By Reshma Jagasia, Ph.D, Scientist
The current standard of care for cancer treatment is surgery, chemotherapy, and radiation therapy – a standard that has persisted for decades. These treatments are invasive and not specific, killing healthy cells and tissues along with tumors. In the past decade, more targeted therapies have emerged, including the monoclonal antibodies (mAbs) rituximab (Rituxan® or MabThera®) and trastuzumab (Herceptin®), and the chemotherapy drug imatinib (Gleevec®). These treatments target cancer cells by taking advantage of the inherent molecular differences between cancer and healthy cells. Now a new class of treatment is emerging, one that purports to harnesses the patient’s own immune system to combat the patient’s disease. Called immunotherapy, this class of treatment is being described by researchers as the “fifth pillar” of cancer treatment. There are currently five types of FDA-approved immunotherapy for the treatment of cancer: (1) monoclonal antibodies, (2) immune checkpoint inhibitors, (3) cancer vaccines, (4) oncolytic viruses, and (5) other, non-specific immunotherapies. This article reviews these commercially available immunotherapies for cancer.
Monoclonal antibodies (mAbs) have been used to treat cancer and a number of other diseases. A therapeutic mAb functions by binding to a specific (targeted) antigen to elicit an immune response in the body against that target. In some cases, a toxin or radioisotope can be attached to the mAb, essentially turning the mAb into a drug-delivery system to an individual cancer cell. The key to this therapeutic strategy lies in identifying an antigen that is specific to the cancer cell over healthy cells. For some cancers, the identification of such an antigen has been difficult, hindering mAb drug development for these cancers. There are currently over two dozen FDA-approved mAbs for the treatment of various types of cancer (see Table 1). Still more mAbs are in clinical trials. As suitable antigens for cancer treatment are identified, new mAbs are being developed for cancer treatment. New developments also include modifying mAbs to reduce potential adverse events, and combining the binding regions of two different mAbs (known as a bispecific antibody) to enhance cell targeting.
Table 1: Current* FDA-Approved Monoclonal Antibodies for Cancer Treatment
|Monoclonal Antibody||Brand Name||Target||FDA Approval Date||Indication|
|alemtuzumab||Campath®||CD52||2001||Chronic lymphocytic leukemia|
|atezolizumab||Tecentriq®||PD-L1||2016||Bladder cancer Non-small cell lung cancer|
|2006||Non-small cell lung cancer|
|2009||Glioblastoma Renal cell cancer|
|2014||Cervical cancer Ovarian epithelial, fallopian tube, or primary peritoneal cancer|
|blinatumomab||Blincyto®||CD19 and CD3 (bispecific)||2014||Acute lymphoblastic leukemia|
|brentuximab vedotin||Adcetris®||CD30||2011||Anaplastic large cell lymphoma Hodgkin lymphoma|
|2006||Head and neck cancer|
|denosumab||Prolia® Xgeva®||RANKL||2013||Giant cell tumor of the bone|
|gemtuzumab ozogamicin (discontinued in 2010)||Mylotarg®||CD33||2000||Acute myeloid leukemia|
|ibritumomab tiuxetan||Zevalin®||CD20||2002||Non-Hodgkin lymphoma|
|necitumumab||Portrazza®||EGFR||2015||Non-small-cell lung cancer|
|2015||Non-small-cell lung cancer Kidney cancer|
|2016||Classical Hodgkin lymphoma Head and neck cancer|
|obinutuzumab||Gazyva®||CD20||2013||Chronic lymphocytic leukemia|
|ofatumumab||Arzerra®||CD20||2009||Chronic lymphocytic leukemia|
|olaratumab||Lartruvo®||PDGFR alpha||2016||Soft tissue sarcoma|
|2015||Non-small-cell lung cancer|
|2016||Head and neck cancer|
|ramucirumab||Cyramza®||VEGFR-2||2014||Adenocarcinoma of the stomach or gastroesophageal junction Non-small cell lung cancer|
|rituximab||Rituxan®, Mabthera®||CD20||2006||Non-Hodgkin lymphoma|
|2010||Chronic lymphocytic leukemia|
|siltuximab||Sylvant®||2014||Multicentric Castleman disease|
|tositumomab (discontinued in 2014)||Bexxar®||CD20||2003||Non-Hodgkin lymphoma|
|2010||Adenocarcinoma of the stomach or gastroesophageal junction|
*As of the authorship of this article. Information was acquired from the American Cancer Society website, www.cancer.org.
Immune Checkpoint Therapies
The immune system functions by recognizing foreign or sick cells from healthy ones using “checkpoints”, stimulatory or inhibitory mechanisms that prevent autoimmunity. Some cancers are able to adopt checkpoint mechanisms, thereby evading detection by the immune system. By inhibiting such checkpoint mechanisms, a cancer cell could become unmasked and potentially be killed. Two checkpoint receptors have emerged as accessible targets for cancer treatment: PD1 and CTLA-4, two cell-surface proteins expressed by T cells. When PD1 on a T cell binds its native ligand, PD-L1, on a healthy cell, the T cell is prevented from attacking. Some cancer cells display large quantities PD-L1, mimicking healthy cells. Pembrolizumab (Keytruda®) and Nivolumab (Opdivo®) are both FDA-approved monoclonal antibodies that target PD1 for the treatment of several types of cancer, including melanoma, non-small cell lung cancer, kidney cancer, head and neck cancers, and Hodgkin lymphoma. Atezolizumab (Tecentriq®), also a mAb, targets PD-L1 for bladder and metastatic non-small cell lung cancer (NSCLC). Ipilimumab (Yervoy®), is an FDA-approved mAb that targets CTLA-4, a checkpoint receptor that functions similarly to PD1. A concern for checkpoint inhibitors is that they can target normal cell functions, affecting healthy cells as well as tumors. Many new checkpoint inhibitor drugs are currently being studied. Also being considered is the use of combination treatment, such as nivolumab, which targets PD-1, and ipilimumab, which targets CTLA-4, to improve efficacy. Use of this combination has been shown to work well in melanoma patients but comes with an increased risk of serious side effects.
Traditional vaccines against viruses are intended to prime the body’s immune system to mount a response should a viral infection occur. Some cancers appear to be linked to viral infections. Various strains of the human papilloma virus (HPV) have been linked to cervical, anal, and throat cancers. People with chronic hepatitis B virus (HBV) are at a higher risk for liver cancer. Traditional vaccines targeting these viruses potentially could reduce the risk of an infected but otherwise healthy person developing one of these associated cancers. Cancer vaccines, on the other hand, are intended to treat patients already diagnosed with cancer. These vaccines attempt to boost the patient’s own immune system to attack cancer cells in the body. Tumor cell vaccines: These vaccines are made from cancer cells that have been removed from the patient during surgery or biopsy. These cells are altered (and killed) in the lab to improve immunogenicity, then injected back into the patient with the intent to elicit a strong immune response. Most tumor cell vaccines are autologous, but allogeneic vaccines are much easier to make. It is not yet clear if one type works better than the other. Antigen vaccines: These vaccines boost the immune system by using only one (or a few) antigens rather than whole tumor cells. These antigens are often proteins or peptide-segments of proteins. Often, these antigens are specific to certain types of cancer mutations and may not be effective for all patients with similar cancer. Dendritic cell vaccines: Dendritic cells are antigen-presenting cells that can be recognized by T cells. The resulting activated T cells then initiate an immune response against any cells in the body that present these antigens. The manufacturing process of dendritic cell vaccines is complex and expensive, involving the removal of white blood cells (primarily dendritic cells) from the patient, modification of the dendritic cell to present the patient’s cancer antigen on its surface, and reinfusion of these cells into the patient to enhance the immune response. Because the starting material for the manufacturing of this “live drug” is the patient’s own white blood cells, each batch of drug is precisely intended only for that patient. It is hoped that the vaccine might continue to work long after being administered, as well as become incorporated into the immune system’s memory. Sipuleucel-T (Provenge®) is a dendritic cell vaccine and the only cancer vaccine currently approved to treat cancer in the United States. This therapy is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic prostate cancer. While this therapy has not been shown to cure the patient, it has been shown to extend patients’ lives on average of several months. Dendritic cell vaccines have shown the most success among vaccines in treating cancer, and have accordingly garnered much excitement in the research community. The concept of adoptive cell therapy (ACT) – the removal, modification, and reinfusion of a patient’s own T cells – is being researched heavily with many new therapies entering early-phase clinical trials. Vector-based vaccines: These vaccines use vectors to deliver a vaccine drug to the tumor site, potentially improving treatment efficacy. Vectors can be viruses, bacteria, yeast cells, or other structures. While these vaccines differ from other vaccine categories only by their delivery system (e.g., there are vector-based antigen vaccines), they do offer some benefits over their counterparts. Vectors allow for the delivery of multiple antigens at a time, increasing the likelihood of an immune response by the body. In fact, the vector itself is a potential immunogen. Vector-based vaccines may also be less expensive to manufacture compared with some other vaccines.
Talimogene laherparepvec (Imlygic®) is an injectable oncolytic virus approved by the FDA in 2015 for the treatment of melanoma lesions that cannot be surgically removed in the skin and lymph nodes. This novel product uses a herpes virus to infect cells at the injection site. While the virus can infect both healthy and cancerous cells, it has been engineered to not replication inside healthy cells. When inside a cancer cell, the replicating virus synthesizes and secretes GM-CSF, a protein that boosts the immune response. The proliferation of the virus and the increased concentration of GM-CSF afford a heightened immune response targeted at the sight of virus delivery, i.e., the tumor. This treatment has been shown to shrink treated tumors but not to affect tumors in other parts of the body.
Instead of targeting cancer cells specifically, non-specific immunotherapies stimulate the immune system globally with the intent to improve the response to a patient’s cancer cells. These therapies can be administered alone as cancer treatments or used as adjuvants with other treatments. Cytokines are the most common non-specific immunotherapeutic. One cytokine, interleukin-2 (IL-2), is approved to treat advanced kidney cancer and metastatic melanoma. Other interleukins, such as IL-7, IL-12, and IL-21, are currently being studied for cancer therapy. Another cytokine, interferon-alpha (IFN-α), is known to enhance the overall immune response but may also directly inhibit cancer cell proliferation and angiogenesis. IFN-α has been used to treat a variety of cancers, including hairy cell leukemia, chronic myelogenous leukemia (CML), follicular non-Hodgkin lymphoma, cutaneous (skin) T-cell lymphoma, kidney cancer, melanoma, and kaposi sarcoma. Other non-specific immunomodulating drugs include thalidomide (Thalomid®), lenalidomide (Revlimid®), and pomalidomide (Pomalyst®). These drugs are used to treat multiple myeloma and some other cancers. Imiquimod (Zyclara®) is a topical cream that stimulates a local immune response against skin cancer, especially early-stage cancers located in sensitive areas on the body. Bacille Calmette-Guérin (BCG) is an attenuated version of a Mycobacterium bovis, a bacterium closely related to Mycobacterium tuberculosis, the agent responsible for tuberculosis. BCG does not cause serious disease in humans but can activate the immune system. BCG was one of the earliest immunotherapies used against cancer and is still being used today to treat early stage bladder cancer. Immunotherapies are quickly gaining momentum to become an important option for cancer treatment. Immunotherapy development has proven to be more difficult than originally anticipated by researchers due to the complex nature of the immune system and the adaptability of cancer to evade immune attack. However, over the past three decades, new knowledge about cancer and immunity has abounded, and researchers are hopeful that, alongside chemotherapy, radiation therapy, and surgery, immunotherapy will play a key role in the future of cancer treatment and prevention.