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, two lymphoid malignancies that primarily strike young healthy adults, classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL), are largely defined by their morphologic appearance and physical location. Current treatments for cHL and MLBCL are based on empiric combinations of available chemotherapeutic agents rather than targeted approaches to disease-specific survival pathways. The most common subtype of cHL, nodular sclerosing Hodgkin lymphoma (NSHL), and MLBCL share certain biological and clinical features. Both diseases commonly present as local/mediastinal tumors that spread to adjacent, rather than distant, nodes and organs. One of the defining paradoxical features of primary cHLs is the presence of an extensive, largely ineffective, inflammatory infiltrate. Primary MLBCLs include scattered infiltrating lymphocytes and variable degrees of sclerosis;however, little is known about an associated host anti-tumor immune response. We have integrated the comprehensive transcriptional profiles and whole-genome HD SNP array data in cHL and MLBCL and identified chromosome 9p24.1 amplification and the associated overexpression of PD-1 ligands and their inducer, JAK2, as major features of these diseases. We hypothesize that: 1) the disease-specific genetic alteration and overexpression of PD-1 ligands in cHL and MLBCL induces PD-1 signaling, """"""""exhaustion"""""""" of PD-1 receptor+ tumor-infiltrating T cells and tumor immune escape;and 2) JAK2 further induces PD-1 ligand expression and augments tumor cell proliferation. As a consequence, molecular analyses of 9p24, PD-1 ligand and JAK2 amplification will likely have prognostic significance and the PD-1 pathway and JAK2 will represent rational therapeutic targets in these diseases. Importantly, immune evasion mediated by the PD-1/PD-1 ligand axis can be inhibited with neutralizing PD-1 receptor monoclonal antibodies and JAK2 signaling can be abrogated with clinical grade small molecules. For these reasons, we propose the following specific aims: 1.0 Assess the frequency and prognostic significance of 9p24 amplification and increased PD-1 ligand and JAK2 expression in patients with cHL and MLBCL;2.0 Elucidate the bases for relative differences in PD-L1 and PD-L2 expression in cHL and MLBCL;3.0 Evaluate the efficacy of PD-1 ligand/PD-1 receptor blockade in patients with cHL and MLBCL;and 4.0 Assess the consequences of chemical JAK2 inhibition in cHL and MLBCL. The proposed studies will translate the comprehensive genomic analyses of cHL and MLBCL into robust clinically relevant diagnostic and prognostic signatures and a targeted, personalized approach to treatment.

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, two lymphoid malignancies that primarily strike young healthy adults, classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL), are largely defined by their morphologic appearance and physical location and treated with empiric combinations of available chemotherapeutic agents rather than targeted approaches to disease-specific survival pathways. The proposed studies will translate the comprehensive genomic analyses of cHL and MLBCL into robust clinically relevant diagnostic and prognostic signatures and a targeted personalized approach to treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA161026-03
Application #
8507178
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Jessup, John M
Project Start
2011-08-22
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$402,341
Indirect Cost
$148,108
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Armand, Philippe; Engert, Andreas; Younes, Anas et al. (2018) Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial. J Clin Oncol 36:1428-1439
Roemer, Margaretha G M; Redd, Robert A; Cader, Fathima Zumla et al. (2018) Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma. J Clin Oncol 36:942-950
Cader, Fathima Zumla; Schackmann, Ron C J; Hu, Xihao et al. (2018) Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell-rich and exhausted T-effector microenvironment. Blood 132:825-836
Liu, W Robert; Shipp, Margaret A (2017) Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2017:310-316
Nayak, Lakshmi; Iwamoto, Fabio M; LaCasce, Ann et al. (2017) PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 129:3071-3073
Carey, Christopher D; Gusenleitner, Daniel; Lipschitz, Mikel et al. (2017) Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood 130:2420-2430
Liu, W Robert; Shipp, Margaret A (2017) Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma. Blood 130:2265-2270
Zinzani, Pier Luigi; Ribrag, Vincent; Moskowitz, Craig H et al. (2017) Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood 130:267-270
Chen, Robert; Zinzani, Pier Luigi; Fanale, Michelle A et al. (2017) Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol 35:2125-2132
Roemer, Margaretha G M; Advani, Ranjana H; Ligon, Azra H et al. (2016) PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J Clin Oncol 34:2690-7

Showing the most recent 10 out of 21 publications