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New Anticancer Immunotherapies: Implications for Physical Therapy

Tabares, Tyler SPT1; Unmack, Todd SPT2; Calys, Mary DPT3; Stehno-Bittel, Lisa PhD4

Author Information
doi: 10.1097/01.REO.0000000000000144
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Worldwide, there were nearly 9 million deaths due to cancer in 2016, making it one of the leading causes of death globally.1 In the United States, cancer is the second leading cause of death. According to the Centers for Disease Control and Prevention, in 2015 approximately 1.6 million new cases of cancer were diagnosed in the United States and more than 500 00 of those died of cancer.2 That means approximately 20% of all deaths in the United States were related to cancer. Yet, the chances of survival after a cancer diagnosis have improved dramatically over the years. From 1990 to 2014, the death rate associated with cancer dropped by 25%.3 This equates to more than 2 million fewer cancer deaths today compared with 20 years ago and is likely due to better treatments and earlier diagnoses. However, cancer survival is associated with an increased risk for other diseases and disabilities. Cancer survivors have a mean annual medical expenditure that is more than twice that of their noncancer counterparts.4 One study found that patients with cancer were 2.5 times more likely to be readmitted into their primary hospital because of complications from infection than patients without cancer.5 Early rehabilitation may positively impact the financial burden of cancer by reducing hospital length of stay and frequency of readmissions due to compromise of the immune system and loss of function.

Cancer is a broad term for several different types of diseases based on genetic, environmental, and behavior factors. The common tie is that they can all be classified as uncontrolled cell division. Because of the varied nature of cancer, there are numerous cancer treatments. New treatments are targeted, depending on which cancer is being treated. The current primary course for treatment of cancer is standard chemotherapy, which has been described as a shotgun approach. The goal of chemotherapy is to kill off the cancer cells using a low-specificity approach that causes death to any rapidly dividing cell. Thus, any healthy tissue that normally undergoes rapid cell division, such as hair follicles and the gastrointestinal tract, suffers cell death due to the chemotherapy.

Targeted cancer treatments are designed to bind to specific proteins that are more frequently found on cancer cells rather than noncancerous cells. One category of targeted cancer therapy that has been gaining attention in the medical world since 2013 is immunotherapy. Immunotherapies are designed with the patient's own body in the foreground. By using the patient's immune system, cancers that were once terminal now have hope for remission and perhaps a permanent cure. The earliest immunotherapies were antibodies designed to bind to cancer cells to block their growth. However, more recent immunotherapies are designed to block targeted signaling molecules on the cancer cell or on the immune cells. These therapies are called checkpoint inhibitors or chimeric antigen receptor T cells (CAR-Ts); in this review, we investigate both of these treatment options, focusing on the implications for the physical therapist.


Mechanism of Action

The first natural defense against cancer is our immune system. A healthy cell in the body has various types of receptors attached to it, allowing it to battle cancer. One defense is called Programmed Cell Death Protein 1 or PD-1. PD-1s are specific receptors that are located on the surface of the immune system's T cells and bind to specific programmed death ligands (PD-L1 or PD-L2), proteins that are found on the surface of the cancer cells (Figure 1A). The interaction of the PD-1 receptor with the PD-L1 ligand results in a suppression of the immune system.6 T cells, a type of lymphocyte, are the primary cells responsible for driving our immune response against foreign substances. Under normal conditions, if a foreign substance such as a virus enters the body, T cells will attack the substance and drive it out. Cancer cells are considered foreign to the body and normally the T cells will destroy the cancer cells. However, if the ligand binds to the PD-1 receptor, it will send an inhibitory signal to the T cell to suppress the immune system.

Fig. 1.
Fig. 1.:
Illustration of the mechanism of action of the checkpoint inhibitor drugs. (A) Cancer cells expressing the PD-L1 surface protein bind to the PD-1 receptor on the immune T cell. This binding blocks the ability of the T cell to attack the cancer cell so that the cancer cells can replicate unchecked. (B) The drug, pembrolizumab, binds to the PD-1 receptor first, inhibiting its ability to bind to the PD-L1 receptor. In this manner, the T cell remains active and recognizes the cancer cell as foreign, subsequently attacking it. (C) Atezolizumab works by binding to the cancer cell's PD-L1 receptor, resulting in the same ability to maintain active T cells.

The reason the body contains a way to suppress its own immune system is not inherently obvious. Research has led to the understanding that the immunosuppressing PD-1 pathway has a role in decreasing the risk of acquiring autoimmune diseases by killing off specific T cells in the lymph nodes.7 Although the process helps prevent autoimmune diseases from spreading throughout the body, it can be hijacked by cancer cells to prevent the healthy immune cells from identifying and battling cancer.7 The cancer cells have evolved to express high levels of PD-L1 on their surfaces and will therefore interact with the PD-1 receptor on healthy T cells and other immune system cells (Figure 1A).8 With the PD-L1 bound to PD-1, cancer cells are able to replicate without being destroyed by the T cells.

In recent years, scientists in multiple pharmaceutical companies have been working on ways to inhibit the interaction between cancer cells and PD-1 receptors. One of the first inhibitors created and predominately used is pembrolizumab. In 2013, the drug was used in clinical trials for advanced melanoma where it was compared with a standard chemotherapy drug, ipilimumab. It was determined that pembrolizumab provided patients with a higher rate of survival and a lower rate of toxicity versus ipilimumab.9 In September 2014, the Food and Drug Administration (FDA) approved pembrolizumab to be manufactured under the FDA Fast Track Development Program, but it came with the stipulation that it could be administered only if the patient had failed prior treatment with ipilimumab.10 In 2015, the drug was approved for metastatic non-small cell lung cancer treatments in patients who had PD-L1-expressing tumors that had not responded to previous chemotherapeutic treatments. Finally, in 2017, pembrolizumab was approved by the FDA for treatments of recurrent or metastatic head and neck squamous cell carcinomas and for any unresectable or metastasized solid tumors or tumors that had progressed following treatment by chemotherapy.11,12 The FDA approval signaled the first instance of an immunotherapy drug approval with no limitation of the type of cancer.13 The list of current checkpoint inhibitors is provided in Table 1 with the generic and brand names. The diagnoses currently approved for treatment (or in clinical trials) are also provided in Table 1, illustrating a wide variety of target cancers.

TABLE 1 - Immunotherapy Categories
Categories Generic Names Brand Names Applications
Checkpoint inhibitors Pembrolizumab Keytruda Melanoma, metastatic solid tumors
Nivolumab Opdivo Melanoma, non-small cell lung cancer, renal cell carcinoma
Atezolizumab Tecentriq Lung cancer
Avelumab Bevencio Merkel cell carcinoma
Durmalumab Imfinzi Metastatic urothelial carcinoma
CAR-Ts Tisagenlecleucel Kymriah Acute lymphoblastic leukemia
Axicabtagene ciloleucel Yescarta Non-Hodgkin lymphoma
Abbreviation: CAR-T, chimeric antigen receptor T cell.

Pembrolizumab is an antibody that works by binding to the immune system's T cells, which have PD-1 receptors on the surface. The drug binding creates a blockade that does not allow the cancer cell to bind to the T cell (Figure 1B).6 With the cancer cells unable to bind to the T cell's PD-1 receptors, T cells and helper cells remain active and able to identify the foreign cancer cells and eradicate them. Thus, checkpoint inhibitors do not directly kill cancer cells like traditional chemotherapy. Instead, they allow the person's own immune system to identify and attack the cancer cells.

Different targets can block the T-cell/cancer cell interaction. Some drugs, such as atezolizumab bind to the PD-L1 receptor on the cancer cell, rather than binding to the T cells. Figure 1C illustrates the difference. The end result is the same; the cancer cells cannot hide from the cells of the immune system. By using different targets, it is possible that combination therapies may someday be applied. Alternatively, if a patient becomes resistant to a drug that binds to PD-1, subsequent treatment with a PD-L1 binding drug may offer successful treatment.

The Patient Experience With PD-1 Inhibitors

Pembrolizumab (Keytruda) was in the forefront of news outlets when it was announced that former President Jimmy Carter was being treated with the new immunotherapy following surgery and radiation therapy to treat melanoma that had metastasized to his liver and brain. He received 4 rounds of pembrolizumab along with radiation therapy when he announced that he was cancer free.14 At the time of President Carter's treatment, only about 20% of patients receiving pembrolizumab had a positive response and another 20% had side effects that were so severe that they prohibited continued treatment with the drug. However, newer developments and greater experience at administering the drug have reduced the side effects and increased the percentage of patients going into remission. Those developments include a better understanding of the minimal required dose to achieve a successful outcome and the identification of biomarkers that predict patients at risk for severe adverse events.15

The mechanism of action for checkpoint inhibitors leading to activation of the immune system can cause a variety of side effects. Common side effects include fatigue (24% of those taking the drug), rash (19%), itchiness (17%), diarrhea (12%), nausea (11%), and joint pain (10%).15 There are also side effects that occur in a smaller portion of patients taking the medicine. Between 1% and 10% of patients will complain of anemia, fever, arthritis, weakness, headache, vitiligo (loss of skin pigmentation), coughing, dizziness, shortness of breath, distortion of taste, high blood pressure, various kinds of acne, dry eyes, dry skin, eczema, abdominal pain, muscle pain, and flu-like symptoms.15,16

However, cases of more severe adverse reactions related to toxicity level are not uncommon. Side effects that include inflammation of the pituitary gland, thyroid, colon, liver, kidney, and/or pancreas and inflammation of the pancreas resulting in type 1 diabetes and diabetic ketoacidosis have been reported.15,17 In one study of 254 patients, 85% developed immune-related adverse events and 35% required corticosteroid therapy.18 If the inflammation is minor, the checkpoint inhibitor therapy will likely be continued during the corticosteroid administration. However, if the symptoms become more severe, the cancer treatment is discontinued and corticosteroids are administered. In cases where the symptoms do not resolve with intravenous corticosteroids, permanent discontinuation of the immune checkpoint inhibitor is suggested.15 Conversely, if the adverse symptoms resolve with steroid treatment, then the immunotherapy is typically reinitiated. Although research on this topic is minimal, the majority of patients will not develop inflammatory adverse events with the reestablishment of the immunotherapy.19

Since these new classes of anticancer drugs act through the immune system, there have been concerns for people with preexisting autoimmune disorders. During the clinical trial phase of drug development for the checkpoint inhibitors, patients with preexisting autoimmune disorders were excluded from the studies. Only after these drugs were approved were such patients able to gain access to the drugs. In a multisite study of 119 patients treated with anti-PD-1, nearly half had some type of autoimmune disorder, including Graves disease, hypo- or hyperthyroidism, psoriasis, multiple sclerosis, Crohn disease, and rheumatoid arthritis.20 Flare-ups of the autoimmunity during checkpoint inhibitor treatment occurred in 38% of the patients, and most were mild. The flare-ups in autoimmune symptoms were most common for people with rheumatological conditions. For 18% of the patients with autoimmune disorders, the checkpoint inhibitor treatment had to be temporarily stopped because of the severity of the flare-ups. The good news was that 33% of the patients with autoimmune disease while taking the inhibitors responded to the drug with a decrease in cancer burden, which was similar to patients without autoimmune disorders. The response rate was lowest in the patients receiving immunosuppressants prior to initiation of the checkpoint inhibitor. Similar results were identified in a study of another checkpoint inhibitor, ipilimumab, although only 20% of the patients with autoimmune disorders responded to that anticancer therapy.21 The current thinking is that autoimmune disease is an important consideration for checkpoint inhibitors but not a contraindication.22 Other questions concerning the risk of new autoimmune disorders following treatment with checkpoint inhibitors will require years to answer.


CAR-T Mechanism of Action

The second major category of immunotherapy is CAR-T, also known as chimeric antigen receptor T cells. This is a new treatment choice for aggressive cancers, specifically hematological B-cell malignancies such as acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML).23 Like checkpoint inhibitors, chimeric antigen receptors are receptors that allow T cells to identify, target, and bind proteins found on the surface of the cancer cells.24 The difference is that CAR-T therapy includes the infusion of live cells that have been genetically modified rather than antibodies. These medically engineered super cells pose less of a threat for rejection than other types of cell therapies, because the CAR-Ts are constructed from the patient's own T cells.20 However, at the current time, patients must undergo lymphodepletion chemotherapy before they can receive the infusion of CAR-Ts.22 In approving the first CAR-T therapies, the FDA ruled that because of the unknown long-term effects of the treatment, chemotherapy/radiation therapy must be attempted and failed before CAR-T treatment is considered. For this reason, treatment is limited to those patients considered terminal without the CAR-T infusion.

Because of the genetic manipulation to the cells during the expansion process, CAR-T therapy can specifically target cancerous cells in the body. Scientists program the CAR-Ts to bind to specific molecules that are highly expressed on cancer cells. After removal of the T cells from the patient, through a process known as leukapheresis, the T cells are genetically modified to target the cancer cells (Figure 2).25 After a few weeks, there is a multiplication of millions of targeted CAR-Ts that are ready to be injected back into the patient's body. When returned to the patient's body, the new engineered cells directly attack the cancer and promote the release of other cells in the body that target and kill the tumor cells. In addition, CAR-Ts promote the proliferation of more endogenous CAR-Ts to amplify the fight against the cancer.26

Fig. 2.
Fig. 2.:
The sequence involved in the CAR-T therapies. Blood is taken from the patient with cancer and the T cells are isolated. Next, they are genetically manipulated so that they express extra receptors on the surface, making them especially sensitive to the cancer cells. The number of genetically modified T cells is expanded dramatically and then infused back into the same patient.

CAR-T clinical use dates to 1989 when Dr Zelig Eshhar made the discovery that engineered cells could target specific cancerous antigens in the body.27 It is worth noting that there has been an evolution of this treatment, resulting in 4 generations of CAR-Ts. Each CAR-T generation has been modified in hopes of better clinical outcomes, including survival rate and proliferation of the cells in the body to increase the likelihood of destroying tumors. The first-generation CAR-Ts were the most basic type and were found to have a positive effect in the laboratory but had limited effects when administered to patients with cancer. The second-generation CAR-Ts were constructed with surface proteins containing costimulatory domains, resulting in increased T-cell proliferation and cytokine release.27 The second-generation CAR-Ts are currently the most useful clinical treatment option for blood hematology. The third- and fourth-generation CAR-Ts, which contain additional costimulatory domains, are still in the research phase and their efficacy is not clear. Thus, patients and health care providers should appreciate that early failures were due to the novel approach that CAR-Ts use and that success rates will continue to improve with new generations of therapies.

While CAR-Ts can be designed to target several different proteins on the surface of cancer cells, they are typically engineered to bind to a protein called CD19 that is specific for blood cancers, because it is expressed at high levels in B cells involved in lymphomas and leukemias but expressed at very low levels in noncancerous B cells.25 CD19 is expressed on ALL and chronic lymphocytic leukemia (CLL) and multiple myeloma cancer cells.25 In a large successful trial targeting CD19, the cell therapy named tisagenlecleucel, also known as Kymriah, was the first CAR-T therapy approved by the FDA.26 This drug has had a considerable effect on blood cancers, especially in young adults and children.

Unfortunately, there are a significant number of patients who will not respond to the CAR-T therapy. Furthermore, of those who experience a complete response, up to a third will see their disease return within a year. Many of these disease recurrences have been linked to the cancer cells no longer expressing CD19, a phenomenon known as antigen loss, which is a method cancer cells use to disguise themselves from the CAR-T therapy.24,28 Thus, while these new immunotherapies provide treatment options for cancers that previously had extremely poor prognoses, they are not the silver bullet and they certainly do not guarantee a cure.

Researchers are currently working on alternative methods or combination therapies that would overcome the CD19 antigen loss. A second protein found in high levels on cancer cells and being target by scientists is CD22. The resulting drug has undergone early clinical trials. Impressively, it was found that nearly all patients who initially had relapse and then were treated with the CD22 target CAR-Ts underwent complete remission for a year.24

The Patient Experience on CAR-T Therapy

Several clinical trials have been completed testing CAR-Ts, especially for the blood cancers such as ALL and CLL. ALL typically affects children but, however rare, can present in the adult population. ALL usually has a high expression of CD19. For children, the survival rate is much higher than it is in the adult population. Unlike children, adults usually develop ALL when the immune system is severely depressed. Suppression can be caused by anti-rejection medications in the cases of organ or stem cell transplants, as well as other factors that cause reduced immunity.

Early on, a CAR-T clinical trial at the Children's Hospital of Philadelphia reported that of 30 pediatric and adult patients who received treatment, 90% were able to achieve complete remission.29 In a separate, smaller study 88% of the 16 patients examined were able to achieve complete remission.29 For CLL, a multisite clinical trial was completed by members of the National Cancer Institute using a CAR-T therapy. Of the 40 patients treated, approximately 60% were positively affected with partial to complete remission.29

Every clinical study using CAR-T therapy has reported major clinical toxicities associated with the CD19 targets.30 Currently, there are 3 major known side effects that occur with CAR-T treatment, cytokine release syndrome (CRS), B-cell aplasia, and neurological toxicity. Diagnosis of CRS is made by a simple blood draw to measure for levels of interferons and interleukins. One of the interleukins (IL-6) can cause severe systemic inflammation. The main reason CRS occurs is due to the overproduction of T cells.24 T cells naturally release cytokines in the body to help in the fight against foreign material. With such a large increase in T-cell releasing cytokines, the body is at risk for cytokine toxicity. Although CRS is very dangerous, it is a sign that the CAR-Ts are working. CRS can present as flu-like symptoms or in a more severe form vasodilatory shock, capillary leak, and respiratory compromise, all of which require intensive care. A majority of patients receiving CAR-T therapy will experience some level of CRS and, depending on the trial, 27% to 64% will experience severe CRS.24 For most patients, CRS is very controllable with the use of steroids. Tocilizumab has been approved to help combat the levels of cytokines in the body, specifically IL-6.24 As mentioned previously, IL-6 causes inflammation in the body, but with the administration of tocilizumab, the inflammatory process is significantly reduced.

Although CD19 is highly expressed with B-cell malignancies, it is important to note that healthy B cells also express low levels of CD19.28 So, when the CAR-Ts are designed to target T cells with expressions of CD19, healthy B cells may also be destroyed, called B-cell aplasia. In the pharmaceutical industry, this is referred to as an “on-target, off-tumor effect”. B-cell aplasia is so common that it can be used as an indication that the therapy is working. If doctors do not see B-cell aplasia during treatment, they often conclude that the therapy is not working. B-cell aplasia results in long-lasting hypogammaglobulinemia, and intermittent immunoglobulin replacement is required to prevent frequent severe infections in the patients.27

Finally, severe neurological toxicities have been reported in several clinical trials. These include aphasia, delirium, and cerebral edema.31 The underlying cause of the neurological side effects are not known but may be related to interleukin toxicity. The neurological effects appear to be transient with the treatment but are severe and have led some patients to withdraw from the trials. In fact, one pharmaceutical company decided to halt further development of its leading CAR-T therapy after several patients in clinical trials died because of treatment-induced cerebral edema.24 However, in most studies, this has not been a persistent issue, but one to seriously monitor.


Side Effects and Signs of Toxicity

In reviewing the indications, actions, and side effects of 2 completely new categories of cancer drugs, a plethora of information has been presented. Our goal is to summarize for the physical therapist how these facts may affect their care for patients with cancer currently or previously exposed to immunotherapy. The following section reviews common symptoms of side effects and signs of toxicity, organized by physiological system regardless of the category of immunotherapy used. It has been reported that immunotherapy toxicities often initially are undiagnosed or attributed to other causes. Thus, the entire health care team should be knowledgeable and vigilant in monitoring the signs of toxicity for patients on these treatments. We end with a suggestion for therapy interventions and a plea for desperately needed research in this field.

Dermatological issues are the most common side effect with immunotherapies and frequently present within the 4 to 7 weeks of treatment.32 For most patients, this is the earliest sign of an adverse immune reaction and presents as widespread blisters or ulcers.32 Between 10% and 20% of patients will experience pruritus while being treated.32 While the patient may not recognize the connection, the physical therapist should be proactive in documenting any sign of inflammation and contacting the oncology office. Most dermatological side effects can be managed with topical corticosteroids.

Gastrointestinal symptoms such as nausea, abdominal pain, and diarrhea are the second most common set of side effects and should be taken seriously as well because they can be a sign of a more severe toxic reaction.32 With a basis of systemic inflammation, the symptoms usually manifest as diarrhea, affecting approximately 30% of patients, but it is rarely severe.33 Progression to colitis occurs in 4% to 16% of patients, and endoscopies have revealed broad mucosal edema.34 These patients must be counseled on the importance of hydration.

The physical therapist should be aware of the physiological basis of the immunotherapies, namely, the activation of the immune system. Diffuse activation of the immune system leads to CRS with macrophage activation. Affected patients mostly report chills, fever, hypotension, and tachycardia during or shortly after the initial treatment. The systemic inflammation can progress to affect organs including the liver, kidneys, and the musculoskeletal system.35 If treatment is halted because of severe toxicity symptoms, the patient will be administered immunosuppressors for immune-related adverse effects. During those times, the patient's immune system will be depressed, and careful hygiene should be followed during treatment by the therapist and all staff members encountering the patient. The immune suppression protocol is typically long and puts the patient at risk for serious infections. In one study of 740 patients, more than 7% reported serious infections that included bacterial, viral, fungal, and parasitic infections.36

Blood disorders include the common B-cell aplasia and, in rare cases, red blood cell aplasia, neutropenia, and hemolytic anemia.32 B-cell aplasia is actually an expected on-target result of CAR-T therapy and serves as a marker for the activity of the infused CAR-Ts. Persistent B-cell aplasia can increase the risk of infection for the patient. While the aplasia can be treated with γ-globulin replacement therapy, such treatment is expensive and does not always reverse the aplasia.37

Endocrine disorders associated with immunotherapies are not uncommon and occur up to 10% of the time. They tend to be diagnosed 7 to 12 weeks after the initiation of the therapy. Hypothyroidism is the most common endocrine disorder, presenting with fatigue, weakness, cold intolerance, weight gain, cognitive dysfunction, depression, and constipation.32 Although less frequent, hyperthyroidism occurs at a rate of 3% in patients taking checkpoint inhibitors.38 Typical symptoms of hyperthyroidism present as the opposite of hypothyroidism, with heat intolerance, anxiety, weakness, and weight loss with increased appetite. In a smaller percentage of patients, hyperglycemia has been noted with immunotherapy treatment. Thus, therapist should be aware of the signs of hyperglycemia including increased thirst, headaches, blurred vision, and frequent urination.

Neurological symptoms are extremely important to identify early, because cerebral edema has led to death in some of the patients enrolled in CAR-T clinical trials.39 However, the neurological side effects are not limited to the CAR-T therapies. Checkpoint inhibitors have also been shown to induce encephalitis40 and cause headaches, sensory impairment, and dizziness.32,41 Unfortunately, to date, there is nothing that can be done to prevent the neurotoxic effects, namely, because the cellular cause of the toxicity is not understood.42 General neurological signs include headaches, hallucinations, seizures, and aphasia. Severe central nervous system complications can occur without CRS. In one study, those patients experiencing neurotoxicity also had fevers and/or hypotension.43 Thus, therapists should check blood pressure for hypotension prior to each physical therapy (PT) treatment.

Table 2 provides a reference guide for therapists working with patients receiving either checkpoint inhibitor or CAR-T treatments, providing both the mechanism of action and the toxicity signs to be aware of. For neurological toxicity, confusion and aphasia appear as some of the early warning signs.35 If any such symptoms appear or change, the therapy session should be immediately halted and the physician notified. For symptoms associated with toxicity, the patient will be admitted to the hospital immediately.

TABLE 2 - Summary of Immunotherapies and PT Implications
Category Pathology Common Side Effects Signs of Toxicity PT implications
Checkpoint inhibitor Binds to and blocks the PD-1 or PD-L1 receptors. Thus, when cancer is present, it prevents the T cells from binding. The immune system can then target cancerous cells and destroy them. Fatigue
Joint pain
Inflamed organs
Monitor during exercise:
  • Blood glucose

  • Hypotension

  • Fatigue

  • Dehydration

Focus on whole-body resistance training and endurance.
CAR-T Performed by removal of some of the patient's own T cells and infusing them with a retrovirus to allow them to express the chimeric antigen receptor on the cell surface. T cells then multiply in the laboratory and the CAR-Ts are injected back into the patient's body. CRS (flu-like)
B-cell aplasia
Cerebral edema
Monitor for systemic inflammation:
  • High fever

  • Malaise

  • Fatigue

  • Myalgia

  • Nausea

  • Anorexia

  • Tachycardia

  • Renal impairment

  • CNS dysfunction

Focus on endurance training initially, with resistance exercises added per tolerance.
Abbreviations: CAR-T, chimeric antigen receptor T cell; CNS, central nervous system; CRS, cytokine release syndrome; PT, physical therapy.

Toxicities associated with immunotherapies, especially the CAR-T drugs, are serious and can lead to death.44 In fact, in clinical trials, 20 patient deaths were attributed to CAR-T therapies.39 The National Cancer Institute created a scoring system for the general immunotherapy toxicity (Table 3), with classifications based on the severity of the clinical signs.45 Although patients can present initially at levels 3 and 4, it is more common to present with the minor symptoms (level 1), which then intensify and progress to more severe levels with time. Early signs to be concerned about include hypotension and low oxygen saturation levels. Therefore, it is even more important for the physical therapist to include a thorough assessment of vital signs during evaluation and throughout the therapeutic interventions. The response to exercise may be altered during cancer treatment, resulting in a further decrease in blood pressure changes, tachycardia, bradycardia, and/or blood glucose level changes.

TABLE 3 - NCI Scoring System
Grade Symptoms
1 Fever, nausea, fatigue, headache, myalgia, malaise
Symptoms are not life threatening and require only symptomatic treatment
2 Low oxygen, hypotension
Symptoms require and respond to moderate intervention including fluids or low-dose vasopressor
3 Oxygen requirement of >40% or hypotension requiring high-dose or numerous vasopressors
4 Life-threatening symptoms requiring ventilator support or grade 4 organ toxicity
5 Death
Abbreviation: NCI, National Cancer Institute.
Adapted with permission from Lee et al.45

Physical Therapy Interventions

Cancer is a term given to a broad range of pathological disorders that share one common theme, uncontrolled cell division. Thus, PT treatments must be tailored to the individual and take into consideration prior functional status and life roles. Interventions may be directed at improving strength, balance, range of motion, endurance, sensory deficits, cancer-related fatigue, and pain. A 2017 meta-analysis reviewed 113 studies assessing cancer-related fatigue as the primary outcome measure.46 Four of the most commonly recommended treatments of cancer-related fatigue were compared: exercise, psychological, combined exercise and psychological, and pharmaceutical. The study concluded that exercise and psychological interventions were effective in reducing fatigue during and following cancer treatment and were significantly better than pharmaceutical options. The recommendations stated that PT referrals should be prescribed as a first-line treatment of cancer-related fatigue. Another systematic review looked at 100 studies assessing exercise behavior of patients following the diagnosis of any type of cancer.47 Findings showed that patients with cancer who exercised had a lower relative risk of cancer mortality and recurrence and concluded that moderate- to vigorous-intensity aerobic and resistance exercise should be performed during and after cancer treatment to provide a beneficial effect on disease and patient outcomes. Not surprisingly, those studies were conducted on people treated with traditional chemotherapy, surgery, and/or radiation. Research specifically focused on the role of PT for patients receiving immunotherapies has not been published. Thus, a conservative approach is warranted when treating a patient on immunotherapies for the first time (Table 2).

While the list of side effects and the signs of toxicity for the patient on immunotherapy is long and daunting, there are possible advantages to these therapies when compared with traditional cancer care. One key advantage to current regimens for checkpoint inhibitors or CAR-T administration is typically a shorter delivery time and total treatment duration compared with individual chemotherapy treatments. Chemotherapy, radiation therapy, and surgery are traditional cancer treatment options and may require months to years to complete. Individual treatment times can last from a couple of minutes to several hours depending on the specific drug and protocol being implemented, thereby imposing disruption to daily life schedules. Treatments often take a cumulative toll on a patient's functional status and quality of life. In general, with reduced treatment durations for CAR-Ts and checkpoint inhibitors, it is anticipated that patients will be able to progress through a PT regimen with improved tolerance compared with traditional therapies.

When treating patients during traditional chemotherapy, fatigue is one of the most common side effects that physical therapists address. Interestingly, in the literature, fatigue does not appear as a major factor for patients on CAR-Ts. However, we must consider that at this time medical professionals are focused on the side effects and toxicities severe enough to warrant treatment. Thus, fatigue may be present but not addressed. In contrast, the checkpoint inhibitor class of drugs is reported to induce some fatigue associated with inflammation. Furthermore, the FDA limits immunotherapy options to patients who have already failed traditional radiation and chemotherapy. Thus, cancer-related fatigue will continue to be a factor until the immunotherapies become first-line treatments. Without more research in this area, the physical therapist should assume that fatigue may be an issue even for patients on CAR-T therapy and screen for fatigue with every patient with cancer.

Research specific to checkpoint inhibitors and CAR-T treatments and their effect on exercise tolerance is desperately needed in order to develop meaningful PT strategies. While the number of research questions that need to be answered is vast, we propose the following as some of the most urgent points requiring answers:

  • What is the prevalence of fatigue for patients administered either checkpoint inhibitors or CAR-Ts?
  • Is there a correlation between the pretreatment activity level and the immunotherapy response rate?
  • Is there a correlation between activity level during treatment and side effects or toxicity reports?
  • Does aerobic exercise exacerbate or relieve the widespread inflammatory response to the CAR-Ts?
  • Which quality-of-life indicators change for people administered immunotherapies?

Because so little is known about the long-term implications of CAR-T or checkpoint inhibitors and the interaction with rehabilitation services, physical therapists certified in oncology care must take the lead. These patients should be viewed as unique due to the novel mechanism of action of these therapies. Initially, general guidelines are required to direct care as research is conducted. Eventually, specific guidelines with targeted interventions and thresholds for changes in care need to be published.


As medical treatment of cancer progresses toward a more targeted, patient-specific approach, physical therapists must stay abreast of changes and pursue research initiatives to determine best practice. Currently, there are insufficient data to determine the long-term effect of checkpoint inhibitors and CAR-T treatments on rehabilitation outcomes. However, emerging treatments do provide a hopeful outlook for future survivors' access to early PT to decrease any functional decline and restore a high quality of life. It is important that therapists proactively educate themselves on these new and very different classes of drugs as the early versions of both categories are now on the market.


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CAR-T; checkpoint inhibitors; immunotherapy

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