Promoting an Effective Antitumor Immune Response in Lymphoma

This proposal addresses the Topic Area Lymphoma and the Military Relevance Focus Area related to 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.

Diffuse large B-cell lymphoma 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 improvements in frontline immunochemotherapy in this disease, 30%-40% of patients relapse or are primarily resistant to chemotherapy treatment and eventually succumb to malignant lymphoma. The objective of this research is to clinically use immune cells (T-cells) that are present at sites of lymphoma to eradicate tumor cells. However, most T-cells at these sites are suppressed and/or immunologically exhausted and thus fail to mount an effective antitumor response, even though they would otherwise be capable of targeting and eradicating tumor cells.

Therefore, we propose to determine the characteristics of effective tumor-specific T-cells and then identify the cellular mechanisms that influence T-cell suppression and exhaustion. We propose to do this by comparing T-cells in lymphoma specimens from patients who have undergone an organ transplant and whose immune system has been purposely suppressed (to accept the new organ). These T-cells function normally because when the level of their immune system suppression is reduced, the T-cells mount an effective tumor response. Thus, this component of research will enable the study of the mechanisms of T-cell suppression alone. We will then study the cellular interactions in patients with diffuse large B-cell lymphoma (DLBCL) whose T-cells are both suppressed and exhausted. In these patients, there is no treatment given to suppress immune function, but the T-cells in the tumor function very poorly. We propose to identify the differences between the T-cells in these two diseases and identify the pathways that lead to T-cell exhaustion. Once these mechanisms are established, we will determine if affected T-cells can be activated and if exhaustion can be prevented or even reversed. This will be done with preclinical experiments and by conducting a parallel, randomized Phase II clinical trial (to be funded under an National Cancer Institute grant) comparing the single immunological agent nivolumab (to prevent suppression of T-cells) to the effectiveness of dual immunotherapy consisting of nivolumab and a second agent called varlilumab (to address both T-cell suppression and exhaustion). Patients with relapsed or refractory DLBCL and post-transplant lymphoproliferative disorder (PTLD) have a very poor prognosis, and, should this novel immunological approach be effective, this patient population will significantly benefit from a new, promising therapy. Although the agents being tested in the clinical trial may activate normal immune cells and thereby cause immune-related side effects, both antibodies have been very well tolerated in patients treated to date. We therefore anticipate that the modest potential risks will be outweighed by the expected therapeutic benefit of this therapy.

This research will benefit patients with diffuse large B-cell lymphoma by stimulating their immune system to be able to defeat tumor cells and thus improve their outcome. The projected time to achieve a patient-related outcome will be less than 4 years, as patients will be treated with immune-activating antibodies in a parallel clinical trial. We anticipate that this approach will lead to improved, less-toxic treatment options for lymphoma patients. The lessons learned are likely to have impact upon many cancer types and potentially improve the outcome of patients with other hematological malignancies and solid tumors. These immune therapies are likely to be easier to tolerate than standard chemotherapy with fewer long-term toxicities. Therefore, they hold the promise to improve the quality of life for active duty Service members, Veterans, and their families who may have been exposed to aggressive solvents such as benzene, toluene, or xylene or Agent Orange (Vietnam War) or high levels of ionizing radiation during their service years and therefore are at risk for developing lymphoma.