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
Herrera, Alex F; Rodig, Scott J; Song, Joo Y et al. (2018) Outcomes after Allogeneic Stem Cell Transplantation in Patients with Double-Hit and Double-Expressor Lymphoma. Biol Blood Marrow Transplant 24:514-520
Budde, Lihua E; Wu, David; Martin, Daniel B et al. (2018) Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial. Br J Haematol 183:601-607
Herrera, A F; Palmer, J; Martin, P et al. (2018) Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Ann Oncol 29:724-730
Zhao, Xingli; Zhang, Zhuoran; Moreira, Dayson et al. (2018) B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors. Mol Ther 26:695-707
Adamus, Tomasz; Kortylewski, Marcin (2018) The revival of CpG oligonucleotide-based cancer immunotherapies. Contemp Oncol (Pozn) 22:56-60
Herrera, Alex F; Moskowitz, Alison J; Bartlett, Nancy L et al. (2018) Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 131:1183-1194
Chen, Robert W; Palmer, Joycelynne M; Tomassetti, Sarah et al. (2018) Multi-center phase II trial of bortezomib and rituximab maintenance combination therapy in patients with mantle cell lymphoma after consolidative autologous stem cell transplantation. J Hematol Oncol 11:87
Wang, Xiuli; Walter, Miriam; Urak, Ryan et al. (2018) Lenalidomide Enhances the Function of CS1 Chimeric Antigen Receptor-Redirected T Cells Against Multiple Myeloma. Clin Cancer Res 24:106-119
Mei, Matthew G; Cao, Thai M; Chen, Lu et al. (2017) Long-Term Results of High-Dose Therapy and Autologous Stem Cell Transplantation for Mantle Cell Lymphoma: Effectiveness of Maintenance Rituximab. Biol Blood Marrow Transplant 23:1861-1869
Herrera, Alex F; Mei, Matthew; Low, Lawrence et al. (2017) Relapsed or Refractory Double-Expressor and Double-Hit Lymphomas Have Inferior Progression-Free Survival After Autologous Stem-Cell Transplantation. J Clin Oncol 35:24-31

Showing the most recent 10 out of 97 publications