ABSTRACT

Introduction 1523 Targets for immunotherapy 1523 Viral antigens 1524 Lineage-specific antigens 1524 Universal antigens 1524 Cancer-testis antigens 1524 Alloantigens 1524 Types of adoptive immunotherapy for lymphoma 1525 Autologous nonspecifically expanded T cells 1525 Infusion of functional subsets 1525 Unmanipulated allogeneic T cells (donor 1525

lymphocyte infusion) T cells transduced with suicide genes 1526 Allodepleted T cells 1527

Antigen-specific T cell therapies 1527 T cell therapies targeting Epstein-Barr virus 1527 Immunotherapy for human immunodeficiency virus 1532 Chimeric antigen-transduced T cells 1532 Natural killer cells 1532 Improving cellular immunotherapy approaches 1533 Improving ex vivo generation 1533 Genetic modification of T cells to overcome tumor 1533

evasion mechanisms Lymphodepletion to improve expansion of 1533

T cells in vivo Conclusions 1534 Key points 1534 References 1534

Adoptive immunotherapy approaches have a defined clinical role in treating relapse of certain malignancies and some types of infection after allogeneic hematopoietic stem cell (HSC) transplantation.1-5 Because of the success of this approach in this scenario a number of studies are investigating whether immunotherapy approaches may be of benefit in the therapy of lymphoma. This modality of treatment is attractive because patients with lymphoma who do not enter remission or who subsequently relapse are rarely cured using therapy at conventional doses.6,7 Moreover, nonfatal sequelae of therapy, such as altered somatic growth, infertility, and restrictive lung disease, can seriously affect the quality of life of survivors.8 It would therefore be desirable to develop novel therapies that could improve disease-free survival in relapsed/refractory patients and might ultimately reduce the incidence of long-term treatmentrelated complications in all patients. This chapter therefore reviews the current status of adoptive immunotherapy

A prerequisite for developing immunotherapy approaches is to identify antigens on the tumor cells that might be targets. Advances in genomics have simplified the identification of putative tumor antigens through the use of technologies such as serological analysis of recombinant cDNA expression libraries (SEREX) and new informatics tools to deduce epitopes from candidate genes, which allows screening of candidate peptides. The identification of candidate tumor antigens and the mapping of specific epitopes recognized by CD4 and CD8 T cells have facilitated the development of strategies designed to augment tumor antigen-specific T cell responses. If a tumor is to be a target it must not only contain unique proteins capable of providing epitopes for specific immune responses, but also present candidate peptides frequently enough and for sufficient duration to engage responder T cells. In addition, either the tumor cell or a specialized antigen-presenting cell through the process of cross priming must express major histocompatibility complex (MHC) antigens and

T cell activation. The T cell response is therefore influenced by the type of antigen-presenting cell, which determines if there is effector and memory T cell generation or development of T cell tolerance.9 CD4 cells also play an important role in providing help for cytotoxic T lymphocytes (CTL) and in the development of memory.10 There are a number of potential inhibitory factors which may also interfere with the generation of a CTL response in vivo11 and these can potentially be circumvented if CTL are cultured ex vivo. However, the adoptively transferred T cell response may not be maintained in vivo in the presence of inhibitory factors and cell populations.