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Chapter 21 T-Cell Immunity 237

THERAPEUTIC MANIPULATION OF Manipulating T Cells to Improve Activity
T CELL–MEDIATED IMMUNITY Against Malignancy
A comprehensive description of the myriad ways in which the In contrast to the need to impede immune responses in organ
manipulation of T cells has led to important clinical advances is transplant, in the setting of malignancy, the desire is to intervene to
beyond the scope of this chapter. Thus only a subset of the ways enhance T-cell activity. T cells face several hurdles in their response
in which an enhanced understanding of the molecular basis for T to spontaneous malignancy. First, they must recognize peptides and
cell–mediated immunity has resulted in changes in clinical practice is proteins that are unique to tumor tissue. These include oncogenic
described here. Many human diseases are related to T-cell dysfunction, mutant proteins, fusion proteins that may have formed during the
both in cases of overexuberant immune responses, as in autoimmune course of tumor development or aberrantly expressed embryonic
diseases and rejection of transplanted organs, and in insufficient proteins that result from altered transcription often found in malig-
immune responses, as in the case of some chronic infections and in nant tissue. Second, T cells must overcome the lack of costimulation
uncontrolled malignancy. Here, we briefly address T-cell responses provided by tumor cells. Because tumor cells originate from normal
in graft rejection and in malignancy as paradigms for how T-cell host tissue, they fail to generate the bacterial or viral products crucial
immunity can be modulated therapeutically. for activating APCs. Third, T cells must overcome the generally
immunosuppressive microenvironment within tumor tissue, which
may include an abundance of TGF-β, Tregs, immunosuppressive
Modulating T Cells to Permit Allograft Transplantation macrophages, and/or the induction of an anergy-like state.
The first broadly successful approach to enhance T cell–mediated
The success of solid organ transplant depends greatly on the ability responses to tumors also makes use of the biology of CTLA-4. In this
to control the immune response of the recipient against the donor case, however, instead of using soluble CTLA-4 as an agent to inhibit
organ. Donor tissues express foreign MHC alleles and other proteins T-cell responses by interfering with costimulation, antibodies against
to which endogenous T cells have not been exposed (and therefore CTLA-4 are being used as a means to block the ability of CTLA-4
tolerized against) during thymic development, and thus these tissues expressed on activated T cells to inhibit T-cell function. Preliminary
serve as potential targets for T cell–mediated immunity. Initially, studies have shown that CTLA-4 blocking antibodies may prolong
the only medications capable of permitting graft survival were high- T-cell activation in response to malignancy, and their use has resulted
dose steroids, medications with potent effects in essentially all organ in long-term disease remission in approximately 15% of patients with
systems and with severe side effects not limited to the immune metastatic melanoma, an otherwise uniformly fatal disease. Some
system. Subsequently, however, several classes of medications were antibodies against CTLA-4 may also function by depleting Tregs
identified that act more specifically on T cells, first cyclosporine from immune organs and the tumor microenvironment. Whether
and subsequently tacrolimus and sirolimus. These agents target the CTLA-4 antibodies mediate their effect by inducing the expansion of
IL-2 axis: cyclosporine and tacrolimus inhibit IL-2 transcription, and newly activated tumor-specific cells or by reversing the immunosup-
sirolimus inhibits mammalian target of rapamycin (mTOR), which pressive microenvironment on existing cells continues to be studied;
is critical for facilitating IL-2 signal transduction. Because T cells, however, one major concern of using antibodies against CTLA-4
depending on the treatment modality, are unable to either produce has been the generation of severe autoimmune colitis in a significant
IL-2 or respond to IL-2, they fail to proliferate, despite conditions fraction of patients.
favorable for stimulation, leading to impaired T cell–mediated The initial success achieved by blocking CTLA-4 on the surface of
immunity and improved survival of transplanted organs. T cells led to the search for other molecules that might similarly be
Cyclosporine and rapamycin were originally identified in screens targeted with blocking antibodies. One obvious candidate molecule
of compounds that interfered with immune cell function, and their is PD-1, the inhibitory receptor present on activated and exhausted T
mechanism of action was discerned only after much of the basic cells. Because many, if not all, patients with cancer have circulating T
biology of T-cell activation was understood. Other agents currently cells capable of binding tumor antigen, albeit with limited responsive-
in use in the clinic were designed precisely because of insights that ness, it was speculated that relieving exhaustion of tumor-specific
emerged from studies probing the molecular basis of immune cell T cells with antibodies that block PD-1 would permit improved
function. For example, antibodies directed against CD3 are potent T-cell responses against malignancy. In fact, therapies targeting PD-1
T-cell inhibitors and are now used in the setting of acute solid and its ligand have demonstrated profound activity in patients with
organ transplant rejection. Similarly, blocking the IL-2 receptor malignancy, with overall survival rates as high as 35% in patients with
with monoclonal antibodies prevents IL-2 receptor signaling and advanced melanoma, and activity in cancers previously thought to be
thus abrogates division of stimulated T cells, thereby quelling T poor targets for immune-based therapy, such as Hodgkin lymphoma,
cell–mediated immune destruction. lung and bladder cancers. Surprisingly, in studies described to date,
Given the importance of costimulation for T-cell activation autoimmune disease occurs much less frequently in patients treated
and the success in interfering with CD28 signaling in various with antibodies targeting PD-1 versus those targeting CTLA-4. The
autoimmune disorders, recent studies have demonstrated efficacy in biologic basis of this finding is unclear, but it suggests that PD-1
transplantation with blockade of the CD28/CD80-CD86 interaction and other “immune checkpoint” receptors, such as Lag-3 and Tim-3,
using soluble CTLA-4 as a competitive inhibitor of the interaction represent superior targets to boost T cell–mediated activity against
between CD28 and CD80/CD86. A soluble CTLA-4 fusion protein tumors. In ongoing research, investigators are evaluating how best
has recently been approved in the setting of transplant rejection. to integrate PD-1 blocking strategies into existing cancer treatment
Additional studies are in progress to examine ways in which modu- regimens.
lation of other costimulatory receptors, alone or in combination In addition to targeting inhibitory receptors on T cells to
with soluble CTLA-4, may be used to preserve allografts. As our augment antitumor responses, studies are underway to engineer
understanding of how different T-cell subsets are induced is becoming T cells to more effectively activate effector T-cell responses against
more precise, new therapeutics are on the horizon that are being malignancies. Knowledge gained through fundamental studies of
designed to redirect immune responses by changing the balance of proximal signaling events important for T-cell activation has led
the various effector subsets that emerge as the recipient responses to investigators to engineer chimeric antigen receptors (CARs), which
the transplanted organ. Additional agents directed against receptors permit direct activation of T cells by tumor cells. These “designer”
and signaling molecules discovered to be key for T-cell activation molecules have a modular structure: an extracellular binding domain
are currently being tested for clinical efficacy and safety and likely for antigens on tumor cells, transmembrane domains from CD8a
will soon be available to block T-cell responses in the setting of solid or other cell surface proteins, cytoplasmic signaling components of
organ transplant. the ζ chain of the TCR complex, and a costimulatory domain(s)