How Does Cancer Immunotherapy Work?

The immune system can recognize and kill cancer cells that incidentally appear in the body. However, cancer cells may have various mechanisms to escape immune surveillance. By overcoming these escape ways or enhancing the immune response, immunotherapy helps the immune system attack cancer cells.

Immunotherapy is an important therapy that has been introduced to cancer treatment. This type of treatment helps lessen the growth of cancer cells and prevent the spread of cancer further, which results in increased survival and, in some cases, durable cancer-free periods.

If you have never heard about immunotherapy, continue reading this article to discover more information about immunotherapy's prediction response and risks.

The types of immunotherapy

1. Monoclonal antibodies

Unlike natural antibodies, therapeutic antibodies target one specific molecule on the cancer cell and are all identical; therefore, they are called monoclonal.

Binding to monoclonal antibodies may cause cancer cell death by blockade of signaling processes responsible for cancer growth and survival (e.g., trastuzumab, an antibody against HER2 protein, used to treat breast and stomach cancers), or by facilitating cancer cells destruction by the immune system (e.g., rituximab, an antibody against CD20 molecule, used to treat lymphomas).

Monoclonal antibodies may also deliver another toxic molecule inside the cancer cell (e.g., brentuximab vedotin, a combination of an antibody against CD30 protein and cytotoxic drug used to treat Hodgkin’s lymphoma).

Monoclonal antibodies of the T Cell Engager (BiTE) type target, both antigens on cancer cells and the activating receptors on immune cells. The CD19-CD3 BiTE blinatumomab conferred a significant clinical benefit to patients with acute lymphoblastic leukemia.

2. Immune checkpoint inhibitors

Some cancer cells can synthesize immune checkpoints, the proteins that give surveilling immune cells signals not to exert an immune response. Monoclonal antibodies blocking these molecules (immune checkpoint inhibitors) have shown increased survival in patients with various cancers, especially melanoma and lung cancer.

Immune checkpoint inhibition is achievable by blocking the cytotoxic T lymphocyte antigen-4 (CTLA-4) or the programmed death-1 (PD-1) protein or its ligand (PD-L1), either alone or in combination.

CTLA-4 blockade promotes the formation of antigen-specific T cells, whereas PD-1/PD-L1 blockade stops the programmed death of antigen-specific T cells.

The discovery of checkpoint inhibition is one of the most significant advances in the history of cancer treatment. The Nobel Prize in Physiology or Medicine 2018 was awarded jointly to James P. Allison and Tasuku Honjo for their research in this field.

Furthermore, an unprecedented 100% response rate was demonstrated, in a small study on a PD-1 inhibitor dostarlimab, in patients with rectal cancer.

3. Adoptive immune cell therapy

In adoptive immune cell therapy, the patient's own immune cells are extracted from the body and modified to increase their ability to kill cancer cells.

Immune cells, such as dendritic cells, natural killer cells, or lymphocytes, may be activated by co-culturing them with stimulatory substances or cells (nonspecific immune cell therapy). Yet the efficacy of such treatment is limited.

In contrast, specific adoptive immune cell therapy such as Chimeric Antigen Receptor T-Cell (CAR-T) immunotherapy (tisagenlecleucel, axicabtagene ciloleucel, etc.) specifically designed to fight cancer, is highly effective, especially in blood cancers.

Immune T cells are extracted from the patient, engineered genetically in the laboratory to produce Chimeric Antigen Receptors (CARs) on their surface, expanded in numbers, and infused back.

The CARs then bind to specific sites at the cancer cell and induce its death by direct killing, involvement of other immune cells, and releasing immune system activating substances. One of the first children to receive CAR-T cell therapy is alive and well, 10 years following her treatment for relapsed blood cancer.

Other specific adoptive immune cell therapies, such as T Cell Receptor (TCR), and Tumor-Infiltrating Lymphocyte (TIL) therapies, have shown promising results during clinical studies and are expected to be approved in the near future.

4. Cancer vaccines and oncolytic viruses

Unlike preventive vaccines used in healthy individuals, therapeutic cancer vaccines are for patients who already have cancer.

One of two approved cancer vaccines, the BCG vaccine, was designed more than a hundred years ago as a vaccine against tuberculosis. More than 40 years ago first used in patients with bladder cancer by infusing it directly into the bladder. It has since become a standard treatment for specific cancer types. The effect of the BCG vaccine mediates by local immune stimulation.

Sipuleucel-T is a dendritic cell-based vaccine used to treat a specific type of prostate cancer. This vaccine is prepared by incubating a patient’s dendritic cells with a fusion protein consisting of a stimulatory molecule and prostate acid phosphatase, a substance produced in high quantities in prostate cancer cells.

Dendritic cells digest and provide prostate acid phosphatase antigen on their surface. Reinfused into the patient dendritic cells promote specific T cell responses to this substance on prostate cancer cells resulting in their destruction.

Like cancer vaccines, oncolytic virus immunotherapy helps to expose cancer antigens, making them recognizable by immune cells. A drug called talimogene laherparepvec, used for specific melanoma type melanoma treatment, employs herpes simplex virus type 1, genetically modified to minimize harm to healthy cells and enhance the capability to induce the immune response.

The virus invades a cancer cell and causes its burst exposing numerous cancer proteins that activate the immune system.

Prediction of immunotherapy response

Not every patient may benefit from immunotherapy. The factors predicting the successful treatment are not unequivocally defined, yet may include the genetic features of cancer, the features of the patient‘s immune system and gut microbiome, and environmental factors such as diet, bacterial infection, or drug use.

Elderly patients may respond poorly to immunotherapy due to the senescence of the immune system.

Resistance to immunotherapy

Immunotherapy may stop working due to different reasons. For instance, cancer cells may start “self-neutralizing” PD-1 and PD-L-1 checkpoints, so they are no longer available for binding with checkpoint inhibitors.

Also, cancer cells may release small vesicles containing PD-L-1 to detract checkpoint inhibitors. Antigen mutation, alteration in signaling pathways, and immune suppression – can all result in the decreased effect of immunotherapy.

In rare cases, so-called hyper-progressive disease, a paradoxical growth of cancer, may develop. This phenomenon is likely related to the expansion of immunosuppressive cells.

Risks of immunotherapy

Since immunotherapy interferes with the functioning of the immune system, it is not without risks. Infused into the patient, the modified immune cells (e.g., CAR-T cells) flood the bloodstream with active substances called cytokines. The cytokines cause a cytokine storm, a dangerous condition manifesting as high fever, drop in blood pressure, rash, diarrhea, trouble breathing, and potential organ failure.

CAR-T cells may also cause neurologic effects, including confusion, seizures, tremors, and impaired speech.

Checkpoint inhibitors may induce immune-mediated rash, gastrointestinal and endocrine system disturbances, heart and lung tissue inflammation, and autoimmune disorders. These effects may be severe but are predictable and manageable by administering steroids.

Immunotherapy: A beneficial treatment option

Overall, immunotherapy is a beneficial treatment option for patients with specific types of cancer. It can provide a positive response in slowing down cancer growth and spread or even eliminating cancer.

Immunotherapy comes with risks and is not appropriate for all patients. It is critical to consult with an oncologist before moving forward with immunotherapy.