Checkpoint inhibitor treatment for EBV+ lymphoma among HIV+ individuals

Division Of Basic Sciences - Nci

Investigators

Abstract

Epstein-Barr virus (EBV) is a worldwide chronic infection that is typically controlled by host immunity in immunocompetent individuals. However, EBV is also causally associated with aggressive lymphomas, especially in individuals with human immunodeficiency virus (HIV) but also for individuals without HIV, particularly in low-income countries. Indeed, EBV was first discovered in children with Burkitt lymphoma in sub-Saharan Africa (SSA), studies that contributed to seminal discoveries in cancer biology and treatment. EBV+ lymphomas can be cured with intensive chemotherapy. However, chemotherapy is often ineffective and unsuitable for many patients in low-and even high-income countries. Lower-intensity, safe, effective treatments for EBV+ lymphomas would have substantial worldwide impact. Yet there are no such proven treatments that can be applied to most of the world's population who suffer from these common, curable, but also frequently fatal cancers. We propose to address this critical need by targeting EBV in malignant lymphocytes using anti-PD-L1 immune checkpoint inhibitor treatment with atezolizumab and by testing this approach in Malawi and Kenya, where EBV+ lymphomas are a major public health problem for HIV+ individuals. SSA has a high burden of EBV+ lymphomas, and patients experience unacceptably poor outcomes after standard-of-care chemotherapy, principally due to lymphoma progression. Testing this therapeutic strategy in this environment therefore presents a truly unique scientific opportunity. Immune checkpoint inhibitor treatment is approved for the treatment of classical Hodgkin lymphoma, which is typically EBV+ in SSA, and has shown promise in preliminary studies for other EBV+ malignancies including gastric cancer, nasopharyngeal carcinoma, extranodal NK/T-cell lymphoma, and plasmablastic lymphoma. Despite widespread international availability and approval across multiple cancer indications, anti-PD-1/anti-PD-L1 immune checkpoint inhibitor treatment has extremely limited data to date specifically in HIV+ populations and extremely limited data specifically from SSA populations. For HIV+ populations in SSA, safety and efficacy are likely to differ substantially compared with populations previously studied in clinical trials conducted to support current therapeutic indications for immune checkpoint inhibitors. We propose to conduct a phase 1b/2 clinical trial evaluating atezolizumab in HIV+ and HIV- patients with EBV+ lymphomas as determined by in situ hybridization (ISH) for EBV-encoded RNA (EBER). This will potentially include Burkitt, Hodgkin, diffuse large B-cell, plasmablastic, and extranodal NK/T-cell lymphomas. Safety will be assessed by describing dose-limiting toxicities (DLTs) using NCI Common Terminology Criteria for Adverse Events (CTCAE). Efficacy will be assessed using overall response rate, duration of response, and progression-free survival. We will also evaluate effects of atezolizumab on plasma EBV kinetics in patients with diverse EBV+ lymphomas. We will assess change in EBV loads over the course of treatment and correlate those changes with clinical outcomes to assess the utility of this highly implementable cell-free tumor DNA biomarker for treatment monitoring in patients receiving atezolizumab. Finally, we will examine EBV-specific CD8 T-cell immunity at baseline and in response to atezolizumab in patients with diverse EBV+ lymphomas. Associations between EBV-specific CD8 T-cell immunity with clinical outcomes will be assessed. Additional funding is now requested for this previously approved proposal following continued concept development and based on the unique scientific opportunity to enroll equivalent numbers of HIV+ and HIV- patients with EBV+ lymphomas in Malawi and Kenya (as opposed to the initially submitted proposal focused on HIV+ patients only). In the revised trial schema, HIV- individuals will serve as a control group to better understand unique safety/efficacy profiles of immune checkpoint inhibition among HIV+ individuals. Such HIV+ versus HIV- comparisons are uniquely possible in SSA and particularly valuable given historical exclusion of HIV+ individuals with cancer from clinical trials conducted in the US including immunotherapy studies, as well as a generalized HIV epidemic in SSA which minimizes the marked confounding effects of age and sociobehavioral differences between HIV+ and HIV- populations in US settings. Although EBV was discovered in African children with Burkitt lymphoma, their outcomes have remained unacceptably poor for 50 years, even while discoveries originating in their tumors have benefited cancer patients worldwide. NIH-funded work in Malawi has provided among the first detailed, prospective descriptions of histologic diversity, molecular features, clinical presentations, and outcomes for HIV+ patients with diverse lymphoma subtypes in SSA. This work in Malawi was previously led by Dr. Satish Gopal, who moved to NCI in 2020 to direct the NCI Center for Global Health and assume an adjunct investigator appointment in the Lymphoid Malignancies Branch of the Center for Cancer Research. He continues to collaborate with on NIAID- and NCI-supported clinical research in Malawi and Kenya. The proposed treatment regimen has strong biologic rationale and encouraging preliminary clinical data. Indeed, there is an ongoing phase 2 clinical trial evaluating nivolumab for EBV+ lymphoproliferative disorders in HIV- individuals at the NIH Clinical Center already being conducted by the Lymphoid Malignancies Branch, led by PI Dr. Mark Roschewski. Building on our extensive lymphoma portfolio in Lilongwe, including other actively accruing NIH-supported lymphoma clinical trials, we are well positioned to conduct this early phase study and have garnered a commitment from Roche to provide atezolizumab for the trial. If successful, this treatment would represent a major advance for EBV+ lymphoma patients in low-income countries, and indeed worldwide, and would support larger and more definitive evaluations through international NCI clinical trial networks, as well as ongoing efforts to increase access to cancer immunotherapies for diverse populations worldwide.