Cellular immunotherapy may use cell-based vaccines derived from tumor cells or antigen-presenting cells expressing TAA/TSA from proteins/peptides, or may depend on the direct adoptive transfer of viable immune cells. The former approach relies on the intact afferent and efferent immune system of the host responding to the stimulus with an effective antitumor response, while the latter is the cellular equivalent of antibody serotherapy, in which the transferred immune cells are expected to attack the tumor cells directly, albeit with a phase of in vivo expansion, and to subsequently establish a pool of memory cells to provide long-term protection against resurgent disease. Several cell sub sets are currently being studied in adoptive transfer protocols, including activated T lymphocytes (ATL), tumor infiltrating T lymphocytes, antigen-specific cytotoxic T lymphocytes (CTL), natural killer (NK) cells, γβ T cells, and natural killer T (NKT) cells. In this chapter, we discuss adoptive transfer of genetically modified ATL and CTL.
Adoptive Cell Therapy With T Lymphocytes
In principle, lymphocytes have the ability to traffic through multiple tissue planes and to be self-renewing. These assets, coupled with their ability to destroy tumor or viral infected target cells through a range of mechanisms makes them an appealing resource for adoptive trans fer, and a multiplicity of clinical studies using this approach have now been described. Adoptive lymphocyte therapies may use allogeneic or autologous cells, which may be of tightly defined specificity (e.g., T-cell clones) or broad phenotype and activity (e.g., tumor infiltrating lymphocytes). As we have learned more about the molecular basis of immune recognition and immune regulation, it has become possible to genetically modify the infused lymphocytes to alter their specificity or behavior. In this section, we describe examples of each type of T-cell adoptive transfer and discuss the relative merits and limitations of each.
Allogeneic Donor Lymphocyte Infusion
It has long been apparent that the curative effects of allogeneic hematopoietic stem cell transplants (HSCTs) for many hematologic malignancies can be attributed to a graft-versus-leukemia (GVL) effect largely mediated by the incoming T cells within the donor graft. Thus, patients with chronic graft-versus-host disease (GVHD) were well recognized as having a lower probability of relapse than individuals without this unpleasant complication. Similarly, recipients of syngeneic grafts have the lowest rate of GVHD and the highest risk of relapse. In 1990, Kolb and colleagues took advantage of this observation and deliberately infused donor lymphocytes in an attempt to eliminate recurrent disease in patients with chronic myeloid leukemia (CML). Their positive results have been confirmed in multiple studies worldwide, and remission can be induced in more than 50% of CML patients who relapse after transplantation by stopping immunosuppressive treatment or infusing donor lymphocytes. Unfortunately, donor lymphocyte infusion (DLI) is much less effective at treating other types of relapsed leukemias after transplantation, with a 29% remission rate for acute myeloid leukemia (AML) and only 5% for acute lymphoblastic leukemia (ALL). It is not clear why these differences occur, since all these leukemias present the minor histocompatibility antigens (mHags) that are likely the targets of this GVL effect, although many mHags have yet to be defined. DLI therapy may also produce severe adverse effects, since the frequency of broadly alloreactive effector cells is usually much higher than the frequency of lymphocytes targeted exclusively to the relapsed malignancy. As a consequence, patients receiving DLI often develop GVHD. This complication of DLI usually increases in frequency and severity if the donor and recipient are either unrelated or human leukocyte antigen (HLA) haploidentical. Strategies aimed at retaining the benefits of GVL while preventing GVHD have included the depletion of alloreactive T cells in the donor lymphocyte product and the incorporation of suicide genes into the infused donor T cells so that they may be killed if the GVHD activity exceeds the benefits from GVL. Manipulation of the stem cell graft to deplete only the αβ T-cell receptor (TCR)+ T lymphocytes while retaining the γδTCR+ T-cell compartment may reduce GVHD without compromising stem cell engraftment and may retain some protection against opportunistic infections. Ultimately, investigators may wish to identify tumor-restricted target antigens on the malignant cells and infuse antigen-specific T cells directed to them. As discussed in Chapter 25 the potential efficacy of this approach has been demonstrated in preliminary studies, although scalability remains a challenge. Furthermore, genetic evolution and neoantigen depletion on tumor cells has been demonstrated as a mechanism of resistance to the GVL effect following allogeneic hematopoietic stem cell transplantation and could similarly limit the efficacy of infusing autologous T cells that target tumor-restricted antigens.
Infusion of Activated T Lymphocytes
When T cells are polyclonally stimulated, for example by simultaneously cross-linking their CD3 and CD28 receptors by CD3/CD28 monoclonal antibodies on beads, they proliferate, secrete tumoricidal cytokines such as tumor necrosis factor alpha (TNFα), and can mediate MHC-unrestricted cytotoxicity toward a range of tumor target cells. Efforts have been made to harness these effects by producing large numbers of CD3/CD28-activated T cells for cancer patients and infusing them. Although infusion of CD3/CD28-ATL after autologous stem cell transplant may improve patients’ T-cell reconstitution, there is not yet evidence to suggest improved antitumor activity. ATL that are additionally primed with interferon gamma (IFN-γ) and interleukin (IL)-2 (so called cytokine-induced killer [CIK] cells) may have superior clinical potential for hematologic malignancies and early phase clinical trials have shown clinical benefits.
