A roadmap for discovery and translation in lymphoma

To the editor:

Non-Hodgkin lymphomas, Hodgkin lymphoma, and chronic lymphocytic leukemia comprise more than 80 unique subtypes¹  that can be further divided based on histology, immunophenotype, genetics, and other aspects of biology. Despite this diversity, advances in the treatment of lymphoma have served as models for curative cancer therapy.^2-5  To review the state of science in lymphoma biology, the American Society of Hematology (ASH) organized the inaugural ASH Meeting on Lymphoma Biology in August 2014. The Steering Committee for the meeting was asked to develop a roadmap for future discovery in lymphoma biology that could inform funding allocations (eg, requests for applications at the National Institutes of Health) and direct advocacy by ASH and other organizations. This roadmap is outlined in Table 1 and consists of both infrastructure and research priorities.

The investigation of individual lymphoma subtypes is largely limited by the same considerations that affect many other tumors, including:

• inadequate numbers of representative cell lines and in vivo models, including patient-derived xenografts and genetically engineered mouse models;

• inadequate characterization of the genetic, epigenetic, transcriptional, proteomic, and metabolomic landscape of each subtype;

• limited interest from pharma in rare subtypes with poorly understood pathobiology; and

• insufficient collaboration across centers, which limits both expertise and resource availability.

These inadequacies are compounded by the biologic heterogeneity within each lymphoma subtype. Preclinical studies that capture this heterogeneity will require large numbers of samples and/or models to facilitate patient stratification and biomarker validation. For most lymphoma subtypes, the necessary reagents to perform these studies either do not exist or are scattered across multiple institutions. As a result, many patients with lymphoma continue to experience poor outcomes. These include patients with mantle cell lymphoma, subtypes of peripheral T-cell lymphoma, and lymphomas that harbor specific genetic markers [eg, del(17p) in chronic lymphocytic leukemia, concurrent MYC and BCL2 translocations in diffuse large B-cell lymphoma].

The biological consequences of most genetic aberrations observed in human lymphomas remain unclear. Therefore, functional approaches are needed to distinguish driver events and to define critical dependencies that can be exploited therapeutically. Another high priority is to develop new prognostic models that incorporate biologically informative predictive factors along with clinical factors to enable patient selection for clinical trials and to highlight the biological pathways and mechanisms that influence therapeutic response. Comprehensive investigations of larger collections of clinically annotated patient samples are needed to identify additional determinants of treatment response, and these predictive features will inevitably shift with new therapies.

Advances in the targeting of lymphoma depend on an improved understanding of the fundamental biology of lymphoid development. Because the majority of B-cell lymphomas arise from cells undergoing the germinal center reaction, insights into this process shed light directly on lymphomagenesis. Lymphomas highjack other aspects of lymphocyte biology, including mechanisms that regulate proliferation, differentiation, interaction with immune and stromal cells in the microenvironment, motility, dissemination, and response to antigens. An important goal of future research will be to define genetic and nongenetic mechanisms that perturb these processes.

Interactions between lymphoma cells and nonmalignant cells within the bone marrow, lymph node, and other tumor microenvironments may represent additional targetable dependencies. Strategies to identify and therapeutically modulate these interactions are a priority, and include interventions to disrupt tumor angiogenesis, block critical adhesion molecules, and abrogate the nurturing effect of cytokines and chemokines released by tumor-associated stromal and immune cells. There is a pressing need for model systems that faithfully recapitulate interactions between human lymphoma cells and the microenvironment to facilitate the preclinical testing of novel therapeutics.

Efforts to augment immune-mediated clearance of lymphoma cells have shown tremendous promise.^6-8  Specific areas for research include the targeting of immune checkpoints, improving the efficacy of adoptive cellular therapies, modulating T regulatory cells, developing novel lymphoma vaccines, and enhancing tumor-specific innate immune responses.

In summary, we outline a roadmap for discovery and translation in lymphoma that focuses on improving the understanding of disease biology across the broad diversity of subtypes. The roadmap is based on the fundamental goal of extending effective treatment to all patients with lymphoma. Achieving that goal with maximum efficiency and expedience will require a broad and collaborative effort between researchers, patients, funding agencies, pharma, and advocacy groups. Comments on the roadmap are welcome and can be posted at http://www.hematology.org/lymphoma-roadmap.