Page 1764 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 100

T-CELL THERAPY OF HEMATOLOGIC DISEASES

Gianpietro Dotti and Malcolm K. Brenner

INTRODUCTION while the latter is the cellular equivalent of antibody serotherapy, in
which the transferred immune cells are expected to attack the tumor
Conventional modalities for treating cancer remain unsatisfactory. cells directly, albeit with a phase of in vivo expansion, and to subse-
Despite the introduction of small molecules that target specific quently establish a pool of memory cells to provide long-term protec-
molecular lesions or pathways within the cancer cells, cure rates for tion against resurgent disease. Several cell subsets are currently being
many common tumors remain low, while adverse events are still studied in adoptive transfer protocols, including activated T lympho-
distressingly high. Cancer immunotherapy represents a promising cytes (ATL), tumor infiltrating T lymphocytes, antigen-specific
extension of highly targeted cancer therapy with a favorable toxicity cytotoxic T lymphocytes (CTL), natural killer (NK) cells, γδ T cells
profile and excellent pharmacoeconomics. Until recently, most atten- and natural killer T (NKT) cells. In this chapter, we discuss adoptive
tion has been on the development of conventional monoclonal transfer of ATL and CTL.
antibodies that target specific tumor-expressed antigens. Over the
past few years, the focus of monoclonal antibody therapy has shifted
to agents that recruit innate or adaptive immune responses against Adoptive Cell Therapy With T Lymphocytes
the tumor, either by blocking immune regulation by tumors or by
simultaneously engaging tumor cells and effector lymphocytes (bispe- In principle, lymphocytes have the ability to traffic through multiple
1,2
cific antibodies). More recently, however, strikingly beneficial tissue planes and to be self-renewing. These assets, coupled with their
results with direct (adoptive) transfer of immune system cells are now ability to destroy tumor or viral infected target cells through a range
3
being reported. Although to date, these have primarily been obtained of mechanisms makes them an appealing resource for adoptive
in patients with leukemia, lymphoma, melanoma, or neuroblastoma, transfer, and a multiplicity of clinical studies using this approach have
methodologies are being developed to allow us to extend the tumor now been described. Adoptive lymphocyte therapies may use alloge-
range. neic or autologous cells, which may be of tightly defined specificity
Many human tumors express tumor-specific antigens (TSAs) or (e.g., T-cell clones) or broad phenotype and activity (e.g., tumor
tumor-associated antigens (TAAs) that can be recognized by the host infiltrating lymphocytes). As we have learned more about the molecu-
immune system and induce antitumor cell-mediated and humoral lar basis of immune recognition and immune regulation, it has
immune responses. Although these responses may be transient and become possible to genetically modify the infused lymphocytes to
are not always associated with clinical responses, they provide evi- alter their specificity or behavior. In this section, we describe examples
dence for the existence of tumor-directed immunity in humans that of each type of T-cell adoptive transfer and discuss the relative merits
may also have antitumor activity. Several barriers block the develop- and limitations of each.
ment of more effective antitumor immunity in people with cancer.
First, many human tumors express few major histocompatibility
complex (MHC) molecules or have poor processing of their potential Donor Lymphocyte Infusion
tumor antigens. Even when TAA/TSA are processed and presented,
most tumors lack the costimulatory molecules necessary to imple- It has long been apparent that the curative effects of allogeneic
ment a long-lived and effective immune response. In addition to these hematopoietic stem cell transplants (HSCT) for many hematologic
passive defenses against immunity, many tumors can “edit” the malignancies can be attributed to a graft-versus-leukemia (GVL)
immune system to their advantage, secreting cytokines such as TGFβ effect largely mediated by the incoming T cells within the donor
or by expressing molecules such as programmed death-ligand 1 graft. Thus, patients with chronic graft-versus-host disease (GVHD)
(PD-L1) that act as inhibitory or check point signals to cytotoxic were well recognized as having a lower probability of relapse than
effector T-cell growth, function and survival, or that favor expansion individuals without this unpleasant complication. Similarly, recipients
of Th2/regulatory T cells rather than effector T cells. Finally, intensive of syngeneic grafts have the lowest rate of GVHD and the highest
chemotherapy and radiotherapy can themselves severely reduce risk of relapse. In 1990, Kolb and colleagues took advantage of this
immune function by destroying antigen presenting cells and dividing observation and deliberately infused donor lymphocytes in an attempt
T lymphocytes. to eliminate recurrent disease in patients with chronic myeloid leu-
As our understanding of the molecular basis of tumor immune kemia (CML). Their positive results have been confirmed in multiple
escape has increased, it has been possible to derive countermeasures studies worldwide, and remission can be induced in more than 50%
that may allow us to induce more potent antitumor immune of CML patients who relapse after transplantation by stopping
responses, and that will soon allow us to extend effective therapies to immunosuppressive treatment or infusing donor lymphocytes.
a broad range of common tumors. Unfortunately, donor lymphocyte infusion (DLI) is much less effec-
tive at treating other types of relapsed leukemias after transplantation,
with a 29% remission rate for acute myeloid leukemia and only 5%
TYPES OF CELLULAR IMMUNOTHERAPY for acute lymphoblastic leukemia (ALL). It is not clear why these
differences occur, since all these leukemias present the minor histo-
Cellular immunotherapy may be active, using cell-based vaccines compatibility antigens (mHags) that are likely the targets of this GVL
derived from tumor cells themselves or antigen-presenting cells effect, although many mHags have yet to be defined. DLI therapy
expressing TAA/TSA from proteins or peptides, or passive, by direct may also produce severe adverse effects, since the frequency of broadly
adoptive transfer of viable immune cells. The former approach relies alloreactive effector cells is usually much higher than the frequency
on the intact afferent and efferent immune system of the host of lymphocytes targeted exclusively to the relapsed malignancy. As a
responding to the stimulus with an effective antitumor response, consequence, patients receiving DLI often develop GVHD. This

1568