) with elevated lactate dehydrogenase; 29% with high International Prognostic Index; and 54% (13/24) non-GCB by immunohistochemistry. The overall response rate was 96% (23/24; 95% CI: 79 – 100%) with 23 attaining functional complete remission by PET/CT (96%, 95% CI: 79 – 100%). The remaining patient went off study for refusal in cycle 1 and attained a complete response with RCHOP. The median follow-up is now 21.5 months (IQR, 17 - 29) with all 24 patients meeting EFS12. None of the 24 patients have died, and none have experienced relapse with DLBCL. The most common grade 3/4 toxicity was hematologic with 18 patients (75%) with grade 4 neutropenia of which five (21%) experienced grade 3 febrile neutropenia. Interpretation Everolimus for 14 days in combination with R-CHOP-21 is safe and produced a 96% CR rate in both GCB and non-GCB DLBCL. With a median follow-up of 21.5 months and all patients meeting EFS12, the lack of DLBCL relapse is of special interest. A randomized trial will be necessary to confirm the benefits of this novel combination. Funding National Cancer Institute of the United States; Novartis provided everolimus.

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“…Everolimus, an mTORC1 inhibitor, was investigated as a monotherapy in T-NHL cell lines and in the setting of a phase II study in 16 relapsed T-cell lymphomas. Results demonstrated significantly inhibited proliferation of malignant T cells, translating into 43% PR in MF patients [39,73]. Subsequent studies with everolimus as monotherapy or as a combination with immune checkpoint blockade or other drugs would be a rational next step.…”

Section: Mtor Inhibitorsmentioning

confidence: 99%

Innovative Treatment Concepts for Cutaneous T-Cell Lymphoma Based on Microenvironment Modulation

et al. 2017

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Cutaneous T-cell lymphomas (CTCL) are a rare and biologically heterogeneous malignant entity comprising mycosis fungoides and Sézary syndrome as the most common subtypes. The current treatment outcome is characterized by high rates of relapse, but survival is usually not significantly shortened in low-stage disease. This is different in tumor-stage disease or aggressive CTCL subtypes where survival is significantly reduced. Recent advances have been made on several levels of tumor biology: Whole genome sequencing has resulted in novel strategies of NF-κB or JAK inhibition, ongoing translational research has revealed new targets like CD30 or CCR4, and, finally, research focusing on impaired immunosurveillance has gained more importance. Based on the growing knowledge about the functional roles of the tumor microenvironment and non-malignant infiltrating cells, current research aims to develop novel CTCL treatment strategies. This review focuses on the mounting evidence for efficiently targeting tumor-infiltrating immune cells and thereby modulating the tumor microenvironment and restoring immunosurveillance.

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The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma

Cited by 101 publications

References 37 publications

Genetic landscape of T- and NK-cell post-transplant lymphoproliferative disorders

Genetic landscape of T- and NK-cell post-transplant lymphoproliferative disorders

Everolimus combined with R-CHOP-21 for new, untreated, diffuse large B-cell lymphoma (NCCTG 1085 [Alliance]): safety and efficacy results of a phase 1 and feasibility trial

Innovative Treatment Concepts for Cutaneous T-Cell Lymphoma Based on Microenvironment Modulation

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