Immunotherapy of lymphoma through in situ manipulation of an involved lymph node can allow for development of an active anti-lymphoma immune response without the need for ex vivo handling or immunization with a specific antigen. A comprehensive and successful approach to in situ immunization in lymphoma would require effective presentation of antigen by the lymphoma cells or professional antigenpresenting cells, activation of lymphoma-specific T cells and suppression of the regulatory arm of the immune response to enhance development of a sustained anti-lymphoma T cell response. The current proposal evaluating a novel approach to in situ immunization is based on scientific advances made possible through the UI/MC SPORE over the prior funding period. The overall hypothesis is that in situ immunization with nanoparticles will allow for induction and maintenance of a robust anti-lymphoma immune response with acceptable toxicity. To test this hypothesis, this project will assess the effect of intratumoral injection of nanoparticles (NPs) containing doxorubicin (dox) on lymphoma cells, the immune microenvironment, and the anti-lymphoma immune response in animal models and in a Phase I clinical trial in subjects with lymphoma. It will then assess the effect of intratumoral injection of NPs containing both dox and the toll-like receptor 9 (TLR9) agonist CpG ODN (CpG dox NPs) in mice and humans. Finally, it will assess how agents capable of maintaining the T cell response impact on the success of in situ immunization with NP. Successful development of such an approach to in situ immunization would be of great significance as a way to treat lymphoma, and could be applicable to other cancers as well.

Public Health Relevance

There continues to be a need for new treatments for lymphoma. In situ immunization holds considerable promise as a way to induce a long term, anti-lymphoma immune response that results in clinical benefit for patients. The proposed studies are designed to explore a novel approach to in situ immunization that, if successful, could represent a novel approach to therapy for lymphoma and other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA097274-13
Application #
8689945
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Johnston, Patrick B; LaPlant, Betsy; McPhail, Ellen et al. (2016) 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. Lancet Haematol 3:e309-16
Wongrakpanich, Amaraporn; Mudunkotuwa, Imali A; Geary, Sean M et al. (2016) Size-dependent cytotoxicity of copper oxide nanoparticles in lung epithelial cells. Environ Sci Nano 3:365-374
Ahmed, Kawther K; Geary, Sean M; Salem, Aliasger K (2016) Development and Evaluation of Biodegradable Particles Coloaded With Antigen and the Toll-Like Receptor Agonist, Pentaerythritol Lipid A, as a Cancer Vaccine. J Pharm Sci 105:1173-9
Boddicker, Rebecca L; Razidlo, Gina L; Dasari, Surendra et al. (2016) Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma. Blood 128:1234-45
King, Rebecca L; Dao, Linda N; McPhail, Ellen D et al. (2016) Morphologic Features of ALK-negative Anaplastic Large Cell Lymphomas With DUSP22 Rearrangements. Am J Surg Pathol 40:36-43
Maurer, Matthew J; Jais, Jean-Philippe; Ghesquières, Hervé et al. (2016) Personalized risk prediction for event-free survival at 24 months in patients with diffuse large B-cell lymphoma. Am J Hematol 91:179-84
Parry, Helen Marie; Damery, Sarah; Hudson, Christopher et al. (2016) Cytomegalovirus infection does not impact on survival or time to first treatment in patients with chronic lymphocytic leukemia. Am J Hematol 91:776-81
Machiela, Mitchell J; Lan, Qing; Slager, Susan L et al. (2016) Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes. Hum Mol Genet 25:1663-76
Mambetsariev, Nurbek; Lin, Wai W; Stunz, Laura L et al. (2016) Nuclear TRAF3 is a negative regulator of CREB in B cells. Proc Natl Acad Sci U S A 113:1032-7
Kenderian, Saad Sirop; Habermann, Thomas M; Macon, William R et al. (2016) Large B-cell transformation in nodular lymphocyte-predominant Hodgkin lymphoma: 40-year experience from a single institution. Blood 127:1960-6

Showing the most recent 10 out of 313 publications