Immunotherapy

Immunotherapy brochureTo help you understand and share this information, you can request our free booklet that summarizes the detailed information in the following sections.

Immunotherapy for lung cancer is a type of treatment that aims to enhance the body’s immune response and stop the lung cancer from evading the immune system.

Find out more about how the immune system works, how treatments to boost it can help fight lung cancer, and whether participating in a clinical trial using immunotherapy might be a good option for you.

 

What is the immune system?

The following video explains what the immune system is and what it does.

Organs of the immune systemThe immune system is a complex network of cells, tissues, and organs that work together to protect the body from foreign invaders such as bacteriaA large group of single-cell microorganisms. Some cause infections and disease in animals and humans or virusesA very simple microorganism that infects cells and may cause disease. The key players in defending the body are a specific type of white blood cellA type of blood cell that helps the body fight infection and other diseases called lymphocytes. There are three types of lymphocytes: B cellsA type of white blood cell that circulates in the blood and lymph seeking out foreign invaders, T cellsA type of white blood cell that helps protect the body from infection and may help fight cancer, and natural killer (NK) cellsA type of white blood cell that patrols the body and is on constant alert, seeking foreign invaders.1,2

Lymphocytes grow and develop in the bone marrowThe soft, sponge-like tissue in the center of most bones, thymusAn organ in the chest behind the breastbone that is part of the lymphatic system, in which T lymphocytes grow and multiply, and spleenAn organ on the left side of the abdomen near the stomach that makes lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. They can also be found in clumps throughout the body, primarily as lymph nodesA rounded mass of lymphatic tissue surrounded by a capsule of connective tissue. Clumps of lymphoid tissue are also found in the appendix, tonsils, and adenoidsA mass of lymphatic tissue located where the nose blends into the throat. The lymphocytes circulate through the body between the organs and nodes via lymphatic vesselsThin-walled tubular structures that collect and filter lymph fluid before transporting it back to the blood circulation and blood vessels. In this way, the immune system works in a coordinated manner to monitor the body for germs and other abnormal cells.2,3,4,5

How does the immune system work?

A key feature of the immune system is its ability to tell the difference between the body's own normal cells, or "self," and cells and other substances that are foreign to the body, or "non-self." Every cell in the body carries a set of distinctive proteinsMolecules made up of amino acids that are needed for the body to function properly on its surface. These identifying surface proteins let the immune system know that they are cells that belong to the body.5 They can be compared to the uniforms a football team wears. In the same way the uniform helps the quarterback know who is on his team, the proteins let the immune system know which cells belong in the body.

Healthy cells display normal proteins on their surface. The immune system has learned to ignore normal proteins. If the surface proteins are abnormal, such as when a virus infects cells or when cells become cancerous, they can be recognized by the immune system. Proteins recognized by the immune system are called antigensA protein on the surface of a cell that causes the body to make a specific immune response.5

If a foreignSomething that comes from outside the body substance—such as a bacteria, virus, or tumorAn abnormal mass of tissue that results when cells divide more than they should or do not die when they should cell—is recognized, the immune system kicks in to try to deal with it. It is the “non-self” antigens on the surface of these cells (the other team’s uniform) that the immune system identifies as abnormal. The immune system is great at recognizing bacteria and virus cells, because they "look" very different from healthy cells. On the other hand, tumor cells started as healthy cells and can look a lot like healthy cells. As a result, the body may have a harder time recognizing tumor cells as foreign.5

In other instances, the immune system may recognize a tumor antigen but may be unable to mount a response strong enough to destroy the tumor. As cancers grow they can evolve ways to escape from attack by the immune system. For these reasons, many people with healthy immune systems still develop cancer and cancer still progresses. In many people with cancer, the cancer cells co-exist with immune cells capable of killing the cancer, but the cancer cells hold the immune cells back from working the way they should.5

What is the role of the immune system in cancer?

The following video explains how the immune system fights cancer.

The immune system has two responses that work together to detect and destroy cancer cells: innate immune responseImmune response to a pathogen that involves the pre-existing defenses of the body and adaptive immune response.

NK cell releasing toxinThe innate immune response is the first line of defense. The innate immune system’s normal function is to protect the body from initial invasion by bacteria and viruses, such as when bacteria invade broken skin or viruses land in the throat. The system includes natural killer (NK) cells, a type of lymphocyte that patrols the body and is on constant alert, looking for foreign invaders and abnormal cells. If cells from the innate immune system recognize a cancer cell as abnormal, they can attach to it and immediately release toxic chemicals that kill it. NK cells and other cells of the innate immune system do not need to recognize a specific abnormality on a cell to be able to do their job.6

If the bacteria, viruses, or cancer cells evade the innate response, then the adaptive immune response becomes active. The adaptive immune response recognizes specific abnormalities on cancer cells that make them different from the cells that are naturally found in the body. Though it is more effective than the innate immune response, the adaptive immune response takes longer to become activated. The cells of the adaptive immune response include the other two types of lymphocytes: B cells and T cells.6

B cell releasing antibodyB cells are like the body's military intelligence system, seeking out their targets and sending defenses to lock onto them. They react to “non-self” antigens by making proteins called antibodiesA protein made by B cells in response to an antigen, the purpose of which is to help destroy the antigen. Antibodies are proteins that can attach to foreign and abnormal cells and let the body know that they are dangerous. Antibodies can kill cancer cells in several ways, including binding natural killer (NK) cells to the cancer. B cells can create "memory"—they start to make antibodies quickly when they recognize a past antigen.2,5

T cells are the major cells the body uses to recognize and destroy abnormal cells. Once a foreign antigen or abnormal cancer protein has been recognized by T cells, the T cells rapidly increase in number. An army of T cells can be formed; these T cells are specifically designed to attack and kill cells that have foreign antigens.6

T cell attacking cancer cellThe T cells are like soldiers, destroying the invaders. They are responsible for coordinating the entire immune responseThe activity of the immune system against foreign substances (antigens) and destroying infected cells and cancer cells. T cells can also create memory after an initial response to an antigen. This memory is meant to ensure that the attack on cancer cells can keep going in the long term, for months or longer. The memory also allows for future responses against the specific abnormal antigen on cancer cells, if and when the cancer comes back.2,4,5

If the immune system recognizes the lung tumor cells and can destroy them, why are lung tumors able to grow? Research has shown that some tumors enable their own growth by turning off the immune response. Immune responses beyond what is normal or necessary can be toxic, so T cells have many normal methods to dampen themselves down and essentially turn themselves off. This may allow the growth and development of tumor cells despite the presence of T cells with the potential to kill cancer cells. Researchers are working to understand exactly how this happens and how best to turn the cancer-killing T cells back on.5,7

What is immunotherapy?

Biological therapies use substances made from living organisms to treat disease. These substances either already exist in nature or are manmade in a laboratory.5

Immunotherapy is considered a type of biological therapyA type of treatment that uses substances made from living organisms to treat disease. It aims to enhance the body’s immune response and stop lung cancers from escaping from the immune system. Immunotherapy is a treatment that strengthens the natural ability of the patient’s immune system to fight cancer. Instead of targeting the person’s cancer cells directly, immunotherapy trains a person’s natural immune system to selectively target and kill cancer cells, either by suppressing factors that block the immune system or by enabling the immune system to mount or maintain a response.5,8

Of the three main types of immunotherapy drugs that are currently being studied in people with lung cancer—immune checkpoint inhibitors, therapeutic cancer vaccines, and adoptive T cell transfer—immune checkpoint inhibitors have made the most progress at this time. All of the currently approved  FDA-approved immunotherapy drugs for lung cancer belong to this type.

Immune checkpoint inhibitors

►What is an immune checkpoint?

Many lung cancers co-exist with T cells capable of killing the cancer cells. However, the immune system has many normal mechanisms for dampening itself down. The immune system has fail-safe mechanisms that are designed to suppress the immune response at appropriate times in order to minimize damage to healthy tissue. These mechanisms are called immune checkpoint pathways. They are essentially the brakes on the immune system.

The PD1/PD-L1 proteins are an example of an immune checkpoint pathway. The PD-1 protein is found on the T cells and acts as the brakes that keep the T cells from attacking healthy cells. PD-L1 is a protein on healthy cells, but it can also be found on cancer cells. When the PD-1 on T cells attaches to the PD-L1 on other cells, the T cells know not to attack those other cells. Cancer cells can thus evade detection by T cells, with the result that the T cells's immune response is lessened at a time when it should be active. This allows cancer cells to thrive.8

How do immune checkpoint inhibitors work?

The immune checkpoint inhibitors work by targeting and blocking the fail-safe mechanisms of the immune system. Their goal is to block the immune system from limiting itself, so that the original anti-cancer response works better.7, 8, 9

What immune checkpoint inhibitors are FDA-approved?

There are currently four FDA-approved immune checkpoint inhibitors for treating patients with lung cancer. Three of them, nivolumab (Opdivo®), pembrolizumab (Keytruda®), and atezolizumab (Tecentriq®), treat both NSCLC and small cell lung cancer patients. Durvalumab (Imfinzi®) is only approved for patients with NSCLC. Specifically:

  • Durvalumab (Imfinzi®):10Approved for patients with stage III NSCLC whose tumors are not able to be surgically removed and whose cancer has not progressed after treatment with concurrent platinum-based chemotherapy and radiation therapy. (The purpose of this treatment is to reduce the risk of the lung cancer progressing.)
  • ​Nivolumab (Opdivo®):11 Approved for patients in the following situations:
    • For patients with metastatic NSCLC whose lung cancer has progressed on or after platinum-based chemotherapy. Patients with EGFR or ALK mutations should have disease progression on FDA-approved therapy for these mutations before receiving this drug
    • For patients with metastatic small cell lung cancer whose disease has progressed after platinum-based chemotherapy and at least one other line of therapy.
  • Pembrolizumab (Keytruda®):12 Approved for patients with NSCLC in the following situations:
    • As a single agent for first-line treatment for patients with EITHER stage III NSCLC who are not candidates for surgery or definitive chemoradiation OR metastatic NSCLC, and whose tumors express PD-L1 and have a Tumor Proportion Score (TPS) greater than or equal to 1%, as determined by an FDA-approved test, with no EGFR or ALK mutations. TPS is the percentage of cancer cells that produce the PD-L1 proteins. The lung cancer tissue is stained with special dyes that mark PD-L1 positive tumor cells. A pathologist counts the number of cells that stain positive to determine the TPS.
    • As a single agent for patients with metastatic NSCLC whose tumor expresses PD-L1 (TPS greater than or equal to 1%), as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK mutations should have disease progression on FDA-approved therapy for these mutations before receiving this drug.
    • As first-line treatment of patients with metastatic non-squamous NSCLC in combination with the chemotherapy drugs pemetrexed (Alimta®) and carboplatin (Paraplatin®), with no EGFR or ALK mutations
    • In combination with the chemotherapy drugs carboplatin (Paraplatin®) and either paclitaxel (Alimta®) or paclitaxel protein-bound (Abraxane®), for first-line treatment of patients with metastatic squamous NSCLC.
    • For patients with  metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.
  • Atezolizumab (Tecentriq®):13
    • Approved for first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK mutations, in combination with bevacizumab (Avastin®), paclitaxel (Taxol® or Onxol®), and carboplatin (Paraplatin®)
    • Approved for adult patients with metastatic NSCLC whose lung cancer has progressed during or after being treated with platinum-containing chemotherapy. Patients with EGFR or ALK mutations should have disease progression on FDA-approved therapy for these mutations before receiving this drug.

Patients with pre-existing autoimmune conditions should discuss these conditions with their doctors. Those who do go on an immune checkpoint inhibitor should be monitored very carefully for autoimmune side effects.14

How are immune checkpoint inhibitors administered?

FDA-approved immune checkpoint inhibitors are given intravenouslyInto or within a vein. Infusion time and schedules vary, depending on the drug.

  • Durvalumab (Imfinzi®) is given intravenously over 60 minutes in a dosage of 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity10
  • Nivolumab (Opdivo®) is given intravenously over 30 minutes in a dosage of either 240 mg every 2 weeks or 480 mg every 4 weeks for non-small cell patients until disease progression or unacceptable toxicity 11
  • Nivolumab (Opdivo®) is given intravenously over 30 minutes in a dosage of 240 mg every 2 weeks for small cell patients until disease progression or unacceptable toxicity  11
  • Pembrolizumab (Keytruda®) is given intravenously over 30 minutes in a dosage of 200 mg every 3 weeks for non-small cell patients until disease progresion, unacceptable toxicity, or up to 24 months in patients with disease progression. When given in combination with chemotherapy, pembrolizumab (Keytruda®) is administered first when given on the same day. .12
  • Pembrolizumab (Keytruda®) is given intravenously over 30 minutes in a dosage of 200 mg every 3 weeks for small cell patients until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.12
  • Atezolizumab (Tecentriq®) is given over 60 minutes for the first infusion. If the first infusion is tolerated, the remaining infusions may be delivered for 30 minutes.
    • As a single agent, it is given until disease progression or unacceptable toxicity in these dosages:
      • 1,680 mg every 4 weeks
      • 1,200 mg every 3 weeks or
      • 840 mg every 2 weeks or
      • In combination with bevacizumab (Avastin®), paclitaxel (Alimta®), and carboplatin (Paraplatin®), the dosage is 1,200 mg every 3 weeks until disease progression or unacceptable toxicity. When given on the same day, it should be given first. Following 4-6 cycles of paclitaxel (Alimta®) and carboplatin (Paraplatin®), and if bevacizumab is discontinued, the dosage, to be continued until disease progression or unacceptable toxicity, is:
        • 840 mg every 2 weeks or
        • 1,200 mg every 3 weeks or
        • 1,680 every 4 weeks13

How well do immune checkpoint inhibitors work?

Patients whose tumors have high levels of PD-L1 expression are more likely to respond to PD-1/PD-L1 therapies. However, even those with tumors that do not express PD-L1 may respond to these treatments.

Not all advanced non-small cell lung cancer patients who are administered immunotherapy respond to it. However, in certain circumstances, the response rate can be as high as 40%: the response rate to pembrolizumab (Keytruda®) as monotherapy for first-line treatment of tumors with high PD-L1 expression has been shown to be about 40%.15

The response may continue after treatment is stopped. Some of the responses to date have been long-term.16

Researchers are studying how to increase the number of people who respond to this treatment. In clinical trialsA type of research study that tests how well new medical approaches work in people, they are combining treatments, boosting the immune system, and using other strategies.

How long does it take to see results from therapy with immune checkpoint inhibitors?

Of those patients in clinical trials with immune checkpoint inhibitors who have responded, most respond within the first two months.17

In a very small subset of patients (1%-3%), the tumor on a CT scanA procedure that uses a computer linked to an X-ray machine to make a series of detailed pictures of areas inside the body may seem to get worse at first and then get better, or there may seem to be new areas of tumor. One theory about this is that the tumors get larger because a large number of the patient’s T cells move into the tumor to attack and kill the cancer cells. For the great majority of patients whose scans show worsening of disease after at least a couple of months on immunotherapy, the scans are accurately showing that the immunotherapy is not working.17

In cases like this, the best course of action will likely be based on a number of factors. If the patient’s scan looks worse but the person is feeling fine, the doctor and patient may decide together to do another course of immunotherapy. If the scan looks worse and the person is feeling worse, then it may not make sense to continue with this type of therapy. In this case, the patient may need another kind of therapy to control the symptoms.

Managing side effects of immune checkpoint inhibitors?

Side effects from lung cancer treatment are common, but just because a side effect is common does not mean that a patient will experience it. Before beginning treatment, the patient should discuss with the healthcare team what side effects might be expected and how to prevent or ease them. The patient should speak with the healthcare team if and when new side effects begin, as treating them early on is often more effective than trying to treat them once they have already become severe; in addition, it needs to be determined whether the side effects are related to treatment or not. What side effects are being experienced may impact future treatment plans. Although most side effects go away when treatment is over, some can last a long time.

The management techniques outlined below for common side effects of immunotheapy are not all-inclusive; your healthcare team will provide you with a more extensive set of possible side effects and what can be done for them.11,12,13,18,19

  • Fatigue: Fatigue can be treated by relieving conditions related to it, such as anemia or depression. If a patient is depressed, for example, antidepressant medications may help.
  • Pneumonitis and other inflammatory conditions: Symptoms of pneumonitis, such as cough, difficulty breathing, and shortness of breath, can develop up to months after therapy and may require anti-inflammatory medication. Pneumonitis and some of the other side effects seen with immune checkpoint inhibitors are related to “turning on” the immune system, which then may also attack some healthy cells and cause inflammation. Other examples of this include:
    • Arthritis
    • Colitis
    • Hepatitis
    • Inflammation of the endocrine glands, like the thyroid
    • Nephritis and renal dysfunction

Inflammation of the thyroid can cause either high or low thyroid hormone levels (hyperthyroidism or hypothyroidism, respectively). Inflammation of the liver can also occur, and so liver function tests may be run periodically to check for that. About half of patients develop some inflammation-related side effects. These are usually easy to manage, but sometimes patients may need to take additional medications, including corticosteroids or thyroid hormone replacement.

  • Upper respiratory tract infection: Signs and symptoms may include fever, cough, frequent urination, pain when urinating, and flu-like symptoms. Antibiotics may be used for treatment.
  • Rash: Depending on the severity of the rash, symptoms can be managed with cream corticosteroids, oral corticosteroids, cream antibiotics, or oral antibiotics.
  • Rare autoimmune side effects are possible as well and may occur weeks or months after the therapy starts, including but not limited to a risk of hypothyroidism, cardiac or kidney damage, or changes in hormone secretion. A patient should tell the healthcare team about any new or unusual symptoms if they develop after starting immunotherapy.

Some patients experience side effects that are severe enough that they need to stop taking the immunotheapy treatment. In general, based on what has been seen to date, these kinds of treatments are well tolerated by most patients.

What new immune checkpoint inhibitors are currently being tested?

A number of immune checkpoint inhibitor drugs not yet approved for lung cancer are currently being tested, including:20

Generic Name Brand Name Types of lung cancer
being studied

Ipilimumab

Yervoy®

NSCLC, SCLC

Avelumab

Bavencio®

NSCLC, SCLC

Tremelimumab

To be determined

NSCLC, SCLC

PDR001 (spartalizumab)

To be determined

NSCLC, SCLC

REGN2810 (cemiplimab)

Libtayo®

NSCLC

     

Learn more about clinical trials here.

Therapeutic cancer vaccines

What is a therapeutic cancer vaccine?

When most people think of a vaccine, they think of a traditional vaccine given to prevent an infectious disease such as measles or polio. In addition to the traditional vaccines, there are two types of cancer vaccines. A preventive cancer vaccine is given to prevent cancer from developing in healthy people. For example, the hepatitis B vaccine is given to children to protect against a hepatitis B viral infection, which can lead to liver cancer. In contrast, a therapeutic cancer vaccine is given to treat an existing cancer by causing a stronger and faster response from the immune system. Most commonly, they are used in patients in remission in an attempt to prevent likely relapseThe return of a disease or the signs and symptoms of a disease after a period of improvement or the cancer from returning.5,21,22 Therapeutic cancer vaccines are being studied in lung cancer patients. There are currently no FDA-approved therapeutic cancer vaccines for patients with lung cancer.

How do therapeutic cancer vaccines work?

Cancer vaccineA therapeutic cancer vaccine is made from a patient’s own tumor cells or from substances taken from the tumor cells. They are designed to work by activating the cells of the immune system to recognize and act against the specific antigen on the tumor cell. Because the immune system has special cells for memory, the hope is that the vaccines will also help keep the lung cancer from coming back.5,21,22

Adoptive T cell transfer

Adoptive T cell transferWhat is adoptive T cell transfer?

The goal of adoptive T cell transfer is to improve the ability of a person’s own T cellsA type of white blood cell to fight cancer. For lung cancer, this approach is still being developed. There are currently no FDA-approved adoptive T cell transfer treatments for patients with lung cancer.

In adoptive T cell transfer, a sample of T cells is removed from the patient and then genetically changed in order to make the T cells more active against specific cancer cells. Scientists can change what is on the surface of the T cells. For example, they can add a receptor to the surface of the T cell that will target a specific antigen on a cancer cell. The receptors work like very specific Velcro that allows T cells to stick to cancer cells and kill the cells. The T cells are then returned to the patient, and the altered T cells quickly home in on their targets.5

How does adoptive T cell transfer work?

Typically during an immune response, T cells multiply. After the initial response, most of the newly made T cells are eliminated. This keeps the total T cell number in the body at a normal level. The normal level of T cells is usually not high enough to sustain a response strong enough to effectively fight cancer.5

However, there is evidence that T cells have the ability to multiply in abundance when given to someone whose immune system has been weakened. Therefore, in an adoptive T cell transfer, patients are given chemotherapy prior to the adoptive T cell transfer in order to suppress their immune system. Once the chemotherapy is completed and the immune system is weakened, billions of modified T cells are reintroduced into the patient. The goal of the T cell transfer is to enable the immune system to attack the tumors in a large number that is otherwise impossible and in a way that it is incapable of doing on its own.23

 how are t cells removed from and returned to a patient?

The three approaches to performing adoptive T cell transfer are:23,24

  • Taking T cells from the body and changing them with special receptors, called chimeric antigen receptors (CARs). CARs recognize specific proteins found on the surface of cancer cells. The CAR T cells then bind to the cancer cells that have those proteins and destroy them
  • Collecting a sample from the actual tumor and multiplying the T cells in a laboratory
  • Taking T cells from the bloodstream through a procedure called leukapheresisRemoval of the blood to collect specific blood cells; the remaining blood is returned to the body and genetically altering them to attack cancer cells that have specific antigensA protein on the surface of a cell that causes the body to make a specific immune response

After any of these, the T cells are then returned to the patient through an infusionA method of putting fluids, including drugs, into the bloodstream.23

Finding a clinical trial that might be right for you

Clinical research is ongoing to evaluate the role of immunotherapy approaches, alone or in combination with other treatments.20

If you are considering participating in a clinical trial, start by asking your healthcare team whether there is one for which you might qualify in your area. In addition, here are several resources to help you find one that may be a good match for you:

LUNGevity Clinical Trial Finder: https://clinicaltrials.lungevity.org/
EmergingMed: 877-769-4834, https://app.emergingmed.com/lcctal/home
National Cancer Institute website: www.cancer.gov/clinicaltrials/search
My Cancer Genome: www.mycancergenome.org/
Lung Cancer Mutation Consortium (LCMC): www.golcmc.com/
Lung Cancer Master Protocol (Lung-MAP): www.lung-map.or

Learn more about clinical trials here.

Questions to ask about clinical trials

Print this list

  • What are the benefits and risks of participating in an immunotherapy clinical trial?
  • How will I be monitored while participating in a clinical trial?
  • What are my responsibilities during the clinical trial?
  • Are there any costs associated with my participation in a clinical trial?
  • Where can I learn more about clinical trials?
  • Who can I speak with if I have questions during the clinical trial?
  • What happens if I decide I do not want to participate in the clinical trial at some point?

Updated July 22, 2019

References

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  3. Zimmerman, A. Lymphatic System: Facts, Functions, & Diseases. LiveScience.com website. https://www.livescience.com/26983-lymphatic-system.html. Posted February 20, 2018. Accessed July 17, 2019.
  4. Lymphocyte. Encyclopaedia Brittanica website. https://www.britannica.com/science/lymphocyte. Accessed July 17, 2019.
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  7. Pardoll D. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12:252-264. doi:10.1.1038/nrc3239. http://www.nature.com/nrc/journal/v12/n4/full/nrc3239.html. Accessed July 18, 2019.
  8. What are PD-1 and PD-L1? Keytruda website. https://www.keytruda.com/keyruda-faq-what-are-pd1-and-pdl1/
  9. Understanding Immunotherapy. Cancer.Net website. https://www.cancer.net/navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/understanding-immunotherapy. Approved January 2019. Accessed July 18, 2019.
  10.  Imfinzi®) (durvalumab) injection [package insert]. Astra-Zeneca Pharmaceuticals LP.  Wilmington, DE; February 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761069s002lbl.pdf. Revised February 2018. Accessed July 18, 2019.
  11. Opdivo® (nivolumab) injection [package insert]. Bristol-Myers Squibb Company. Princeton, NJ; 2015. http://packageinserts.bms.com/pi/pi_opdivo.pdf. Revised May 2019. Accessed July 18, 2019.
  12. Keytruda® (pembrolizumab) injection [package insert]. Merck & Co., Inc. Whitehouse Station, NJ; 2014. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Revised June 2019. Accessed July 18, 2019.
  13. Tecentriq® (atezolizumab) injection [package insert]. Genentech, Inc., South San Francisco, CA; 2016. https://www.gene.com/download/pdf/tecentriq_prescribing.pdf. Revised May 2019. Accessed Juy 18, 2019.
  14. Johnson, DB, Bckermann, KE, Wang, DY. Immune Checkpoint Inhibitor Therapy  in Patients with Autoimmune Disease. cancernetwork.com website. https://www.cancernetwork.com/oncology-journal/immune-checkpoint-inhibitor-therapy-patients-autoimmune-disease/page/0/1. Posted April 15, 2019. Accessed July 18, 2019.
  15. Correspondence with Edward B. Garon, MD, UCLA, July 21, 2019.
  16. Nadal E, Massuti B, et al. Immunotherap with checkpoint inhbitors in non-small cell lung cancer: insights from long-term survivors. Cancer Immunology, Immunotherapy; (2019) 68:341-352. https://www.ncbi.nlm.nih.gov/pubmed30725206. Publis`hed February 6, 2019. Accessed July 18, 2019.
  17. Garon, E. Time to Response to Immunotherapy and the Concept of Pseudoprogression. Global Resource for Advancing Cancer Education website. http://cancergrace.org/lung/files/2015/12/GCVL-LU-Immunotherapy_Response_Time_and_Pseudoprogression-Concept.pdf. Posted December 15, 2015. Accessed July 19, 2019.
  18. Fatigue. Cancer>net website. https://www.cancer.net/coping-with-cancer/physical-emotional-and-social-effects-cancer/managing-physical-side-effects/fatigue. Approved August 2018. Accessed July 22, 2019.
  19. Fatigue (PDQ®)—Patient Version. National Cancer Institute website. https://www.cancer.gov/about-cancer/treatment/side-effects/fatigue/fatigue-pdq. Approved May 15, 2019. Accessed July 22, 2019.
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  21. Cancer Vaccines. American Cancer Society website. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/cancer-vaccines.html. Reviewed August 8, 2016. Accessed July 19, 2019..
  22. What are Cancer Vaccines? Cancer.Net website. https://www.cancer.net/navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/what-are-cancer-vaccines. Approved June 2018. Accessed July 19, 2019.
  23. CAR T-Cell Therapy: Engineering Patients' Immune Cells to Treat Their Cancers. National Cancer Institute website. http://www.cancer.gov/about-cancer/treatment/research/car-t-cells#side-     effects. Updated December 14, 2017. Accessed July 19, 2019.
  24. Balch CM, Kaufman HL (eds). Understanding Cancer Immunotherapy, Fifth Edition. Overland Park, KS. Society for Immunotherapy of Cancer (SITC) and PRP Patient Resource Publishing, 2018. . https://www.sitcancer.org/HigherLogic/System/DownloadDocumentFile.ashx?DocumentFileKey=567abb47-c7f1-2fa3-b008-053953020940&forceDialog=0#page=1&zoom=.... Accessed July 19, 2019.

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