Our current approaches to the diagnosis and treatment of lymphoid malignancies do not reflect emerging data regarding pathogenetic mechanisms and associated rational treatment targets. For example, one of the main lymphoid malignancies to strike young and otherwise healthy adults, classical Hodgkin lymphoma (cHL), is largely defined by its morphologic appearance and treated with an empiric combination of available chemotherapeutic agents. We previously hypothesized that 9p24.1/PD-L1/PD-L2 copy number alteration (CNA) was a genetic mechanism of immune evasion in cHL and considered the PD-1 pathway to be a rational therapeutic target in this disease. After defining recurrent 9p24.1 copy gain and increased PD-L1/PD-L2 expression as high-frequency events in cHL, we explored the clinical activity of PD-1 blockade in this lymphoid malignancy. In independent pilot studies of two different PD-1 blocking agents, patients with multiply relapsed/refractory cHL experienced remarkable clinical responses that were often durable. In our competitive renewal application, we propose to build on these findings with the following specific aims: 1.0) Determine the relationship between PD-L1/PD-L2 alterations and outcome, response to PD-1 blockade and additional genetic bases of immune evasion in cHL; 2.0) Elucidate mechanisms of response and resistance to PD-1 blockade in cHL patients; 3.0) Develop a comprehensive approach to analyze genetic bases for immune evasion in cHL; and 4.0) Define the clinical activity of PD-1 blockade at earlier timepoints in the treatment of cHL. The proposed studies, will define complementary and/or confounding genetic bases of immune evasion and mechanisms of response and resistance to PD-1 blockade and inform our incorporation of PD-1 blockade into the standard therapy of cHL.

Public Health Relevance

Our current approaches to the diagnosis and treatment of lymphoid malignancies do not reflect emerging data regarding pathogenetic mechanisms and associated rational treatment targets. For example, one of the most common lymphoid malignancies to strike young and otherwise healthy adults, classical Hodgkin lymphoma (cHL), is largely defined by its morphologic appearance and currently treated with empiric combinations of available chemotherapeutic agents rather then targeted approaches to disease-specific survival pathways. The proposed studies build on our identification of a genetically defined and targetable immune escape pathway in cHL and delineate an associated approach to targeted immunotherapy of this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA161026-07
Application #
9326921
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Agrawal, Lokesh
Project Start
2011-08-22
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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