Latent Epstein-Barr (EBV) infection is associated with both Hodgkin's disease (HD) and non-Hodgkin'slymphomas (NHL), and EBV antigens expressed in these lymphomas are potential targets forimmunotherapy. Although clinical studies with EBV-specific cytotoxic T cells (CTLs) have yielded promisingresults, their antilymphoma activity is limited by several factors. For example, 1) EBV-specific CTL linesgenerated by standard methods are dominated by T-cell clones not reactive to the subdominant EBVproteins LMP1 and LMP2 expressed in HD and NHL and 2) infused EBV-specific CTLs do not significantlyexpand in vivo after adoptive transfer. Our central hypothesis is that by overcoming these limitations, we willenhance the antitumor activity of EBV-specific CTLs and improve clinical outcome in lymphoma patientstreated with these cells. To demonstrate the feasibility of this strategy, we propose three specific researchaims.
AIM 1 : We will infuse LMP1- and LMP2-specific CTLs into EBV-positive HD or NHL patients togenerate the broadest possible CTL response against the malignant cells, and to ensure that suitable CTLepitopes are available, regardless of the patient's HLA type.
AIM 2 : We have shown that the infusion ofmonoclonal antibodies targeting the CD45 antigen results in transient lymphodepletion and enhanced EBV-specific CTL expansion. We will build on these findings and test in an animal model the ability of differentvaccines to further enhance the proliferation of adoptively transferred CTLs post lymphodepletion. Wehypothesize that the expression of IL-15 or the silencing of SOCS1, in combination with LMP1 and LMP2expression, will enhance the vaccine-induced proliferation and expansion of LMP1- and LMP2-specific CTLsadministered to patients. Finally, in AIM 3, we will test in a second Phase I clinical trial the safety and effectsof an optimized vaccine on the expansion, persistence and antitumor effector function of pre-existing oradoptively transferred LMP1- and LMP2-specific CTLs in HD or NHL patients with relapsed disease.Lay summary: The body's immune defenses against cancer are usually not effective because the cancercells, by themselves, do not attract a strong immune response. Some lymphomas contain parts of theEpstein-Barr virus that do stimulate the immune system. We plan to collect T cells, a component of theimmune system, from patients' blood samples and train them to recognize the LMP1 and LMP2 segments ofthe Epstein-Barr virus. After these cells are returned to the patient, they should attack and destroy thetumors cells that contain LMP1 and LMP2.
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