Localized Low-Dose Radiotherapy for Follicular Lymphoma: History, Clinical Results, Mechanisms of Action, and Future Outlooks

Ganem, G.; Cartron, Guillaume; Girinsky, T.; Haas, Rick L.; Cosset, J.M.; Solal‐Céligny, Philippe

doi:10.1016/j.ijrobp.2010.06.056

Cited by 44 publications

(24 citation statements)

References 64 publications

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“…Although complement inhibition is normally anti-inflammatory, in the context of localized RT, complement inhibition was found to promote inflammation within the tumor, induce an early influx of neutrophils, and to promote a systemic anti-tumor immune response. We focused on a lymphoma model, since lymphoma represents a generally radiosensitive type of cancer, with induction of apoptosis a known mechanism of tumor cell killing (Ganem et al, 2010). Localized fractionated RT was shown to result in complement activation within the tumor environment, and the subsequent targeted inhibition of complement in the tumor resulted in an early increase in the level of apoptotic tumor cells after initiation of treatment.…”

Section: Discussionmentioning

confidence: 99%

Complement-Dependent Modulation of Antitumor Immunity following Radiation Therapy

Elvington¹,

Scheiber²,

Yang³

et al. 2014

Cell Reports

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Summary Complement is traditionally thought of as a pro-inflammatory effector mechanism of anti-tumor immunity. However, complement is also important for effective clearance of apoptotic cells, which can be an anti-inflammatory and tolerogenic process. We show that localized fractionated radiation therapy (RT) of subcutaneous murine lymphoma results in tumor cell apoptosis and local complement activation. Co-treatment of mice with tumor-targeted complement inhibition markedly improved therapeutic outcome of RT, an effect linked to early increases in apoptotic cell numbers and increased inflammation. Improved outcome was dependent on an early neutrophil influx, and was characterized by increased numbers of mature dendritic cells and the subsequent modulation of T cell immunity. Appropriate complement inhibition may be a promising strategy to enhance a mainstay of treatment for cancer.

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Section: Discussionmentioning

confidence: 99%

Complement-Dependent Modulation of Antitumor Immunity following Radiation Therapy

Elvington¹,

Scheiber²,

Yang³

et al. 2014

Cell Reports

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“…Low-grade follicular lymphomas for example show complete response rates of 50-60% with only 4 Gy in 2 fractions. 5 This is in contrast with Stage III NSCLC, with progression-free survival rates of 5-25% at 5 y with doses of 60 Gy or more in 2 Gy fractions. 2 This can be understood at least in part because unlike B cells, which undergo TP53-mediated apoptosis in response to low dose IR, NSCLC cells undergo limited apoptosis.…”

Section: Introductionmentioning

confidence: 94%

USP9X inhibition promotes radiation-induced apoptosis in non-small cell lung cancer cells expressing mid-to-high MCL1

Kushwaha

O’Leary

Cron

et al. 2015

Cancer Biology & Therapy

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Background and Purpose: Radiotherapy (RT) is vital for the treatment of locally advanced non-small cell lung cancer (NSCLC), yet its delivery is limited by tolerances of adjacent organs. We sought therefore to identify and characterize gene targets whose inhibition may improve RT. Materials and Methods: Whole genome pooled shRNA cytotoxicity screens were performed in A549 and NCI-H460 using a retroviral library of 74,705 sequences. Cells were propagated with or without daily radiation Monday-Friday. Radiosensitization by top differential dropout hits was assessed by clonogenic assays. Apoptosis was assessed using a caspase 3/7 cell-based activity assay and by annexin V-FITC and PI staining. MCL1 expression was assessed by qPCR and Western blotting. Results: USP9X, a deubiquitinase, was a top hit among druggable gene products. WP1130, a small molecule USP9X inhibitor, showed synergistic cytotoxicity with IR. MCL1, an anti-apoptotic protein deubiquitinated by USP9X, decreased with USP9X inhibition and IR. This was accompanied by increases in caspase 3/7 activity and apoptosis. In a panel of NSCLC lines, MCL1 and USP9X protein and gene expression levels were highly correlated. Lines showing high levels of MCL1 expression were the most sensitive to USP9X inhibition. Conclusions: These data support the use of MCL1 expression as a predictive biomarker for USP9X inhibitors in NSCLC therapy.

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“…Indolent B-cell NHL became an early area of interest in research and development of RIT given the exquisite sensitivity of indolent histology to radiation [4,5]. RIT was initially studied in the relapsed and refractory setting and has demonstrated substantial single-agent activity.…”

Section: Single-agent Rit In Refractory Indolent and Aggressive Nhlmentioning

confidence: 99%

Advancing Radioimmunotherapy and Its Future Role in Non-Hodgkin Lymphoma

Reagan

Friedberg

2015

Future Oncol.

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Radioimmunotherapy is an effective treatment modality with an acceptable toxicity profile in both indolent B-cell non-Hodgkin lymphoma and histologic transformation. Its ease of administration from a patient's perspective sets it apart from chemoimmunotherapy regimens. It has demonstrated efficacy in a range of different treatment scenarios. Despite its promise as a treatment modality, radioimmunotherapy has been seldom used, and one of the previously available agents is now off the market. Radioimmunotherapy has shown impressive activity in both the relapsed and upfront settings in follicular lymphoma, histologic transformation, as consolidation after chemotherapy, and in conjunction with high-dose chemotherapy and autologous stem cell support. Future efforts should focus on its optimal employment in the upfront setting for follicular lymphoma as well as further investigation of the promising activity in histologic transformation.

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Localized Low-Dose Radiotherapy for Follicular Lymphoma: History, Clinical Results, Mechanisms of Action, and Future Outlooks

Cited by 44 publications

References 64 publications

Complement-Dependent Modulation of Antitumor Immunity following Radiation Therapy

Complement-Dependent Modulation of Antitumor Immunity following Radiation Therapy

USP9X inhibition promotes radiation-induced apoptosis in non-small cell lung cancer cells expressing mid-to-high MCL1

Advancing Radioimmunotherapy and Its Future Role in Non-Hodgkin Lymphoma

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