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Health Protocols

Cancer Immunotherapy

Immunotherapy: Harnessing the Immune System to Treat Cancer

The goal of cancer immunotherapy is to enhance the body’s natural ability to find and destroy cancer cells (ACS 2016b). Immunotherapy can be either passive or active. In passive immunotherapy, general immune-enhancing strategies attempt to bolster the intrinsic immune response against cancer. This may be an effective approach for someone who is generally immunocompromised or afflicted with immune senescence. In contrast, active approaches give the immune system a new way of attacking cancer cells. Active immunotherapeutic approaches stimulate a new immune response in patients whose immune systems are capable of responding (Papaioannou 2016).

Monoclonal Antibody Therapy

Monoclonal antibodies are Y-shaped proteins produced by mature B cells. The term “monoclonal” denotes that the antibodies are made by identical immune cells that are all progeny of a unique parent cell. One of the functions of antibodies is to tag foreign invaders for elimination by the immune system (Delves 2017; Gabrilovich 2016). Each B cell produces one type of antibody, and each antibody is specific for one antigen (Janeway 2001a; Abbas 2009).

Researchers can create antibodies in the lab and develop them for clinical use (Steplewski 2015). Over the past few decades, scientists have learned how to create antibodies highly specific for tumor antigens (Saxena 2016).

Several antibodies are already used to treat cancer. Bevacizumab (Avastin) is used to treat some types of brain, colorectal, lung, and kidney cancers (NCI 2014). This antibody targets a protein called vascular endothelial growth factor (Raphael 2017). Panitumumab (Vectibix) and cetuximab (Erbitux) target the cellular receptor for epidermal growth factor and are used to treat metastatic colorectal cancer (Chen 2016; Lv 2017). Several other antibody drugs target various other cancer-specific cellular markers.

Another way antibodies are used to combat cancer is by delivering cell-killing agents, such as chemotherapy drugs or radioisotopes. Therapies that combine an antibody, which targets cancer cells, with a cell-killing drug are called antibody-drug conjugates (Thomas, Teicher 2016). Brentuximab vedotin (Adcetris) is an example of an antibody-drug conjugate. This drug targets a certain marker (called CD30) that is more common on some types of lymphoma cells than on healthy cells (Berger 2017). Ibritumomab tiuxetan (Zevalin) is another antibody-drug conjugate. It combines rituximab (Rituxan), an antibody that binds to the CD20 marker on the surface of non-Hodgkin lymphoma and chronic lymphocytic leukemia cells, with a radioactive isotope (Rizzieri 2016; Gold Standard 2017j).

While some antibodies deliver poisons to the tumor, others recruit the patient’s immune cells to the tumor in a form of passive immunotherapy (Table 2). Rituximab is an example of this approach. This antibody attracts NK cells that destroy malignant B cells. This process is called antibody-dependent cellular cytotoxicity (Wang 2015; Seidel 2013).

Some other antibodies also trigger antibody-dependent cellular cytotoxicity and have been used clinically. For instance:

  • alemtuzumab (Campath) targets CD52-positive chronic lymphocytic leukemia cells (Warner 2012)
  • daratumumab (Darzalex) targets CD38-positive multiple myeloma cells (Costello 2017)
  • elotuzumab (Empliciti) targets a molecule (SLAMF7) on both multiple myeloma cells and NK cells (Lonial 2015)
  • trastuzumab (Herceptin) is an antibody to HER2, a growth factor receptor sometimes overexpressed in breast cancer (Nahta 2003; Vu 2012). Trastuzumab was approved by the FDA in 1998 to treat human epidermal growth factor receptor-2-positive (HER2+) breast cancer. By binding to HER2, trastuzumab both blocks growth factor signaling and attracts immune cells to the cancer cells. Trastuzumab is typically used as part of a treatment course that includes chemotherapy.
  • Pertuzumab (Perjeta) is another antibody to HER2 that is also used in breast cancer treatment. It binds to a different part of the HER2 receptor than trastuzumab, but triggers a similar response. In some cases, trastuzumab and pertuzumab may be used together for dual HER2-targeted therapy (NCCN 2017; Prat 2013). Pertuzumab was approved by the FDA in 2012 (NCCN 2016).

There are many other ways that antibody-based therapies can kill cancer cells. Some antibodies may trigger multiple anti-cancer responses (Weiner 2010).

Blinatumomab (Blincyto) is a newer type of antibody called a bispecific T-cell engager or BiTE (Wu 2015). These compounds link two antibodies, with one binding to a marker on the patient’s T cells and the other to a particular marker on malignant B cells in a certain type of acute lymphoblastic leukemia. This results in a T-cell attack on cancer cells carrying that specific marker (Amgen 2017; Gold Standard 2017e).

Table 2: FDA-approved Monoclonal Antibodies that Engage the Immune System


Name (Trade name)


Cancer types

Antibody dependent cellular cytotoxicity (ADCC)

Rituximab (Rituxan)


Non-Hodgkin lymphoma, chronic lymphocytic leukemia

Alemtuzumab (Campath)


Chronic lymphocytic leukemia, cutaneous T-cell lymphoma

Daratumumab (Darzalex)


Multiple myeloma

Elotuzumab (Empliciti)


Multiple myeloma

Trastuzumab (Herceptin)


Breast cancer

Cetuximab (Erbitux)


Colorectal cancer, head and neck cancer

Ofatumumab (Arzerra)


Chronic lymphocytic leukemia


Blinatumomab (Blincyto)


Acute lymphoblastic leukemia

Checkpoint inhibitor

Ipilimumab (Yervoy)



Nivolumab (Opdivo)


Melanoma, lung cancer, renal cell carcinoma, urothelial carcinoma, head and neck cancer, Hodgkin lymphoma

Pembrolizumab (Keytruda)


Melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, urothelial carcinoma

Atezolizumab (Tecentriq)


Urothelial carcinoma, non-small cell lung cancer

Avelumab (Bavencio)


Urothelial carcinoma
Merkel cell carcinoma

(Wu 2015; Li 2017; ACTIP 2013; Gold Standard 2017f; Gold Standard 2017g; Gold Standard 2017a; Gold Standard 2017h; Gold Standard 2017i; Gold Standard 2017c; Gold Standard 2017d)

*Cetuximab also blocks EGRF signaling

Immune Checkpoint Inhibitor Therapy

Normally, checkpoint proteins on the surface of T cells help them balance between attacking dangerous cells and protecting healthy cells. This system is often referred to as the “brakes” of the immune system. Manipulating this checkpoint system is one way cancer cells evade the immune system (NCI 2017a; Pardoll 2012).

Early in tumor development, these brakes on the immune system are “turned off,” and T cells are able to recognize and destroy many of the cancer cells. However, tumors can mask themselves with proteins that activate T cells’ checkpoint proteins, which turns down the immune response to the cancer cells (DFCI 2017).

Fortunately, new drugs have been developed that help stop cancer cells from activating the immune system’s checkpoints. These drugs are a form of active immunotherapy. The first checkpoint inhibitor antibody, ipilimumab (Yervoy), was approved by the Food and Drug Administration (FDA) in 2011. This drug targets a checkpoint protein called CTLA-4 (Letendre 2017). When CTLA-4 is blocked by the antibody, T cell activation can proceed (Menon 2016).

Ipilimumab has already been shown to successfully extend lifespan in patients with metastatic melanoma (Hodi 2010). Hundreds of studies of ipilimumab are planned as of mid-2017 (NIH 2017). In early trials, another CTLA-4 blocking antibody, tremelimumab, showed promise in patients with advanced melanoma (Ribas 2013). Tremelimumab received the FDA’s Orphan Drug Designation for treatment of malignant mesothelioma in 2015 (AstraZeneca 2015).

Former President Jimmy Carter was treated with a checkpoint inhibitor called pembrolizumab (Mulcahy 2015). This drug blocks a checkpoint protein called PD-1 that is found on the surface of T cells. Blocking PD-1 prevents T cells from being “turned off” (Gold Standard 2017i). In a clinical trial, pembrolizumab improved survival compared with ipilimumab in advanced melanoma patients, with a lower rate of severe toxicity (Robert 2015). Nivolumab (Opdivo) is another FDA-approved drug that blocks PD-1, allowing the immune system to attack certain cancers (Gold Standard 2017h). Pembrolizumab and nivolumab are FDA approved for several types of cancer (Table 2) and are being tested for treatment of many other types.

Other drugs also target the PD-1 pathway. One of these, atezolizumab (Tecentriq), has been approved by the FDA for patients with certain advanced lung and bladder cancers that no longer respond to standard chemotherapy (Gold Standard 2017c). Another drug, avelumab (Bavencio), has been approved for advanced cases of urinary tract cancers that no longer respond to conventional chemotherapy (Andtbacka, Agarwala 2016; Gold Standard 2017d).

Although checkpoint inhibitors have helped many cancer patients, they are not appropriate for everyone and can cause side effects including rashes, diarrhea and colitis, liver toxicity, and hypothyroidism and other endocrine abnormalities (Villadolid 2015). PD-L1 expression testing is a strategy used to determine which patients will be most likely to benefit from PD-1-targeted therapy. This test involves determining if a patient’s cancer cells express a marker called PD-L1. This marker binds and activates the PD-1 immune checkpoint, thus suppressing the immune response. If a patient’s cancer cells express a lot of PD-L1, that means the PD-1 immune checkpoint system is likely playing an important role in helping the cancer evade destruction by the immune system. Higher PD-L1 expression usually suggests a better expected response to PD-1 targeted therapy (Dang 2016). Other tests to determine the likelihood of success of immune checkpoint-targeted therapy are in development and will likely help guide targeted therapy in the future.

Cytokine Therapy

Cytokines are biochemicals that immune cells use to communicate with each other (Lee 2011). In some conditions such as asthma and rheumatoid arthritis, excessive cytokine concentrations cause inflammation, but in tumors, some cytokines can recruit and activate immune cells that can destroy cancer cells (Lee 2011; Turner 2014). Two classes of cytokines are used to treat cancer: interferons and interleukins. They play roles in the activation and proliferation of white blood cells, enhancing the immune response against cancer (NCI 2013).

One particular type of interferon is called interferon alpha. This cytokine increases the ability of T cells and dendritic cells to destroy some types of cancer cells. Three forms of interferon alpha are commercially available; they are used to treat melanoma and other cancers (Rafique 2015; Floros 2015).

The other group of cytokines used in cancer treatment is interleukins. Specifically, aldesleukin (Proleukin) is a form of interleukin-2 (IL-2) that is approved for the treatment of metastatic melanoma and a form of metastatic kidney cancer (Jiang 2016). IL-2 activates T cells and NK cells (Lee 2011; Jiang 2016). T cells and NK cells can destroy cancer cells and also release more cytokines to recruit other immune cells to the tumor (Abbas 2009; Wu 2003).

Cytokines modulate the immune response, and therefore they are excellent candidates for combination with other cancer treatments, including immunotherapies such as tumor vaccines and checkpoint inhibitors (Lee 2011; Ott 2017).

Ongoing Research on Immunotherapy

The field of cancer immunotherapy continues to expand. Some research is focused on finding new targets. New therapies are being tested to target immune cells in the tumor that aid tumor growth, such as tumor-associated macrophages (Williams 2016).

Researchers are also trying to find ways to improve antibodies currently in use. For instance, antibodies can be altered in the lab to make them more effective at inducing antibody-dependent cellular cytotoxicity or last longer in the body (Gabellier 2016; Saxena 2016).

Immunotherapy drugs are candidates for combination therapy. Passive immunotherapy approaches boost immune function, while active immunotherapies aim to eliminate the tumor’s defenses (Papaioannou 2016). Combination therapies combine these two approaches and represent one promising area of immunotherapy research. Combination therapies may also include conventional cancer therapies like chemotherapy, radiation, and targeted therapies. For instance, various combinations of cytokines and checkpoint inhibitors are being tested. Other researchers are testing the effect of combining more than one checkpoint inhibitor drug (Ott 2017). In melanoma patients, those treated with the PD-1 inhibitor nivolumab in combination with ipilimumab responded better than those treated with ipilimumab alone (Postow 2015). Checkpoint inhibitors that target the PD-1 pathway are usually considered the best candidates for the foundation of most combination therapies (Ott 2017).

So far, the immunotherapeutic approaches discussed have all been drugs. But new treatments are being developed with an approach called adoptive cell transfer. In this process, the patient’s own T cells are removed from his or her body, grown in large numbers in a laboratory, and then returned to the patient by infusion. This laboratory process can allow for selection of T cells especially capable of recognizing and attacking tumor cells. Another strategy used in adoptive cell transfer is genetic engineering to create T cells that express specific anti-tumor receptors on their surface. These new receptors allow the T cells to recognize and destroy cancer cells (Perica 2015; Rosenberg 2015).

Various adoptive cell transfer treatments are being tested in early clinical trials, with promising results (Brown 2016; Garfall 2015; Maude 2014; Locke 2017). Early trials of a chimeric antigen receptor T-cell therapy called KTE-C19 have shown promising results in diffuse large B-cell lymphoma, with an interim analysis in one trial reporting complete remission in one-third of patients after three months (AACR 2017; Locke 2017). Chimeric antigen receptor (CAR) therapy is one of the most exciting areas of adoptive cell transfer research. In CAR therapy, T cells from cancer patients are modified to develop specificity for a marker on the patient’s cancer cells. The cells are then cultured in the lab so their numbers expand before being reintroduced into the patient. One reason that CAR therapy is so promising is that the T cells can be engineered to target a wide range of markers. This flexibility makes it easier to target each cancer’s specific properties. CAR has shown success in blood cancers and appears promising in solid tumors as well. Many trials are underway, and the hope is that CAR techniques will be refined and become available to many cancer patients (NCI 2017b; Barrett 2014; Luskin 2017; Maude 2016).