Project 3 seeks to address the high relapse rate of non-Hodgkin follicular lymphoma (FL) using immunocytokine (ICK) therapy combined with rituximab and single fraction radiation. We have developed and produced a clinical-trial grade immunocytokine composed of de-immunized anti-CD20 mouse monoclonal antibody (Leu16) fused with two IL2 molecules. DI-Leu16-IL2 (IND100885) has been administered to two patients with B-cell NHL and exhibits low toxicity with good immune activation. This project proposes three specific aims to assess the effectiveness and safety of DI-Leu16-IL2 therapy.
Specific Aim 1 : Perform a Pilot-Phase I study of DI-Leu16-IL2 combined with rituximab and single fraction involved-field radiation for treatment of follicular NHL. The primary objective of the trial is to select the schedule and dose of DI-Leu16-IL2. when given in combination with rituximab and single fraction radiation (XRT) that yields the more favorable immunologic response while maintaining safety. The secondary objective is to describe the safety, tolerability. and toxicity profile of DI-Leu16-IL2, given in combination with rituximab and XRT.
Specific Aim 2 : Perform a Phase II study of DI-Leu16-IL2 combined with rituximab and single fraction involved-field radiation for treatment of follicular NHL. In this aim. we will conduct a two-center Phase II trial of patients with FL who have relapsed or progressed after at least one prior regimen. The primary objective is to determine the anti-tumor activity of DI-Leu16-IL2 when combined with rituximab and single fraction radiation as assessed by overall response rate (CR+PR).
Specific Aim 3 : Evaluate the Biodistribution of DI-Leu16-IL2 using ^^^In labeled DI-Leu16-IL2. The primary goal of this study is to assess the biodistribution of DI-Leu16-IL2 using '^''in Dl-Leu16-IL2. The secondary goal is to obtain preliminary data that explores the possible association between DI-Leu16-IL2 uptake and FDG images (pre- and post- therapy) and tumor response. Significance: This non-transplant ICK-based therapy, if able to improve response duration for patients with follicular lymphoma, would have a significant clinical impact due to the increasing prevalence of this disease. The low toxicity profile of the combined treatment would be especially beneficial in older patients. Innovation: Our approach to targeted eradication of follicular lymphoma via the Dl-Leu16-1L2 immunocytokine in concert with single fraction local irradiation is novel in both its design and implementation. We have manufactured our own DI-Leu16-IL2, obtained FDA approval and commenced preliminary testing of this promising reagent. The addition of low-dose irradiation to this immunotherapy is hypothesized to enhance the immunologic response to DI-Leu16-IL2 treatment without significant additional toxicity.

Public Health Relevance

This project evaluates a low-toxicity novel therapy for follicular lymphoma. Our immunotherapy agent targets cancer cells using an antibody against CD20 and activates the endogenous immune system using the cytokine IL-2. The addition of single fraction irradiation to this immunotherapy is hypothesized to enhance the immunologic response to treatment without significant additional toxicity. The induction of adaptive immunity should result in long term remissions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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City of Hope/Beckman Research Institute
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Jonnalagadda, Mahesh; Mardiros, Armen; Urak, Ryan et al. (2015) Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy. Mol Ther 23:757-68
Lacoste, Sandrine; Bhatia, Ravi; Bhatia, Smita et al. (2014) Granulocytes affect double-strand break repair assays in primary human lymphocytes. PLoS One 9:e93185
Herrmann, Andreas; Priceman, Saul J; Swiderski, Piotr et al. (2014) CTLA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cells. J Clin Invest 124:2977-87
Chadalavada, Deepti; Adamson, Trinka W; Burnett, John C et al. (2014) Irradiated compared with nonirradiated NSG mice for the development of a human B-cell lymphoma model. Comp Med 64:179-85
Yang, Chunmei; Lee, Heehyoung; Pal, Sumanta et al. (2013) B cells promote tumor progression via STAT3 regulated-angiogenesis. PLoS One 8:e64159
Xin, Hong; Lu, Rongze; Lee, Heehyoung et al. (2013) G-protein-coupled receptor agonist BV8/prokineticin-2 and STAT3 protein form a feed-forward loop in both normal and malignant myeloid cells. J Biol Chem 288:13842-9
Zhou, Jiehua; Tiemann, Katrin; Chomchan, Pritsana et al. (2013) Dual functional BAFF receptor aptamers inhibit ligand-induced proliferation and deliver siRNAs to NHL cells. Nucleic Acids Res 41:4266-83
Ng, Thomas S C; Wert, David; Sohi, Hargun et al. (2013) Serial diffusion MRI to monitor and model treatment response of the targeted nanotherapy CRLX101. Clin Cancer Res 19:2518-27
Jonnalagadda, M; Brown, C E; Chang, W C et al. (2013) Efficient selection of genetically modified human T cells using methotrexate-resistant human dihydrofolate reductase. Gene Ther 20:853-60
Yang, Chunmei; Lee, Heehyoung; Jove, Veronica et al. (2013) Prognostic significance of B-cells and pSTAT3 in patients with ovarian cancer. PLoS One 8:e54029

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