Sustained Complete Responses With Novel Immunotherapy in Lymphoma
Approximately 40% of patients with Hodgkin or non-Hodgkin lymphoma have tumor cells that express the type II latency Epstein-Barr virus (EBV) antigens latent membrane protein 1 (LMP1) and LMP2. T cells specific for these antigens are present in low levels and may be rendered nonreactive by the tumors expressing the antigens. As reported in the Journal of Clinical Oncology, Bollard et al succeeded in expanding autologous LMP-specific cytotoxic T-lymphocytes and using them in treatment of patients with EBV-associated lymphoma at high risk of relapse or in relapse after standard therapy. Long-term remission was maintained in nearly all patients in remission at the time of LMP cytotoxic T-lymphocyte infusion, and a high response rate was achieved in those with active disease.
Study Details
In the study, populations of LMP cytotoxic T lymphocytes from lymphoma patients were expanded using autologous dendritic cells and EBV-transformed B-lymphoblastoid cell lines transduced with an adenoviral vector expressing LMP2 alone (n = 17) or both LMP2 and LMP1 (n = 33). The modified antigen-presenting cells expanded the population of cytotoxic T lymphocytes enriched for specificity against type II latency LMP antigens. Patent ages ranged from 7 to 79 years, and initial disease presentation ranged from stage IA to IVB; 25 patients had Hodgkin lymphoma, 11 had NK/T-cell non-Hodgkin lymphoma, 7 had diffuse large B-cell lymphoma, 2 had post-transplant lymphoproliferative disorder, 1 had peripheral T-cell non-Hodgkin lymphoma, and 4 had other lymphomas, including chronic active EBV infection and lymphomatoid granulomatosis.
Patients received two infusions of cytotoxic T lymphocytes 2 weeks apart and were eligible for eight additional infusions if they achieved partial response or stable disease 8 weeks after initial treatment.
Durable Remissions
No infusional toxicities were observed in the 50 patients receiving cytotoxic T-lymphocyte infusion. Of 29 patients in first or later remissions, 9 received cytotoxic T lymphocytes against LMP2 and 20 received cytotoxic T lymphocytes against LMP1/2. One patient died as a result of complications from preexisting cardiac disease before the 8-week evaluation; 27 of the remaining 28 patients remained in complete remission at a median of 3.1 years after infusion.
There were eight additional deaths from nonrelapse causes (secondary malignancies in three, allogeneic stem cell transplantation in one, infection in two, central nervous system [CNS] hemorrhage in one, and complications of lung transplantation in one), lowering 2-year event-free survival to 82%. No toxicity was attributed to LMP cytotoxic T lymphocytes.
High Response Rate
Among the 21 patients with relapsed or resistant disease at the time of cytotoxic T-lymphocyte infusion, 8 received LMP2 cytotoxic T lymphocytes and 13 received LMP1/2 cytotoxic T lymphocytes. Clinical response was observed in 13 patients (62%), including complete response in 11 (52%). The 2-year event-free survival rate was approximately 50% for both the LMP2 and LMP1/2 cytotoxic T-lymphocyte groups, with equal numbers of deaths due to relapse and nonrelapse causes occurring in both groups.
With regard to potential toxicity, one patient had CNS deterioration 2 weeks after infusion that was attributed to disease progression, although an inflammatory response at a site of CNS disease could not be excluded. Another patient developed respiratory complications 4 weeks after the second cytotoxic T-lymphocyte infusion at the time of achieving complete response; although this was attributed to an intercurrent infection and the patient completely recovered, a cytotoxic T-lymphocyte–related systemic inflammatory response syndrome could not be excluded.
Increased Circulating Cytotoxic T Lymphocytes
Most patients who achieved response or remained in durable remission had circulating LMP1- and/or LMP2-specific T cells compared with few nonresponders. Neither responders nor nonresponders had an increase in cytomegalovirus-specific T cells, indicating that changes in LMP1/2 T-cell frequency were not just a marker of generalized increase in virus reactivity. Assessment of suppressive T regulatory cell immune reconstitution in patients who received LMP1/2 cytotoxic T lymphocytes showed mean changes of –50.1% in nonresponders and 9.7% in responders between 0 and 2 weeks and 25.8% and 11.2% between 2 and 8 weeks.
Epitope Spreading
Tumor-specific T-cell populations from seven responders and five nonresponders with non-Hodgkin or Hodgkin lymphoma were assessed to determine if the LMP–cytotoxic T-lymphocyte–mediated attack on tumor cells elicited epitope spreading resulting in broader immune reactivity against tumor cells. Infusion was followed over an 8-week period by a dramatic increase in T cells specific for the lymphoma-associated antigens MAGE A4, survivin, and PRAME in four of seven responders and in none of five nonresponders.
The investigators concluded, “Autologous T cells directed to the LMP2 or LMP1 and LMP2 antigens can induce durable complete responses without significant toxicity. Their earlier use in the disease course may reduce delayed treatment-related mortality.”
Catherine M. Bollard, MD, of Baylor College of Medicine, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by the National Institutes of Health, Leukemia Lymphoma Society, Production Assistance for Cellular Therapies program, Clinical Research Center at Texas Children’s Hospital, Methodist Hospital, Dan L. Duncan Institute for Clinical and Translational Research at Baylor College of Medicine, and Dan L. Duncan Cancer Center. For full disclosures of the study authors, visit jco.ascopubs.org.
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