Recently, it has become clear that cancer and our immune system communicate with each other. Because of this, our immune system eventually allows cancer cells to go unchecked, and at a certain point, cancer cells ‘escape’ our immune system's response. With this understanding, more recent anti-cancer medications are targeting the different immune checkpoints that are known to fail in identification of cancer cells.
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immunology laboratory at the central cancer research labs

Image: “Immunology laboratory at the Central Cancer Research Labs.” by Unknown photographer – This image was released by the National Cancer Institute, an agency part of the National Institutes of Health, with the ID 1866. License: Public Domain


Introduction

Our immune system can identify cancer cells and is, in fact, capable of getting rid of them until cancer cells develop some strategies to avoid this natural protective mechanism. These strategies include immunoediting and immune checkpoint pathways.

Cancer cells can be classified into two types: those that express antigens that can be recognized by T-cells, and those that do not. Our immune system can only identify the first type of cancer cells and by selectively eliminating them, it allows room for cancer cells, which do not express any identifiable surface antigens to T-cells, to grow and proliferate. This process is known as immunoediting.

On the other hand, some cancers can produce certain molecules that suppress the immune response, and they grow in an environment that is suppressive to T-cells. This process is known as immune checkpoint pathways.

Cancer cells, at first, are identified by T-cells and are promptly eliminated. In the equilibrium phase, sporadic tumor cells that do not express any identifiable antigens to our T-cells survive. Finally, these sporadic cancer cells grow and proliferate in the escape phase, and our immune system fails to identify them and protect us against them.

Possible Important Targets in the Immune Checkpoint Pathway

Several targets have been identified that are thought to be responsible for blocking the action of CD8+ cytotoxic T-cells against cancer cells. It is thought that cancer cells release possible mediators that can act on receptors such as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programed cell-death 1 (PD1).

Targeting these receptors or engineered T-cells that do not express them make it possible for immune cells to escape the checkpoints imposed by the cancer microenvironment and to fight cancer cells. Engineered T-cells have been recently used in acute lymphoblastic leukemia.

Anticancer Therapies and the Immune Checkpoint Pathway

Our current understanding of the CTLA-4 pathway allows to understand why tumor cells might escape our immune system. The CTLA-4 pathway is also involved in regulating our immune response against autoimmunity and infections. Cancer cells hijack the CTLA-4 pathway and make our immune cells—especially cytotoxic T-cells—fail to recognize them as foreign cells. Thus, the tumor cells can grow unchecked and eventually escape our immune response.

10 years ago, the first trials with anti-CTLA-4 antibodies were started. Patients with melanoma were prescribed anti-CTLA-4 medications, and the results were very encouraging. Tumors’ invasiveness, metastasis and overall survival improved after the introduction of anti-CTLA-4 treatment.

Because of these encouraging results, researchers started experimenting with ipilimumab, an anti-CTLA-4 antibody, in other cancers with similar results. Eventually, the FDA approved ipilimumab for melanoma.

Anti-PD-1 antibodies such as pembrolizumab and nivolumab have been undergoing extensive trials in diverse cancers including non-small-cell lung carcinoma, renal cell carcinoma, bladder cancer, lymphoma and melanoma. In 2011, the FDA approved pembrolizumab for melanoma, and in 2015 they approved nivolumab for non-small-cell lung carcinoma.

In 2014, it was found that the PD-1 and the CTLA-4 pathways inhibit cytotoxic T-cells in two different and non-overlapping pathways. Thus, it was suggested to combine anti-PD-1 and anti-CTLA-4 treatments looking for possible synergetic effects. Currently, a phase I clinical trial is testing the efficacy of anti-PD-1 plus anti-CTLA-4 combined therapy versus monotherapy in advanced melanoma, and the preliminary results confirm the presence of a synergetic effect.

Who Will Respond to Immunotherapy Targeting the Immune Checkpoint Pathway?

Unfortunately, a significant number of cancer patients do not respond to anti-CTLA-4 or anti-PD-1 therapy. It was suggested that good responders usually have high expression of the PD-1 legend, which is responsible for inhibiting the cytotoxic T-cells via the PD-1 pathway. Therefore, patients with low PD-1 legend levels are not good candidates for anti-PD-1 therapy.

Additionally, patients with little or no tumor-infiltrating lymphocytes are not expected to show good response to immunotherapy. Patients with clearly mutated cancers, such as non-small cell lung carcinoma and melanoma, are more likely to respond to immunotherapy, compared to patients with well-differentiated tumors.

Additionally, patients might not respond to immunotherapy because their T-cells are exhausted. T-cells that express PD-1 receptors can secrete lymphocyte-activation gene 3 (LAG-3), which is known to decrease the activity of cytotoxic T-cells by exhaustion. Anti-LAG-3 therapies are being currently tested in a clinical trial, but the results are yet to be published. Preclinical results with anti-LAG-3 in cellular and animal models of cancer showed promising results.

Adoptive Cell Transfer as Immunotherapy in Cancer

Patients with tumors that are highly infiltrated by lymphocytes might benefit from adoptive cell transfer techniques. Tumor infiltrating lymphocytes (TIL) are known to be able to destroy the tumor if they are promptly activated and are in enough numbers.

Adoptive cell transfer helps with the second problem by isolating and expanding TILs, and then reinfusing the expanded autologous lymphocytes back to the blood. Immunotherapy by anti-PD-1 and anti-CTLA-4 is responsible for promptly reactivating TILs.

Patients with specific forms of immune cancers, such as B-cell malignancies, including multiple myeloma, are possible candidates for engineered T-cell therapy. Engineered T-cells can express tumor specific antigen receptors or CAR receptors. They have been used in melanoma, with little success.

Patients with acute lymphoblastic leukemia, chronic lymphocytic leukemia, neuroblastoma and glioblastoma have shown excellent response to CAR+ engineered T-cells with remission rates of up to 90% in acute lymphoblastic leukemia.

Cancer Vaccines

Cancer cells are known to share certain antigens which can be used to induce immunity against them. Wilms-tumor-1 antigen is shared by acute myelogenous leukemia and breast cancer. Vaccination with wilms-tumor-1 antigen might lead to tumor regression.

Another example is the anaplastic lymphoma kinase antigen, which is shared by anaplastic large cell lung and non-small-cell lung carcinoma, in addition to neuroblastoma. This antigen was also used as a vaccine in secondary prevention of these tumors with good results.

The best results of cancer vaccines can be achieved when combined with other forms of immunotherapy or chemotherapeutics. Unfortunately, primary prevention of cancer by cancer vaccines is yet to be tried in humans, despite several studies in animals.

Human papilloma virus is known to be the most common cause of cervical and vaginal carcinoma. Human papilloma virus vaccines dramatically decreased the incidence of these cancers, but such vaccines are not cancer vaccines per our definition. Cancer vaccines should use an antigen that is known to be expressed by certain tumors to illicit an immune response.

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