A comprehensive description of the myriad ways in which the manipulation of T cells has led to important clinical advances is beyond the scope of this chapter. Thus, only a subset of the ways in which an enhanced understanding of the molecular basis for T-cell-mediated immunity has resulted in changes in clinical practice is described here. Many human diseases are related to T-cell dysfunction, both in cases of overexuberant immune responses, as in autoimmune diseases and rejection of transplanted organs, and in insufficient immune responses, as in the case of some chronic infections and in uncontrolled malignancy. Here, we briefly address T-cell responses in graft rejection and in malignancy as paradigms for how T-cell immunity can be modulated therapeutically.

Modulating T Cells to Permit Allograft Transplantation

The success of solid organ transplant depends greatly on the ability to control the immune response of the recipient against the donor organ. Donor tissues express foreign MHC alleles and other proteins to which endogenous T cells have not been exposed (and therefore tolerized against) during thymic development, and thus these tissues serve as potential targets for T-cell-mediated destruction. Initially, the only medications capable of permitting graft survival were high-dose steroids, medications with potent effects in essentially all organ systems and with severe side effects not limited to the immune system. Subsequently, however, several classes of medications were identified that act more specifically on T cells, first cyclosporine and then tacrolimus and sirolimus. These agents target the IL-2 axis: cyclosporine and tacrolimus inhibit IL-2 transcription, and sirolimus inhibits mammalian target of rapamycin (mTOR), which is critical for facilitating IL-2 signal transduction. Because T cells, depending on the treatment modality, are unable to either produce IL-2 or respond to IL-2, they fail to proliferate, despite conditions favorable for stimulation, leading to impaired T-cell-mediated immunity and improved survival of transplanted organs.

Cyclosporine and rapamycin were originally identified in screens of compounds that interfered with immune cell function, and their mechanism of action was discerned only after much of the basic biology of T-cell activation was understood. Other agents currently in use in the clinic were designed precisely because of insights that emerged from studies probing the molecular basis of immune cell function. For example, antibodies directed against CD3 are potent T-cell inhibitors and are now used in the setting of acute solid organ transplant rejection. Similarly, blocking the IL-2 receptor with monoclonal anti bodies prevents IL-2 receptor signaling and thus abrogates division of stimulated T cells, thereby quelling T cell–mediated immune destruction.

Given the importance of co-stimulation for T-cell activation and the success in interfering with CD28 signaling in various autoimmune disorders, recent studies have demonstrated efficacy in trans plantation with blockade of the CD28/CD80-CD86 interaction using soluble CTLA-4 as a competitive inhibitor of the interaction between CD28 and CD80/CD86. A soluble CTLA-4 fusion protein has been approved for use in the setting of transplant rejection. Additional studies are in progress to examine ways in which modulation of other costimulatory receptors, alone or in combination with soluble CTLA-4, may be used to preserve allografts. As our understanding of how different T-cell subsets are induced is becoming more precise, new therapeutics are on the horizon that are being designed to redirect immune responses by changing the balance of the various effector subsets that emerge as the recipient responses to the transplanted organ. Additional agents directed against receptors and signaling molecules discovered to be key for T-cell activation are currently being tested for clinical efficacy and safety and likely will soon be available to block T-cell responses in the setting of solid organ transplant.

Manipulating T Cells to Improve Activity Against Malignancy

In contrast to the need to impede immune responses following organ transplant, in the setting of malignancy, the goal is to enhance T-cell activity. T cells face several hurdles in their response to spontaneous malignancy. First, they must recognize peptides and proteins that are unique to tumor tissue. These include oncogenic mutant proteins, fusion proteins that may have formed during the course of tumor development or aberrantly expressed embryonic proteins that result from altered transcription often found in malignant tissue. Apart from generation of aberrant peptides, these pep tides also require efficient presentation by MHC on the cell surface to permit recognition by T cells. Second, T cells must overcome the limited co-stimulation provided by tumor cells. Because tumor cells originate from normal host tissue, they fail to generate the bacterial or viral products crucial for activating APCs, although pathogen-independent inflammation plays a significant role in the immunogenicity of some cancers, such as melanoma and cancer of the bladder. Third, T cells must overcome the generally immunosuppressive microenvironment within tumor tissue, which may include an abundance of TGF-β, Tregs, immunosuppressive macrophages, and/or the induction of an anergy-like state.

The first successful approach to enhance T-cell-mediated responses to tumors also makes use of the biology of CTLA-4 (Fig.1). In this case, however, instead of using soluble CTLA-4 as an agent to inhibit T-cell responses by interfering with co-stimulation, antibodies against CTLA-4 are used to block the ability of CTLA-4 expressed on activated T cells to inhibit T-cell function. Phase III studies have shown that CTLA-4 blocking antibodies may prolong T-cell activation in response to malignancy, and their use has resulted in long-term disease remission in approximately 15% of patients with metastatic melanoma, a previously uniformly fatal dis ease. Some antibodies against CTLA-4 may also function by depleting Tregs from immune organs and the tumor microenvironment. Whether CTLA-4 antibodies mediate their effect by inducing the expansion of newly activated tumor-specific cells or by eliminating Tregs from the immunosuppressive microenvironment continues to be studied; however, one major concern of using antibodies against CTLA-4 has been the generation of severe autoimmune colitis in a significant fraction of patients, and poor tolerance in older patients, which constitutes a significant fraction of cancer patients.

Fig1. IMMUNE CHECKPOINT BLOCKADE. Cancer patients often mount ineffective T-cell responses to their tumors, thus recent advances in immunotherapies manipulate T-cell activity to promote antitumor immune responses. Upregulation of inhibitory receptors such as cytotoxic T lymphocyte anti gen-4 (CTLA-4) and programmed death 1 (PD-1) on the tumor-specific T cells, and expression of the ligand PD-L1 on the tumor cells, blunts tumor-specific T-cell responses. Blocking anti-CTLA4 antibodies (top) or anti-PD-1 or anti-PD-L1 antibodies (bottom) are highly effective in treating several types of advanced tumors, by releasing the inhibition of tumor-specific T cells by these molecules. Anti-CTLA-4 may work by blocking CTLA-4 on effector T cells (shown) or on Tregs. (From Abbas AK, Lichtman AH, Pillai S, Baker DL, Baker A. Cellular and Molecular Immunology. 9th ed. Philadelphia: Elsevier; 2017.)

The initial success achieved by blocking CTLA-4 on the surface of T cells led to the search for other molecules that might similarly be targeted with blocking antibodies. One such candidate molecule identified was PD-1, the inhibitory receptor present on activated and exhausted T cells. Because many, if not all, patients with cancer have circulating T cells capable of binding tumor antigen, albeit with limited responsiveness, it was speculated that relieving exhaustion of tumor-specific T cells with antibodies that block PD-1 would permit improved T-cell responses against malignancy. In fact, therapies targeting PD-1 and its ligand have demonstrated profound activity in patients with malignancy, with overall survival rates as high as 35% in patients with advanced melanoma, and activity in many other cancers, such as highly mutated colorectal cancer, classical Hodgkin lymphoma, lung and bladder cancers.14 Surprisingly, in studies described to date, autoimmune disease occurs much less frequently in patients treated with antibodies targeting PD-1 versus those targeting CTLA-4. The biologic basis of this finding is unclear, but it suggests that PD-1 represents a superior target to boost T cell mediated activity against tumors. Emerging research has identified factors that correlate with higher response rates to anti-PD-1 therapies. These include high levels of expression of PD-L1 on tumor cells (as in Hodgkin lymphoma), high mutational burden (as in highly mutated colorectal cancer), and the presence of significant immune infiltrate (as in bladder cancer). Further research using next-generation sequencing of immune cell infiltrates should identify additional biocorrelates that can better refine choices of immunotherapies. Apart from CTLA-4 and PD-1, other potential targets include exhaustion receptors LAG-3 and Tim3, and certain isoforms of the epacadostat receptor on T cells. Ideal efficacy will likely result by combining immunotherapies. For instance, simultaneous targeting of CTLA-4 and PD-1 results in an approximate 70% response rate and 50% five-year survival in melanoma, and 42% response rate in renal cell carcinoma. The combination therapy is approved as first line therapy in both diseases.

In addition to targeting inhibitory receptors on T cells to augment antitumor responses, another major approach for using T cells as anti-cancer therapy has been through engineering T cells to directly target tumor antigens. Knowledge gained through fundamental studies of proximal signaling events important for T-cell activation has led investigators to engineer chimeric antigen receptors (CARs), which permit direct activation of T cells by tumor cells.15 These “designer” molecules have a modular structure: an extracellular binding domain for antigens on tumor cells, transmembrane domains from CD8a or other cell surface proteins, cytoplasmic signaling components of the ζ chain of the TCR complex, and a costimulatory domain(s) containing other key activating co-receptors (Fig. 2). T cells are removed from patients, genetically engineered to express CARs, and reintroduced into patients with the anticipation that these T cells will engage the tumor through the CAR, resulting in T-cell activation. These activated T cells, when effective, generate robust antitumor responses, bolstering antitumor immunity sufficiently to eliminate the cancer.

Fig2. CHIMERIC ANTIGEN RECEPTOR T CELLS. The modular design of successful chimeric antigen receptors (CARs) uses the knowledge gained through the study of fundamental properties of antigen recognition and signaling pathways in immune cells. The extracellular antigen recognition domain is typically derived from a single-chain variable fragment of an antibody specific for a surface antigen expressed by the tumor cells. This domain is coupled to a transmembrane domain, which has been derived from either CD8 or CD28 molecules. The CAR transmits an activation signal through the costimulatory domains and the CD3ζ chain to intracellular T-cell signaling pathways. The costimulatory domain contains one (or more) signaling domains derived from costimulatory molecules, including CD28, CD27, 4-1BB, and inducible costimulator (ICOS). This costimulatory domain significantly augments signaling from the CD3ζ chain and has been shown to improve CAR-T-cell function, proliferation, and persistence.

One of the most well-studied tumor antigens selected for CAR T-cell therapy is CD19, a cell surface costimulatory receptor found exclusively on B cells. In patients with refractory B-cell leukemias and lymphomas, treatment with CD19-directed CAR-T cells have demonstrated striking success, with a significant proportion of patients achieving complete and durable remission. As predicted from selection of CD19 as the cellular target, these patients also develop B-cell aplasia and hypogammaglobulinemia resulting from the elimination of healthy B cells by CAR-T cells; however, this long-term side effect can be effectively managed by antibody infusions or coupling CAR-T-cell therapy with subsequent bone marrow transplantation. Identification of appropriate target antigens for CAR-T cells is a key challenge because many tumor antigens may also be expressed on normal tis sues and “on-target, off-tumor” effects of CAR-T cells could potentially lead to unacceptable toxicity. These concerns will require careful evaluation of each CAR targeting domain for both efficacy against the tumor and potential deleterious effects on normal tissues. Currently, trials are underway testing multiple targets in hematologic malignancies and solid tumors. Additionally, it has been observed that certain CD19+ tumors can develop resistance to CAR-T cells by downregulation of CD19. Thus, newer CAR-T cell therapies in B cells engineer T cells to recognize two or more B-cell antigens.

Apart from identifying the best targets for CARs, much effort has also been placed on optimal construction of the CAR signaling domains. First-generation CARs, which contain only the ζ chain of the TCR complex, led to suboptimal antitumor responses. The incorporation of an additional intracellular signaling domain derived from costimulatory molecules, such as CD28 or 4-1BB, into second generation CARs augmented CAR-T-cell activation and antitumor efficacy, and third-generation CARs include signaling domains from two costimulatory receptors. Currently, most CARs adhere to the second-generation model. Which intracellular costimulatory domains will work best in CARs and how many costimulatory domains are required for optimal T-cell activation and antitumor efficacy are under active investigation. Other outstanding questions in the bio chemistry of CARs concern the optimal number of functional ITAMs present in ζ chain domains and the length and composition of the transmembrane hinge domain and interdomain junctions. Defining the biochemistry and signal transduction of CARs should permit broadening its use to more common malignancies.

A major side effect of CAR-T-cell therapies has been the development of cytokine release syndrome (CRS). Rapid lysis of target cells can result in overexuberant inflammation that results in systemic pathology including vasodilation and hypotension, multi-organ failure, and neurologic changes. Early identification of CRS and appropriate intervention with steroids and antibodies that target IL-6 and TNFα are capable of blunting many sequelae of CRS.

A third approach for directing T-cell responses against malignancies is with Bispecific T-cell Engagers (BiTEs). BiTEs are fusion proteins containing two antibody recognition domains – one that recognizes the CD3 complex on T cells, and a second that recognizes a receptor present on tumor cells. BiTE binding to T cells in the absence of tethering to a tumor surface protein is insufficient to generate T-cell activation. However, dual binding of BiTEs to a tumor antigen and T cells in close proximity result in activation of cytotoxic T-cell and tumor cell lysis, independent of the TCR specificity of the T cell. In some B-cell malignancies, BiTE therapies have demonstrated efficacy similar to CAR-T cells, and do not require T-cell engineering. Similar to CAR-T-cell therapies, CRS remains a significant hurdle.

The examples presented here are only a small subset of novel approaches in use or being tested to modulate immune cell function based upon our understanding of the molecular basis of T-cell activation. It is anticipated that as more is learned about the molecules and pathways critical for control of T-cell-mediated immunity, additional new agents with greater efficacy and improved safety profiles will become available for clinical use. The advent of these new therapeutics and their potential to improve treatments for serious human dis eases underscore the importance of continued efforts to understand the mechanisms of T-cell development and function.

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مواضيع ذات صلة

T-Cell Exhaustion: Impaired Response after Chronic Antigen Exposure

T-Cell Memory

Regulatory T Cells

T-Cell Function

The T-Cell Receptor Complex

Antigen Presentation: Creating the Ligand for the T-Cell Receptor

Therapeutic Passive Immunization and Monoclonal Antibody Therapy

Adverse Events Related to Intravenous Immunoglobulin Infusion

Therapeutic use of Immunoglobulin : Intravenous Immunoglobulin

Immunoglobulins

Complement and Cancer

Complement and T-Cell Immunity