Immunotherapy for Cancer

Immunotherapy is a cancer treatment that enhances the body’s ability to fight cancer cells by boosting its immune system. Significant research advances have recently raised immunotherapy’s profile as a cancer treatment, and dramatic responses seen in some patients have led many to view this approach as the future of cancer therapeutics. It’s important to note, however, that success rates remain modest, and the approach is still very much a work in progress. Scientists are now working to understand why efficacy varies from patient to patient, and how quality of life and life expectancy can be improved for more patients using this approach.

How is cancer usually treated?

  • Surgery is performed when possible to remove a cancerous tumor.

  • Radiotherapy uses high-energy X-rays to kill or damage cancer cells in a specific area of the body.

  • Chemotherapy involves drugs that kill or damage rapidly dividing cells in the body, including cancer cells but also some healthy cells that have naturally high replication rates, like those in the intestines, bone marrow, and immune system.

  • Targeted therapy involves drugs that attack the abnormal proteins inside of tumors that cause uncontrolled tumor cell growth.

How does immunotherapy work?

  • Unlike other common cancer treatments that target cancer cells directly, immunotherapy activates an individual’s own immune system to fight cancer.

  • The immune system is a network of molecules, cells, and organs that protect the body from infection. Lymphocytes are one type of immune system cell; these are small white blood cells and include what are known as ‘T-cells’ and ‘B-cells’. T-cells directly kill infected or cancerous cells, while B-cells make antibodies (proteins that fight infection) that can neutralize viruses, bacteria, and other threats.

  • Most immunotherapies focus on T-cells, though treatments that target other immune system cells are in development.

  • Tumors often evade or suppress the immune system’s attacks, either by masquerading as healthy cells or by expressing molecules to block immune system cells.

  • In clinical studies, immunotherapy has shown the ability to:

    • Boost the immune system as it works to destroy cancer cells;

    • Stop or slow the growth of cancer cells; and/or

    • Prevent cancer cells from metastasizing (spreading) to other parts of the body.

How effective is immunotherapy?

  • There is a broad disparity in patient reactions to immunotherapy.

  • While some patients show dramatic improvements using immunotherapies, most experience either immediate or delayed “resistance” to immunotherapy treatment. In these cases, the cancer either does not respond to treatment or responds initially but then adapts in some way that allows it to progress, causing the patient to relapse.

  • Different responses and resistance patterns among patients could be due to individual genetic differences, timing of immunotherapy treatment in relation to other treatments, and the type and stage of cancer, among other factors.

    • Even when immunotherapy does not completely remove a cancer, it can improve a patient’s condition enough that previously inoperable tumors can be removed surgically or a patient’s responsiveness to chemotherapy and radiotherapy may increase.

Types of immunotherapy

The Food and Drug Administration (FDA) has approved several cancer immunotherapy drugs to date, and novel immunotherapies are available to certain eligible patients. Most immunotherapies involve direct injection into tumors or intravenous infusions of antibodies or tumor-fighting immune system cells.

Monoclonal Antibodies

  • Monoclonal antibodies (also called mAbs) are a type of antibody made in a laboratory. Once injected into a patient, they attach to specific proteins on cancer or immune system cells.  When attached to a cancer cell, mAbs mark that cell for the immune system to destroy.

  • There are three main types of monoclonal antibodies used in cancer immunotherapy:

  • Naked monoclonal antibodies that attach to cancer cells and/or immune system cells and mark tumor cells for the immune system to destroy or otherwise stop cancer cells from growing or spreading;

  • Conjugated monoclonal antibodies that attach to cancer cells and/or immune system cells while carrying a chemotherapy drug or radioactive particle that help destroy a tumor;

  • Bispecific monoclonal antibodies that attach to two different proteins, a cancer cell protein and an immune system cell protein, at the same time. By linking these two cells together, the immune system is then triggered to attack the cancer cells.

Immune Checkpoint Inhibitors

  • Immune checkpoint inhibitors are a type of naked mAb and are the most widely used class of cancer immunotherapies.

  • Normally, the immune system has “checkpoints,” small proteins attached to the surface of immune system cells, that ensure that the immune system doesn’t attack healthy cells. When the checkpoint proteins encounter healthy cells, they tell the immune cells to “stand down” and spare those cells from attack.

  • Cancer cells can exploit these checkpoints by producing deceptive, normal proteins on their surface so that when they encounter immune cells they appear to be healthy and avoid attack.

  • Checkpoint inhibitor drugs prevent cancer cells from communicating deceptively with immune system cells, allowing them to recognize the cancer cells as harmful and destroy them.

  • The most commonly used checkpoint inhibitors block the multiple checkpoints CTLA-4 and PD(L)-1. When these immunotherapy drugs are circulating, checkpoint proteins can’t detect the false outward signs of normalcy being displayed on cancer cells, and so they are not fooled into putting the brakes on the immune system.

  • In 2011, anti-CTLA-4 was the first of this kind of immunotherapy to be approved by the FDA, for late-stage melanoma.

  • Anti-PD-1, anti-PD-L1, and anti-CTLA-4 have since demonstrated positive clinical results in a wide variety of cancers.

Oncolytic Virus Therapy

  • Oncolytic Virus Therapy (OVT) uses modified live viruses that destroy cancer cells while leaving healthy cells intact. Some OVTs kill cancer cells directly, while others trigger immune responses.

  • Currently there is only one OVT approved by the FDA—a genetically modified version of the herpes virus that causes cold sores, called T-VEC (talimogene laherparepvec), approved for some patients with melanoma.

    • When the T-VEC virus is injected into the melanoma tumor, it makes many copies of itself, filling the cancer cells and causing them to burst and die. As the cancer cells die, they release antigens—proteins that trigger an immune response against remaining tumor cells.

    • Patients may experience a “local response,” which affects the injected tumor and nearby areas, or a “systemic response,” which affects tumors that were not originally targeted for treatment.

  • Researchers are studying newer OVTs—modified versions of the reovirus and poliovirus—as treatments for breast cancer and brain tumors.

T-cell Therapy

  • T-cell therapy collects and remodels a patient’s own immune system cells to treat their cancer (though for certain cancers, cells from a healthy donor are needed instead). There are currently three kinds of T-cell therapy either approved or in clinical trials.

  • CAR Therapy:

    • CAR therapy is a highly personalized therapy that takes T-cells from patients’ blood and modifies them in a laboratory with specific receptor proteins, called chimeric antigen receptors (CAR), that help the T-cells recognize cancer cells by identifying specific proteins on the cancer-cell surface.

    • Once a sufficiently large quantity of these modified T-cells has grown in the lab, they are infused into the patient’s body, where they seek and destroy cancer cells.

    • CAR T-cell therapy has been used primarily for the treatment of blood cancers, such as leukemia, lymphoma, and myeloma.

  • TIL Therapy:

    • Tumor-infiltrating lymphocytes (TIL) therapy operates similarly to CAR therapy, except on solid tumors.

    • Patient-derived tumor-infiltrating lymphocytes are allowed to multiply in the laboratory and then injected into the patient’s solid tumor, where they cause the tumor cells to burst.

  • TCR Therapy:

    • Similar to CAR Therapy, T-cell receptor gene (TCR) therapy also uses a patient’s own T-cells and engineers them with special receptors that target proteins located on the surface or inside of cancer cells.

    • TCR therapy differs from CAR therapy in its ability to target proteins inside cancer cells; CAR therapy can only target specific, outer-cell-surface proteins that not all cancer cells have.

Cancer Vaccines

  • Cancer vaccines contain antigens—immune system stimulating proteins—that prime the immune system to attack cancer cells or viruses that can cause cancer.

    • Cancer prevention vaccines aim to prevent cancer from developing by spurring the early production of protective antibodies against antigens found on cancer-causing viruses. Examples include the human papillomavirus (HPV) vaccine and the Hepatitis B vaccine.

    • Cancer treatment vaccines aim to treat cancer already present in the body by mounting immune system responses that slow or stop cancer cells from growing, prevent cancer from returning, or kill cancer cells that have been unresponsive to other forms of treatment.

  • In 2010, a cancer treatment vaccine designed to treat metastatic prostate cancer, called sipuleucel-T, became the first therapeutic cancer vaccine to be approved by the FDA.

  • Current clinical trials are exploring vaccines in a wide variety of other cancers.

Immunotherapy in combination

Research suggests that for many cancers, combining immunotherapy with other treatment strategies may be most effective in fighting the disease.

  • Immunotherapy + Chemotherapy: Clinical trials have shown that combining immunotherapy and chemotherapy treatments results in significantly longer overall survival than chemotherapy alone. Research is required to identify the ideal combination of drug types and dosage, as well as their schedule and sequence of administration.

  • Immunotherapy + Immunotherapy: Another option is to integrate two types of immunotherapy treatments. For example, patients who received OVT combined with immune checkpoint inhibitors responded better than those who received the checkpoint inhibitor alone.

  • Immunotherapy + Radiotherapy: In one clinical trial of metastatic late-stage cancer patients, radiotherapy, given either at the same time as or sequentially to immunotherapy, helped trigger an immune response, causing tumor growth to slow.

  • Immunotherapy + Targeted Therapy: Generally, targeted therapy incurs responses in more patients than immunotherapies while immunotherapies have more durable, long-lasting remissions. By combining both treatment strategies, researchers hope to increase the rate and duration of patient remission.

Future research

  • Researchers aim to better understand the mechanisms cancer cells use to go unnoticed by the immune system and how these mechanisms can be turned off.

  • Researchers are also working to find ways to reduce the cost and complexity of cancer immunotherapy research and are developing tests to more quickly assess a patient’s response to treatment and predict long-term survival, which could give an early indication of how treatment should be personalized.

  • New clinical studies are examining treatment variations such as the stage of the cancer’s spread at which it’s appropriate to use immunotherapy, optimal dosage and treatment schedules, and duration of therapy.

LAST UPDATED OCTOBER 24, 2018

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 An oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response.  [National Cancer Institute]

An oral squamous cancer cell (white) being attacked by two cytotoxic T cells (red), part of a natural immune response. [National Cancer Institute]

Sources

key references for those who want to dig deeper

  1. The National Center for Health Statistics at the Center for Disease Control has listed cancer as one of the top ten leading causes of death in the United States.  According to the National Cancer Institute, 38.4% of Americans are expected to contract cancer at some point in their lifetimes.

  2. The original immunotherapy treatment was discovered by Dr. William B. Coley, a physician who, in the early 20th century, discovered that his cancer patients made miraculous recoveries when exposed to bacterial toxins. Coley’s paper, The Treatment of Inoperable Sarcoma by Bacterial Toxins (the Mixed Toxins of the Streptococcus erysipelas and the Bacillus prodigiosus), was influential when it was first published in 1909, but soon new treatments, such as chemotherapy and radiotherapy, became more practical. Immunotherapy didn’t reappear as a viable cancer treatment until the late 20th and early 21st centuries.

  3. A landmark 1996 paper, Enhancement of Antitumor Immunity by CTLA-4 Blockade, published in Science, provided evidence that the CTLA-4 immune checkpoint inhibited T-cell function. The paper’s authors found that T-cells weren’t attacking cancer cells because CTLA-4 was preventing them and that by blocking CTLA-4 with an antibody, tumor growth in mice could slowed or stopped.

  4. Given the large and potentially devastating impact of cancer, researchers and practitioners, including the team of oncologists that published the 2017 paper Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape, published in the European Journal of Cancer, are encouraged by the results some patients have had using immunotherapies.

  5. Most patients who receive immunotherapy only respond partially to treatment, or don’t respond at all. A 2017 paper, Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy, in the journal Cell, describes the various ways in which patients can show resistance to immunotherapy treatment and concludes that research is needed to determine how immunotherapies can be an effective treatment for more patients. Mechanisms of resistance to immune checkpoint inhibitors (2018), published in Nature, describes the various ways in which patients have shown resistance to CTLA-4 and PD-1 checkpoint blockers.

  6. A comprehensive review of immunotherapy, published in Nature Reviews Cancer, Immunosuppressive networks in the tumour environment and their therapeutic relevance, 2005, explores why immunotherapies tend to result in poor patient response rates. The author proposes that the reason may be that tumors themselves develop mechanisms for escaping immunity strategies. 

  7. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations, 2016, published in Science Translational Medicine, is the first to show evidence for an alternative type of immune checkpoint inhibitor therapy.

  8. Cancer is irrevocably tied to the immune system, so much so that they form a “cancer-immunity cycle”, as is described in the 2013 paper Oncology Meets Immunology: The Cancer-Immunity Cycle, published in the journal Immunity. Immunotherapies have been shown to be most effective when they target the correct step of this cycle.

  9. Researchers continue to study the various side effects of different immunotherapies, which can range from mild to severe or life-threatening. The prevalence of certain side effects is still being explored, such as in the 2015 paper Risk of endocrine complications in cancer patients treated with immune check point inhibitors: a meta-analysis, published in Future Oncology.

  10. Not all patients respond to immunotherapy, so more studies are being done to investigate this disparity in patient reaction. A 2012 paper published in The New England Journal of Medicine titled Safety and Activity of Anti-PD-L1 Antibody in Patients with Advanced Cancer explores how to increase patient responsiveness while minimizing negative impact.

 

 

biomedicine, healthBecky Hazen