The long-term goal of Project 1, led by C. Rooney, is to improve the outcome of immunotherapy forlymphomas associated with Epstein-Barr virus (EBV), especially Hodgkin disease (HD) and non-Hodgkinymphoma (NHL). Although studies during the previous funding cycle showed that cytotoxic T lymphocytes(CTLs) specific for the LMP2 protein of EBV home to tumor sites and produce antitumor effects (completeresponses in 4 of 6 patients with relapsed disease), such therapy had clear shortcomings that would limit itseffectiveness in future protocols for HD and NHL patients, and for other malignancies. Most prominent werethe short-lived increases in the frequency and function of tumor-specific CTLs, particularly in patients withbulky disease. These observations suggested that optimal immune responses were being suppressed bythe tumor microenvironment and by the tumor cells themselves, leading the investigators to propose (i) thatLMP1- and LMP2-specific CTLs resistant to TGF-p, an immune inhibitory molecule produced by HD tumors,will have prolonged persistence and function in patients with relapsed disease, (ii) tumor antigen (TA)-specific CTLs expressing IL-12 will reverse the Th2 and negative immunoregulatory phenotype/function oftumor-infiltrating mononuclear cells, and (iii) TA-specific CTLs expressing IL-12 or constitutive T-bet, themaster regulator of Tc1/Th1 functions and an inhibitor of GATA-3 , will have enhanced resistance to andefficacy against Th2 and Treg containing tumors. These predictions will be tested in three specific aims: todetermine the safety and clinical efficacy of adoptively transferred LMP1- and LMP2-specific CTLsgenetically modified to express a transdominant-negative TGF-beta type II receptor (DNR) in patients withEBV-positive HD or NHL (Aim 1); to evaluate the functional persistence of adoptively transferred DNR genemodifiedEBV-CTLs in these patients (Aim 2); and to compare the safety and antitumor efficacy of TAspecificCTLs expressing IL-12 or T-bet in a model that mimics the regulatory environment of human HD. Ifthe DNR, IL-12 or T-bet gene modifications of CTLs prove safe and enhance the survival and function ofCTLs at tumor sites, this strategy could be introduced into the T-cell therapies evaluated in Projects 3 and 4.Lay summary - In many patients with Hodgkin disease and non-Hodgkin lymphoma, the cancer cells areinfected with Epstein-Barr virus. The viral proteins in the lymphoma cells are attractive targets forimmunotherapy. The investigators in this project are taking advantage of these viral targets by engineering aspecific type of T cell to express proteins that should improve the ability of the modified cells to find anddestroy EBV-positive tumors without producing toxic effects in the patient.
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