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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA107399-09
Application #
8731632
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010
Rohr, J; Guo, S; Huo, J et al. (2016) Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. Leukemia 30:1062-70
Wang, Sophia S; Deapen, Dennis; Voutsinas, Jenna et al. (2016) Breast implants and anaplastic large cell lymphomas among females in the California Teachers Study cohort. Br J Haematol 174:480-3
Zhang, Chunyan; Xin, Hong; Zhang, Wang et al. (2016) CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer. Immunity 44:913-23
Beharry, Andrew A; Lacoste, Sandrine; O'Connor, Timothy R et al. (2016) Fluorescence Monitoring of the Oxidative Repair of DNA Alkylation Damage by ALKBH3, a Prostate Cancer Marker. J Am Chem Soc 138:3647-50
You, Changjun; Wang, Pengcheng; Nay, Stephanie L et al. (2016) Roles of Aag, Alkbh2, and Alkbh3 in the Repair of Carboxymethylated and Ethylated Thymidine Lesions. ACS Chem Biol 11:1332-8
Wang, Xiuli; Popplewell, Leslie L; Wagner, Jamie R et al. (2016) Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. Blood 127:2980-90
Küçük, Can; Hu, Xiaozhou; Gong, Qiang et al. (2016) Diagnostic and Biological Significance of KIR Expression Profile Determined by RNA-Seq in Natural Killer/T-Cell Lymphoma. Am J Pathol 186:1435-41
Zhou, Jiehua; Rossi, John J; Shum, Ka To (2015) Methods for assembling B-cell lymphoma specific and internalizing aptamer-siRNA nanoparticles via the sticky bridge. Methods Mol Biol 1297:169-85
Mardiros, Armen; Forman, Stephen J; Budde, Lihua E (2015) T cells expressing CD123 chimeric antigen receptors for treatment of acute myeloid leukemia. Curr Opin Hematol 22:484-8
Zhang, Wang; Zhang, Chunyan; Li, Wenzhao et al. (2015) CD8+ T-cell immunosurveillance constrains lymphoid premetastatic myeloid cell accumulation. Eur J Immunol 45:71-81

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