This proposal addresses the Topic Area Lymphoma and the Military Relevance Focus Area of gaps in cancer treatment and/or survivorship that may affect the general population but have a particularly profound impact on the health and well-being of active duty Service members, Veterans, and their beneficiaries. Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of B-cell non-Hodgkin lymphoma (NHL) in the United States, encompassing 30%-40% of the estimated 70,000 cases of NHL in 2016. Despite major advances in frontline immunochemotherapy for this disease, 30%-40% of patients relapse or are primarily resistant to treatment and eventually succumb to malignant lymphoma. While the tumor microenvironment in B-cell NHL contains T-cells that can target and lyse malignant B-cells, we have found that most T-cells are suppressed or immunologically exhausted and fail to mount an effective antitumor immune response. The critical problem to be addressed is how to clinically use the immune cells that are present at sites of lymphoma to eradicate the malignant B-cells.Hypothesis: Our hypothesis is that an effective antitumor response in B-cell NHL requires both activation of suppressed effector cells and simultaneous reversal of immune exhaustion in a defined population of tumor antigen-directed T-cells.Specific Aims: Even when immune inhibition in immune-competent DLBCL patients is decreased by immune checkpoint blockade, T-cells still fail to develop an effective immune response, while immune-suppressed patients who develop a post-transplant lymphoproliferative disorder (PTLD) with DLBCL morphology often display an effective T-cell response when immune suppression is decreased. Using serial specimens from 10 patients with either PTLD or DLBCL, we propose to:(1) Assess the phenotype and function of intratumoral T-cells using mass cytometry (CyTOF), cytokine production, and tumor cell lysis.(2) Determine the role of immune-activating antigens by comparing immune function in Epstein-Barr virus (EBV)-positive PTLD compared to EBV-negative PTLD and DLBCL.(3) Evaluate whether simultaneous immune checkpoint blockade and immune activation promotes intratumoral T-cell function in preclinical models, and in clinical specimens obtained from a clinical trial of nivolumab plus varlilumab.Study Design: We will first identify the cell populations in the tumor microenvironment that have an immunosuppressive phenotype using cytometry by time-of-flight (CyTOF) and by co-culturing suppressive immune cell populations with autologous intratumoral T-effector cells to determine their relative ability to suppress immune effector function. Next, to determine what activates the effector cells, we will determine the relevance of antigens in lymphoma cells by characterizing immune responses to EBV+ PTLD and DLBCL through profiling of genotypic background, gene expression (mRNA), and protein expression. Finally, we will determine whether T-cell suppression can be reversed by CD27 and PD-1 ligation. In parallel to these preclinical efforts, we will perform a randomized Phase II clinical trial (independent of TTSA; funded by the National Cancer Institute) of an agonistic anti-CD27 antibody (varlilumab) and a blocking anti-PD-1 antibody (nivolumab). We will then test here, both preclinically and using up to 96 samples from the Phase II clinical trial, whether blocking inhibition due to PD-1 signaling in combination with activating T-cells by CD27 stimulation results in restored T-cell function. Patients treated with both agents will be compared to patients treated with nivolumab alone.Collaboration/Translational Aspects: This multi-institutional, interdisciplinary research effort brings together researchers with expertise in lymphoma biology (Ansell), mass cytometry (Villasboas), and immune suppression (Lazaryan). Patients and tissue specimens will be provided by the Mayo Clinic and the University of Minnesota -- the strength of the partnership is that Mayo Clinic sees more patients with DLBCL, while the University of Minnesota sees more patients with PTLD, both of which are integral to the proposed research.Military Relevance and Impact: This project will address gaps in lymphoma treatment, quality of life, and survivorship that affects both the general population and active duty Service members, Veterans, and their beneficiaries. This research will reveal how to effectively use the immune cells that are present at sites of lymphoma to eradicate malignant B-cells and thus will lead to much improved patient outcomes of patients with aggressive B-cell lymphoma. It is also anticipated that the understanding of how to mobilize the immune system to fight lymphoma will have relevance to patients with other hematological malignancies and solid tumors.
|Effective start/end date||9/15/18 → 9/14/22|
- Congressionally Directed Medical Research Programs: $514,325.00