A relatively new approach for cancer treatment is biological therapy. This cancer treatment is also known as biotherapy, immunotherapy, or biological response modifier therapy.

Biological therapy began with the discovery of immunization more than 200 years ago. Edward Jenner discovered the benefits of injecting humans with fluid taken from sores on cattle infected with cowpox, a disease also known as vaccinia. This fluid contains the organisms that produce the disease. His inoculation worked because the cells of the immune system developed antibodies against the cowpox organism.

About a century later, William Coley, a New York surgeon, started using biological therapy to treat cancer patients. He noticed that people with some kinds of cancer appeared to enter remission after developing certain bacterial infections. He concluded that the body's response to the infection must be exerting some effect on the cancer. He injected cancer patients with live bacteria, then later with filtered toxins. This induced an infectious response that sometimes led to a remission of their cancer. This method of treatment became known as Coley's toxins and was used for decades.

In the mid-1980s, encouraging results were seen in the use of interferon to treat a rare blood disorder called hairy-cell leukemia. The FDA has approved interferon for this disease, as well as chronic myelogenous leukemia, AIDS-related Kaposi's sarcoma, and genital warts.

More recently, Steven Rosenberg, a researcher at the U.S. National Cancer Institute, proved that the human immune system could be directed to discriminate between healthy cells and cancerous ones. Handled properly, immunotherapy could indeed stimulate the body's defenses. In 1992 genetically engineered IL-2 received the FDA's approval for treating advanced kidney cancer. In 1994 clinical trials were started to determine whether another interleukin, interleukin ("IL-12"), might have some benefit against metastatic cancer and AIDS. Since that time research has identified many uses for interleukin and the FDA has approved many treatments for various cancers including Nivolumab (Opdivo) for melanoma 2014, non-small cell lung cancer (NSCLC), metastatic renal cell carcinoma 2015, and metastatic urothelial bladder cancer 2017.

To understand biological therapy, it helps to know some basics about the immune system, a complex network of organs and cells.

There are two basic types of defense protecting the body from foreign invaders such as bacteria, viruses, or cancer cells. The first line of defense is a physical barrier involving the skin, mucous membranes, the lining of the respiratory tract. This line of defense produces a nonspecific response because it works regardless of the invader.

The second line of defense, unlike the physical barrier, recognizes these invaders and then develops the specific weapons to fight them. It is even able to remember what the invader looked like so that the next time its response will be even swifter. This line of defense that produces a specific response is made by immune system cells. The immune system cells circulate throughout the body and defend the body against attacks by foreign invaders.

This immune network is one of the body's main defenses against disease. It works against diseases, including cancer, in a variety of ways. For example, the immune system may recognize the difference between healthy cells and cancer cells in the body and work to eliminate those that become cancerous.

Immune system cells include lymphocytes (white blood cells) and other immune cells. Lymphocytes are the most important cells of the immune system and can be categorized into

• T-cells
• B-cells
• NK (Natural Killer) cells

T-cells directly attack infected, foreign, or cancerous cells. T-cells also regulate the immune response by signaling other immune system defenders.

• B-cells secrete antibodies, the proteins that recognize and attach the foreign substances known as antigens
• Natural Killer cells produce powerful chemical substances that bind to and kill any foreign invader. They attack without first having to recognize a specific antigen
• Monocytes are white blood cells that circulate in the bloodstream. When they settle in tissue, the macrophages engulf the invaders and actually digest them

Understanding how immune system cells exchange messages and finding ways to make these messages clearer and stronger are the goals of research in immunology. Each of these components, and each step in the immune response, represents a potential avenue for the development of a cancer therapy.

Biological therapy research focuses on isolating specific cells of the immune system and their chemical products, then manipulating them in the laboratory to target their activity and control their effects.

In summary, biological therapies use the body's immune system, either directly or indirectly, to fight cancer or to reduce the side effects that may be caused by some cancer treatments.

There are two basic categories of biological therapy: immunotherapy and cytotoxic therapy. Immunotherapy uses a variety of methods and drugs to manipulate the immune system. This creates a hostile environment for the existence or growth of cancer in the body. Cytotoxic therapy involves changing the cancer cells' biology so that they become weak and die.

Immunotherapy

Immunotherapy can be either active or passive. Active immunotherapy involves setting an immune response in the cancer patient to fight cancer cells. In passive immunotherapy, immune molecules are given to patients who do not produce them on their own. Both approaches can be specific or nonspecific.

Specific Active Immunotherapy

One way the immune system can recognize differences among cells is by molecules called antigens that appears on the cell surface. In active immunotherapy, cancer cells are analyzed in the lab and their antigens are identified. Then, a treatment is designed to stimulate a specific immune response against them. This is called specific active immunotherapy.

Nonspecific Active immunotherapy

The nonspecific active approach uses agents that set in motion a general immune response, activating a wide range of immune cells. The approach aims at strengthening the overall activity of the immune system instead of selectively arousing those elements most able to fight cancer.

The agents used in this method include interferons and interleukins (IL-2 and IL-12, for example), as well as bacillus (or bacilli) Calmette-Guerin (BCG), the organism that causes tuberculosis. The immune response to tuberculosis can cause certain cancers to regress. Researchers have achieved success by injecting nonspecific agents directly into body cavities where tumors are located. In two studies, for example, the use of BCG led to the complete remission of recurrent bladder tumors in about 70 percent of the patients.

T cell Transfer Therapy – t-cells are removed from the patient, then modified in the laboratory to enhance their ability to target the patient’s cancer. Then cells once grown are returned to the patient via an intravenous route.

Immune Checkpoint Inhibitors – These drugs block the cancers ability to avoid attack by the body immune system.

Passive Immunotherapy

Passive immunotherapy, sometimes called adoptive immunotherapy, gives the cancer patient antibodies and other agents so that the patient adopts an immune response that has been developed in a test tube.

The passive approach can be specific or nonspecific. Specific treatments include monoclonal antibodies (MABs), the so-called magic bullets, which can be designed to target certain cancer cells.

One nonspecific technique involves removing some of the person's T-cells, culturing the cells in the lab, and then injecting expanded populations of the treated cells into cancer patients.

An alternative approach is to activate lymphocytes taken from a person's tumor to create yet another agent, called tumor-infiltrating lymphocytes (TILs) and returning these "stranger" cells to the patient where they can fight the cancer cells.

Cytotoxic Therapy (Tumor Cell Modulation)

The second main category of biological therapy is sometimes called cytotoxic (cell-killing) therapy. This approach uses proteins called cytotoxins that are produced by the body's cells to attack the cancer either by destroying the cancer cells or by making it difficult for them to grow and reproduce. Another term for this approach is tumor cell modulation.

Tumor cell modulation changes the cancer cell's biology so that they become weak and die. Some of the agents used in this approach are called cytotoxins. Perhaps the best-known cytotoxin in this category is tumor necrosis factor (TNF), a toxin secreted by activated macrophages to selectively kill tumor cells, principally by interfering with their blood supply.

Certain agents make the antigens on cancer cells more recognizable to antibodies or make them stickier so that antibodies bind to them more easily. Other compounds interfere with the cancer cell's ability to metastasize.

Biological therapy involves the use of biologically derived agents to modify the relationship between tumor and host, altering the host's biologic response to tumor cells, with a resultant therapeutic effect. Most biological therapies are designed to activate the patient's immune system and induce it to attack cancer cells. Common biological agents that have been approved for use in treating specific types of cancer are described below.

Interferons

Interferons are proteins secreted by immune cells that interfere with a virus' ability to reproduce and proliferate. The human body produces interferons as part of the immune response. The name comes from the fact that they literally interfere with virus replication.

Through recombinant DNA technology, various interferons have been genetically engineered for use in the medical treatment of disease. These agents increase the cell-killing activity of the immune system, making tumor cells more vulnerable to immune attack by increasing antigens and blocking the formation of new blood vessels by tumors. They also slow tumor cell replication by inhibiting DNA and protein synthesis.

There are three known classes of interferons: alpha-, beta-, and gamma-interferons. Only alpha-interferon has been approved as a cancer treatment. For example, inteferon alfa-2b (Intron A) is used in conjunction with chemotherapy in patients with follicular lymphoma and has proven to be effective for treating malignant melanoma.

Monoclonal Antibodies (MABs)

Monoclonal antibodies are lab-engineered products. They are components of the immune system which are able to recognize and bind to a specific antigen. These lab-made antibodies are designed to react directly against certain tumor-associated proteins. They may be used by themselves or equipped with other molecules, such as toxins, chemotherapy drugs, or radioactive isotopes.

There are many monoclonal antibodies available for routine use for various types of cancer. The early results of treatment with these therapeutic monoclonal antibodies have been quite promising. Sometimes they have been given on their own, but more commonly in combination with conventional chemotherapy.

Targeted Therapy

Some monoclonal antibodies/therapeutic antibodies are considered to be targeted therapies because they do not cause a response from the immune system. They act by

• Marking cancers cells so they are more visible and can be killed by the immune system
• Directly stopping cancer cells from growing
• Causing cancer cells to self-destruct
• Serving as a vehicle to carry toxins to cancer cells

Besides monoclonal antibodies, small molecule-drugs are considered a targeted therapy. These drugs can easily enter the cancer cell because of their small size and targets areas inside the cell.

Monoclonal antibodies are used in the treatment of many cancers. For example

• Atezolizumab (Tecentriq) is used to treat advanced stage and metastatic, breast, small cell lung, non-small cell lung and urothelial cancer.
• Bevacizumab (Avastin, Mvasi) is used alone or in combination to treat cervical, colorectal, ovarian epithelial, fallopian tube, primary peritoneal, and non-squamous non-small cell lung cancer as well as Glioblastoma and renal cell carcinoma.
• Cetuximab is used alone or in combination with radiation or chemotherapy to treat head and neck squamous cell carcinoma, colorectal cancer and non-small cell lung cancer.
• Daratumumab is used alone or in combination to treat multiple myeloma.
• Ramucirumab is used alone or in combination to treat stomach, gastroesophageal junction adenocarcinoma, and hepatocellular carcinoma.

Interleukins

Interleukin (abbreviated IL) is a group of bioactive proteins produced by leukocytes, monocytes, and other cells that regulate the immune response. They act like messengers between the white blood cells of the immune system. Interleukin-2 increases the activity of lymphocytes, especially killer T-cells. Recombinant IL-2 is used for cancer therapy and continues to be studied as a biological therapy agent for other diseases.

Growth factors are colony stimulating factors or hematopoietic growth factors. These substances promote the growth and maturation of normal cells. There are two types used in cancer treatment: one type stimulates bone marrow to make normal cells; the other acts as an anticancer agent. Colony stimulating factors are being used increasingly in the treatment of bone marrow transplant patients. They are also used for patients who develop anemia or low white blood cell counts because of cancer or cancer therapy.

Tumor Vaccines

Vaccines against viral disease are effective in preventing human infections. They are administered to prevent infections for which effective treatments are not available, especially when active infection is associated with high mortality.

Tumor vaccines are a type of immunotherapy that attempt to stimulate the patient's own immune system to respond to tumor antigens. Melanoma vaccines have been administered to patients for several decades in hopes of boosting immunity to the patient's melanoma, usually as an adjuvant to surgery. Tumor vaccines are still in the early clinical trial phase.

With further research and more secrets about the immune system revealed, the prospect of biological therapies looks promising and hopefully the role of biological therapies in the successful treatment of cancer will grow in future years.

A bone marrow transplant (BMT) is the removal of bone marrow from one person and the return of its blood-forming cells later to the same person or the transfer of the blood-forming cells to someone else. It is a medical procedure used to treat diseases such as

• aplastic anemia
• Hodgkin's Lymphoma
• immune deficiency disorders
• leukemia
• multiple myeloma
• some solid tumors such as Ewing sarcoma and medulloblastoma

Bone marrow is the soft, sponge-like tissue found within the cavities of bones that contain fat and blood-forming tissue. It contains immature cells called stem cells that produce the body's blood cells. These blood cells include

• white blood cells (leukocytes), which fight infection
• red blood cells (erythrocytes), which carry oxygen to, and remove waste products from, organs and tissues
• platelets, which enable the blood to clot

Stem cells can also be collected from the peripheral blood in a process called “apheresis” and is much easier to collect than the stem cells from the bone marrow. Many patients receiving stem cell transplants today have the stem cells obtained from the peripheral blood, which is called “Peripheral Blood Stem Cell Transplant (PBSCT).” Stem cells can also come from umbilical cord blood.

Healthy bone marrow tissue constantly renews the blood supply and is essential to life. Unfortunately, the amount of drugs or radiation needed to kill cancer cells also destroys bone marrow. Bone marrow transplantation or stem cell transplant is often used as a rescue procedure, replacing stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy. In some cancers, particularly those involving the blood cells, bone marrow transplantation is used to attack the malignancy directly. Acute leukemia, for example, was the first cancer to be successfully treated with bone marrow transplantation.

The transplant procedure begins with the patient or donor providing stem cells. These blood-forming cells are stored while the patient's cancer cells are destroyed by chemotherapy drugs and/or radiation. The stem cells are then returned to the patient to speed the recovery of bone marrow.

Most bone marrow transplantation procedures are successful. The recipients are discharged promptly from the hospital after they have recovered. The long-term response rate varies greatly depending on the type and stage of cancer.

There are three types of transplants according to the source of the stem cells.

• Autologous - An autologous transplant is the removal of bone marrow from the person with cancer before treatment and is returned to him/her after treatment with high doses of chemotherapy or radiation therapy or both
• Allogeneic - An allogeneic transplant is donated by someone other than the patient or an identical twin. Siblings are always a closer match than parents and more likely to be compatible than other family members. The best matches also come from someone of the same ancestry
• Syngeneic - In syngeneic transplants, patients receive stem cells from their identical twin

As with some other cancer therapies, bone marrow transplants may also cause side effects, which should be recognized and effectively managed.

Almost everyone who undergoes bone marrow transplant experiences lethargy, nausea, and vomiting because of the high doses of chemotherapy and/or radiation that precede the transplant. Infection is an early serious danger for the patient, so the patient is closely monitored for fever and other signs of infection. Some patients may develop veno-occlusive disease, a very serious disease of the liver. Another major risk of bone marrow transplant is that the recipient's immune system may reject the transplanted "foreign" marrow.

Despite the risk involved with bone marrow transplant, the procedure is still recommended by physicians and opted for by cancer patients as an effective weapon against cancer. Most cancer patients receiving them benefit greatly from successful bone marrow transplants.

Immune Cell Therapy – Immune cell therapy, which is also call “Adoptive Immunotherapy” or “Adoptive Cell Therapy” involves enhancing a patient’s own immune cells ability to attack the cancer. This process involves removing the immune cells from the patient and growing large numbers of them in the lab then reinfusing them back to the patient. There are two approaches used for this process, which include

• Tumor-infiltrating lymphocytes (TILs) – T cells that are naturally found in the patients tumor are used that best recognize the patients tumor cells. These are grown in the laboratory and treated with cytokines which are infused back into the patient which signals the immune system to attack the tumor cells
• CAR T-cell therapy – patients T-cells are extracted and genetically engineered to bind to specific antigens in the cancer cell and destroy the cancer cells

Figure. CAR T-Cell Therapy. Source: National Cancer Institute (NCI).

Edward Jenner, William Coley, Paul Ehrlich, and Steven Rosenberg are important names in the brief history of biological therapy research.

Our immune system is a very important line of defense against "foreign invaders" such as bacteria, viruses, or cancer cells. What makes it unique is that it can recognize "foreign invaders," and then develop the specific weapons to fight them. Biological therapy uses materials made by our own body or made in a laboratory to boost, direct, or restore our body's natural defenses against diseases such as cancer.

Two basic biological therapies exist: immunotherapy and cytotoxic therapy. Immunotherapy uses a variety of methods and drugs to manipulate the immune system to create a hostile environment for the cancer in the body, while cytotoxic therapy involves changing the cancer cells' biology so that they become weak and die.

In biological therapy, biologically derived agents are either used to modify the relationship between tumor and host. This is altering the host's biologic response to tumor cells with a resultant therapeutic effect or by activating the patient's immune system and inducing it to attack cancer cells. Common biological agents include

• interferons
• monoclonal antibodies
• interleukins
• growth factors
• tumor vaccines

Bone marrow or stem cell transplantation is often used to replace stem cells destroyed by high doses of chemotherapy and/or radiation therapy, or to directly attack the malignancy. Depending on the donor of the bone marrow, bone marrow transplant can be categorized as

• allogeneic
• autologous
• syngeneic

Stem cells can come from the

• bone marrow
• peripheral blood
• the umbilical cord