Blocking inhibitory receptors on T cells or their ligands stimulates antitumor immune responses. The realization that tumors evade immune attack by engaging regulatory mechanisms that suppress immune responses has led to a novel and remarkably effective new strategy for tumor immunotherapy. The principle of this strategy is to boost host immune responses against tumors by blocking normal inhibitory signals for T cells, thus removing the brakes (checkpoints) on the immune response (Fig. 1). This has been accomplished with blocking monoclonal antibodies specific for the T cell inhibitory molecules CTLA-4 and PD-1, first approved for treating metastatic melanoma in 2011 and 2014, respectively. Since then, the use of anti-PD-1 or anti-PD-L1 antibodies has expanded to many different cancer types. The most remarkable feature of these therapies is that they have dramatically improved the chances of survival of patients with advanced, widely metastatic tumors, which previously were almost 100% lethal within months to a few years.

Fig1. Tumor immunotherapy by immune checkpoint blockade. Tumor patients often mount ineffective T cell responses to their tumors because of the upregulation of inhibitory receptors such as CTLA-4 and PD-1 on the tumor-specific T cells, and expression of the ligand PD-L1 on the tumor cells. Blocking anti-CTLA-4 antibodies (A) or anti-PD-1 or anti-PD-L1 antibodies (B) 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 responding T cells (shown) or on Treg. CTL, Cytotoxic T lymphocyte; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; TCR, T cell receptors.

The efficacy of antibodies specific for other T cell inhibitory molecules, such as LAG-3 and TIM-3, are being tested in clinical trials. There are several novel features of immune checkpoint blockade and limitations that still need to be overcome to enhance their usefulness. • Although the efficacy of checkpoint blockade therapies for many advanced tumors is superior to any previous form of therapy, only a subset of patients (25% to 40% at most) respond to this treatment. The reasons for this poor response are not well understood. Nonresponding tumors may induce T cell expression of checkpoint molecules other than the ones being targeted therapeutically, or they may rely on evasion mechanisms other than engaging these inhibitory receptors. Oncologists and immunologists are currently investigating which biomarkers will predict responsiveness to different checkpoint blockade approaches.

 • One of the most reliable indictors that a tumor will respond to checkpoint blockade therapy is if it carries a high number of mutations, which correlates with high numbers of neoantigens and host T cells that can respond to those antigens. In fact, tumors that have deficiencies in mismatch repair enzymes, which normally correct errors in DNA replication that lead to point mutations, have the highest mutation burdens of all cancers, and these cancers are the most likely to respond to checkpoint blockade therapy. Remarkably, anti-PD-1 therapy is now approved for any recurrent or metastatic tumor with mismatch repair deficiencies, regardless of the cell of origin or histologic type of tumor. This is a paradigm shift in how cancer treatments are chosen.

• The combined use of different checkpoint inhibitors, or one inhibitor with other modes of therapy, will likely be necessary to achieve higher rates of therapeutic success. The first approved example of this is the combined use of anti-CTLA-4 and anti-PD-1 to treat melanomas, which was shown to be more effective than anti-CTL-4 alone. This reflects the fact that the mechanisms by which CTLA-4 and PD-1 inhibit T cell activation are different (see Fig. 1). There are numerous ongoing or planned clinical trials using combinations of checkpoint blockade together with other strategies, such as small molecule kinase inhibitors, oncolytic viral infection of tumors, and other immune stimulants.

 • The most common toxicities associated with check point blockade are autoimmune damage to organs. This is predictable, because the physiologic function of the inhibitory receptors targeted is to maintain tolerance to self-antigens . A wide range of organs may be affected, including colon, lungs, endocrine organs, heart, and skin, each requiring different clinical interventions, sometimes including cessation of the life-saving tumor immunotherapy. 

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: Adoptive T Cell Therapy

Cancer Immunotherapy: Passive Immunotherapy With Monoclonal Antibodies

Evasion of Immune Responses by Tumors

PROCESS OF PHAGOCYTOSIS

GRANULOCYTIC CELLS

B Cell Epitope Binding Predictions