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.
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.
|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|
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