Tumor immunologists have attempted to enhance antitumor immunity by removing T cells from cancer patients, activating the cells ex vivo so there are more of them and they are more potent effector cells, and transferring the cells back into the patient. Many variations of this approach, called adoptive T cell therapy, have been tried.

 • Adoptive therapy with autologous tumor- specific T cells. T cells specific for tumor antigens can be detected in the circulation and among tumor- infiltrating lymphocytes of cancer patients. T cells can be isolated from the blood or tumor biopsies of a patient, expanded by culture with growth factors, and injected back into the same patient (see Fig. 1A). Presumably, this expanded T cell population contains activated tumor-specific CTLs, which migrate into the tumor and destroy it. This approach, which has been combined with administration of T cell-stimulating cytokines such as interleukin-2 (IL-2) and traditional chemotherapy, has shown inconsistent results among different patients and tumors. One likely reason is that the frequency of tumor-specific T cells is too low to be effective in these lymphocyte populations.

Fig1. Tumor immunotherapy by adoptive transfer of antibodies and T cells. A, Passive immunotherapy with tumor specific T cells or monoclonal antibodies. B, Adoptive T cell therapy with CAR-T cells: T cells isolated from the blood of a patient are expanded by culture with anti-CD3 and anti-CD28, genetically modified to express recombinant chimeric antigen receptors (CARs) , and transferred back into the patient.

 • Chimeric antigen receptor (CAR) expressing T cells. In a more recent modification of adoptive T cell therapy, blood T cells from cancer patients are transduced with viral vectors that express a chimeric antigen receptor (CAR), which recognizes a tumor antigen and provides potent signals to activate the T cells (see Fig. 1B). The CARs currently in use have a single chain antibody-like extracellular portion with both heavy- and light-chain variable domains, which together form the binding site for a tumor antigen (Fig. 2). The specificity of the endogenous T cell receptors (TCRs) of the transduced T cells is irrelevant to the effectiveness of this approach. The use of this antibody-based antigen recognition structure avoids the limitations of MHC restriction of TCRs and permits the use of the same CAR in many different patients, regardless of the human leukocyte anti gen (HLA) alleles they express. Furthermore, tumors cannot evade CAR-T cells by downregulating MHC expression. In order to work in T cells, the CARs have intracellular signaling domains of both TCR complex proteins, for example the ITAMs of the TCR complex ζ protein, and the signaling domains of costimulatory receptors such as CD28 and CD137. Therefore, upon antigen binding, these receptors provide both antigen recognition (via the extracellular immunoglobulin [Ig] domain) and activating signals (via the introduced cytoplasmic domains). CAR-expressing T cells are expanded ex vivo and transferred back into the patient, where they recognize the antigen on the tumor cells and become activated to kill the cells. CAR-T cell therapy targeting the B cell protein CD19, and more recently CD20, has shown remarkable efficacy in treating and even curing B cell-derived leukemias and lymphomas that are refractory to other therapies. CARs with other specificities for different tumors are in development and clinical trials. The most serious toxicity associated with CAR-T cell therapy is a cytokine release syndrome, mediated by massive amounts of inflammatory cytokines, including IL-6, interferon-γ, and others, that are released because all of the injected T cells recognize and are activated by the patients’ tumor cells. These cytokines cause high fever, hypotension, tissue edema, neurologic derangements, and multi-organ failure. The severity of the syndrome can be mitigated by treatment with anticytokine antibodies. CAR-T cell therapy may also be complicated by on-target, off-tumor toxicities, if the CAR-T cells are specific for an antigen present on normal cells as well as tumors. In the case of CD19- or CD20-specific CARs, the therapy results in depletion of normal B cells, requiring antibody replacement therapy to pre vent immunodeficiency. Such replacement may not be feasible for other tissues that are destroyed because of the reactivity of the CAR. Although CAR-T cell therapy is effective against leukemias and tumors in the blood (to which the injected T cells have ready access), it has so far not been successful in solid tumors because of difficulties in getting T cells into the tumor sites and the challenge of selecting optimal tumor antigens to target without injuring normal tissues.

Fig2. Chimeric antigen receptor. The receptor that is expressed in T cells consists of an extracellular Ig part that recognizes a surface antigen on tumor cells and intracellular signaling domains from the TCR complex and costimulatory receptors that provide the signals that activate the killing function of the T cells.

مواضيع ذات صلة

Immune Mechanisms of Graft Rejection

Induction of Immune Responses Against Transplants

Transplantation Antigens

Glycans and Immunity

Immune Responses Against Transplants

Cancer Immunotherapy : Stimulation of Host Antitumor Immune Responses by Vaccination With Tumor Antigens

Cancer Immunotherapy: Immune Checkpoint Blockade

Cancer Immunotherapy: Passive Immunotherapy With Monoclonal Antibodies

Evasion of Immune Responses by Tumors

PROCESS OF PHAGOCYTOSIS

GRANULOCYTIC CELLS

B Cell Epitope Binding Predictions