FINAL PROGRAM - American Society of Gene & Cell Therapy

13 th AnnUAL MEETing | Washington, DC USA May 19-22, 2010 39Program ScheduleEducation Session 1335:30 pm - 7:00 pmRoom: Virginia SuiteTopical Review: Immunotherapy of CancerThe immune system can be properly modified to eradicate cancer. Currently, effector molecules, such as monoclonal antibodies and cells such as tumor-reactive lymphocytes,are able to selectively target and eliminate tumors, may be isolated and/or engineered. The potency of cellular adoptive immunotherapy has been revealed bypersistent and complete clinical responses obtained with by the transfer of allogeneic T lymphocytes in the context of allogeneic hemopoietic cell transplantation (allo-HSCT) and by the transfer of autologous tumor specific cytotoxic T lymphocytes (CTLs) in cancer patients. Major hurdles limiting adoptive T cell therapy relate to toxicity(ie: graft-versus-host disease-GvHD in allo-HSCT), feasibility and efficacy (ie: difficulty in expanding rare, high-avidity tumor-specific CTLs). Gene transfer technologies mayallow to overcome all these hurdles. The transfer of tumor-specific TCR or chimeric antigen receptors (CARs), confers tumor-specificity and activity to autologous T cells.The transfer of a suicide gene into allogeneic lymphocytes allows to tame toxicity of allogeneic lymphocytes. In this session, we will discuss clinical results, challenges andadvances recently made to improve the potency and specificity of adoptive immunotherapy with genetically modified lymphocytes to treat cancer.ChairChiara Bonini, MDSpeakersRichard A. Morgan, PhDUsing Engineered T Cells for the Treatment of CancerAdoptive cell transfer (ACT) using anti-tumor antigen reactive T cells has proven to be a useful strategy for the treatment of metastatic melanoma, with objective responserates of up to 72%, with 16% of patients rendered disease free. These studies involved the extraction and ex-vivo expansion of naturally occurring tumor infiltratinglymphocytes (TIL). Only one-half of patients are able to receive this therapy due to lack of harvestable tumors, inability to grow TIL, or a lack of cellular reactivity. Recentstrategies aimed at broadening ACT involve the use of chimeric antigen receptors (CAR) or T-cell receptor (TCR) genes specific for tumor associated antigens and the use ofviral vectors to transduce these genes into peripheral blood lymphocytes. TCR gene therapy has been applied with some success in recent trials targeting MART-1, gp100and NY-ESO-1. CAR gene therapy trials are also showing promising results in protocols targeting CD19+ lymphomas. Efforts aimed at improving the response rate andminimizing on-target toxicity are in progress.Gianpietro Dotti, MDCar-Based Gene Transfer in T LymphocytesExpression of a transgenic “T-body” or “chimeric antigen receptor” (CAR) in human T lymphocytes combines the specificity of an antibody with the homing and target-celldestruction capabilities of T cells. This technology was first described 15 years ago, and after significant improvements in gene transfer technologies and better understandingof immunological pathways is now reaching a critical phase of clinical evaluation. In this presentation we will summarize the concept of CAR-based immunotherapy,describe the steps accomplished, and outline the future progress we need to make if this approach is truly to improve cancer immunotherapy.Chiara Bonini, MDT-Cell Based Gene Therapy in Hematopoietic Stem Cell TransplantationThe potency of cellular adoptive immunotherapy for the treatment of cancer has been clearly revealed by the persistent and complete clinical responses observedin patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) followed by the adoptive transfer of donor T lymphocytes. However, severalhurdles remain to be overcome before adoptive immunotherapy can become a broadly applicable therapeutic approach to treat cancer, and gene transfer approachesrepresent ideal solutions to overcome these hurdles. In allo-HSCT, most of the antileukemic potential resides in alloreactivity towards patient-specific antigens, such asminor and major histocompatibility antigens, by donor lymphocytes. Unfortunately, alloreactivity is also responsible for the most serious and frequent complication ofallo-HSCT: the Graft-versus-Host-Disease (GvHD). The risk of GvHD increases with the level of HLA disparity between host and donor, and leads to impaired quality oflife and reduced survival expectancy, particularly in patients transplanted from HLA-mismatched donors. Gene transfer technologies are promising tools to manipulatedonor T cell immunity to enforce the graft-versus-tumor (GvT) effect, to promote a functional post-transplant immune reconstitution (graft-versus-infection-GvI) and toprevent or control GvHD. To this purpose, several cell and gene transfer approaches, have been investigated at pre-clinical level, and are being implemented in clinicaltrials. The majority of these approaches, based on negative or positive selection of specific T cell subpopulations, aim at reducing the repertoire of donor lymphocytesinfused with or after the graft, so to prevent alloreactivity. In contrast, suicide gene therapy aims at a selective control of GvHD in treated patients, thus permittingthe full exploitation of alloreactivity against cancer cells. In a phase I-II clinical trial enrolling 54 pts undergoing haploidentical HSCT, we showed that the transfer of asuicide gene into donor lymphocytes, allows to provide rapid and effective immune reconstitution, and control of GvHD. By taming the toxicity of allo-HSCT the suicidegene approach renders haploidentical HSCT a feasible, safe and more effective option for cancer patients of all ages. Cell and gene therapy approaches currentlyimplemented for a safe exploitation of donor immunity against cancer, in the context of allo-HSCT will be discussed.Wednesday, May 19 th