What’s New in Cancer Treatments

Understanding Immunotherapy

Kendra Hoepper DNP, APRN, PNP-BC,

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Learner Objectives At the completion of this presentation the participants will be able to meet the following objectives:

ØEnhance their knowledge on a new cancer treatment called Immunotherapy

ØRecall the mechanism of immunotherapy and how it differs from other cancer treatments.

ØList the different types of immunotherapy and their specific mechanism of action

Ø Differentiate specific system immune related adverse events (irAEs)

Ø Define the importance of using the CTACE grading and reporting system for irAEs

ØIdentify the current impact of immunotherapy on pediatric cancer treatment

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Understanding the Immune SystemØThe immune system is the body’s own natural defense against infection and

disease

ØThe immune system continuously works to keep the body free from infection and disease by identifying cells that are harmful and respond appropriately

Ø Immune cells will try to destroy and kill invaders in a general attack but may not be able to destroy all or prevent these invaders from multiplying

• Can also help to protect against cancer cells but does not always recognize cancer cells as foreign � Cancer cells are not different enough from normal cells� The immune system is not strong enough to destroy the cancer cells� Cancer cells also give off substances that keep the immune system in check

(National Cancer Institute- Fact sheet- Retrieved 1/6/2019)

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What is Immunotherapy

ØImmunotherapy began in 2011, with the first checkpoint inhibitor approved for Melanoma (Ipilimumab)

ØOncology immunotherapy is a type of biological therapy that helps a patient’s immune system fight cancer

ØImmunotherapy uses organisms, such as bacteria or viruses, cells from the human body, antibodies, or vaccines, made in the laboratory to treat cancer

ØThe goal of Immunotherapy is to optimize the immune system to fight the disease while limiting autoimmune toxicity

(Conn, 2018; Barber, 2018; Bayer et al., 2018)

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What is Immunotherapy

ØThere has been revolutionary breakthroughs in the past decade and more exciting new treatments on the horizon

ØImmunotherapy has changed clinical practice across hematologic and solid tumor cancers and generated both academic interest and public attention

ØImmunotherapy can be used in combination with other treatment modalities or as a single agent therapy in some cases

ØMuch of the research today is on adults, however recently interest has grown in pediatric research

(Conn, 2018; Barber, 2018; Bayer et al., 2018)

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Immunotherapy Administration

ØIntravenous (IV)-the immunotherapy goes directly into a vein

ØOral- pills or capsules

ØVarious length and method of administration

ØTopical- the immunotherapy comes in a cream that you rub on your skin.

ØThis type of immunotherapy can be used for very early skin cancer.

ØIntravesical- goes directly into the bladder.

•

(Conn, 2018; Barber, 2018; Bayer et al., 2018, National Cancer Institute )

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Types of ImmunotherapyThe main types of immunotherapy now being used to treat cancer include:

ØMonoclonal antibodies: These are man-made versions of immune system proteins

ØImmune Checkpoint inhibitors: These drugs basically take the ‘brakes’ off the immune system, which helps it recognize and attack cancer cells

ØCancer Vaccines: Vaccines are substances put into the body to start an immune response against certain diseases

ØCAR T-Cell Therapies: CAR T-cell therapy is a promising new way to get immune cells called T cells (a type of white blood cell) to fight cancer

ØOther non-specific immunotherapies: These treatments boost the immune system in a general way, but this can still help the immune system attack cancer cell

(American Cancer Society www.cancer.org; Barber, 2018; Bayer et al., 2018; Conn, 2018)

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Monoclonal AntibodiesØMonoclonal antibodies are given intravenously (injected into a vein)ØThe antibodies themselves are proteins, so giving them can sometimes cause

something like an allergic reaction which are more common when the drug is first given

ØThree types of monoclonal antibiotics include§ Conjugated monoclonal antibodies§ Naked monoclonal antibodies§ Bispecific monoclonal antibodies

ØPossible side effects can include:§ Fever§ Chills § Weakness§ Headache § Nausea§ Vomiting or Diarrhea

(American Cancer Society: www.cancer.org ; Barber, 2018; Bayer et al., 2018; Conn, 2018)

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Monoclonal Antibodies Conjugated monoclonal antibodies

ØMonoclonal antibodies (mAbs) joined to a chemotherapy drug or to a radioactive particle are called conjugated monoclonal antibodies.

ØThe mAb is used as a homing device to take one of these substances directly to the cancer cells.

ØThe mAb circulates throughout the body until it can find and hook onto the target antigen and then delivers the toxic substance where it is needed most

§ Ibritumomab tiuxetan (Zevalin®)- Non-Hodgkin Lymphoma

§ Brentuximab vedotin (Adcetris®)- Hodgkin Lymphoma

§ Ado-trastuzumab emtansine (Kadcyla®, also called TDM-1)- HER2Breast Cancer

(American Cancer Society www.cancer.org; Conn, 2018; Barber, 2018; Bayer et al., 2018;

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Monoclonal Antibodies Naked monoclonal antibodies

ØNaked mAbs are antibodies that work by themselves. There is no drug or radioactive material attached to them.

ØMost naked mAbs attach to antigens on cancer cells, but some work by binding to antigens on other, non-cancerous cells, or even free-floating protein

§ alemtuzumab (Campath®)- CLL

§ trastuzumab (Herceptin®)- Breast Cancer

Bispecific monoclonal antibodies

ØThese drugs are made up of parts of 2 different mAbs, meaning they can attach to 2 different proteins at the same time.

§ blinatumomab (Blincyto) some types of acute lymphocytic leukemia (ALL). (American Cancer Society www.cancer.org; Barber, 2018; Bayer et al., 2018; Conn, 2018)

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Immune Checkpoint InhibitorsØAn important part of the immune system is its ability to tell between normal cells in

the body and those it sees as “foreign which allows the immune system to attack the foreign cells while leaving the normal cells alone

ØThe immune system uses “checkpoints” molecules on certain immune cells that need to be activated (or inactivated) to start an immune response

ØCancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system. But drugs that target these checkpoints hold a lot of promise as cancer treatments

ØImmune checkpoint blockade increases antitumor immunity by blocking intrinsic down regulators of immunity§ CTLA-4 § PD-1§ PD-L1

(American Cancer Society www.cancer.org; Barber, 2018; Bayer et al., 2018; Conn, 2018; Kahir, 2018)

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Immune Checkpoint InhibitorsØPD-1 is a checkpoint protein on immune cells called T cells. It normally acts as a

type of “off switch” that helps keep the T cells from attacking other cells in the body when it attaches to PD-L1, a protein on some normal (and cancer) cells.

ØMonoclonal antibodies that target either PD-1 or PD-L1 can block this binding and boost the immune response against cancer cells

ØPD-1 inhibitors:§ Pembrolizumab (Keytruda)§ Nivolumab (Opdivo)

Ø PD-L1 inhibitors:§ Atezolizumab (Tecentriq)§ Avelumab (Bavencio)§ Durvalumab (Imfinzi)

ØCTLA-4 is another protein on some T cells that acts as a type of “off switch” to keep the immune system in check§ Ipilimumab (Yervoy) is a monoclonal antibody that attaches to CTLA-4 and stops it from

working. (American Cancer Society www.cancer.org ;Barber, 2018; Bayer et al., 2018; Conn, 2018; Kahir, 2018)

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Immune Checkpoint InhibitorsØThe main concern with all of these drugs is that they can allow the

immune system to attack some normal organs in the body, which can lead to serious side effects in some people

ØCommon side effects of these drugs can include§ fatigue, cough, nausea, loss of appetite, skin rash, and itching

Ø Less often they can cause more serious problems§ lungs, intestines, liver, kidneys, hormone-making glands, or other

organs

ØCompared to drugs that target PD-1 or PD-L1, serious side effects seem to be more likely with the CTLA-4 agent ipilimumab

(American Cancer Society www.cancer.org ;Barber, 2018; Bayer et al., 2018; Conn, 2018; Kahir, 2018)

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Figure 1. T-cell Activation in the Lymph Node.

Ribas, 2015

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Figure 2. T-cell Activation in Tumor Milieu.

Ribas, 2015

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(Kabir, Chauhan, Anthony, Hildebrandt, 2018)

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Table 1. Immune Checkpoint–Blocking Antibodies Approved by the Food and Drug Administration.

MA Postow et al. N Engl J Med 2018;378:158-168.

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Cancer Vaccines

Vaccines to help prevent cancer

ØSome strains of the human papilloma virus (HPV) have been linked to cervical, anal, throat, and some other cancers. § Vaccines against HPV may help protect against some of these cancers.

ØPeople who have chronic (long-term) infections with the hepatitis B virus (HBV) are at higher risk for liver cancer§ Getting the vaccine to help prevent HBV infection may therefore lower

some people’s risk of getting liver cancer.

(American Cancer Society www.cancer.org; Barber, 2018; Bayer et al., 2018; Conn, 2018)

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Cancer Vaccine (cont.)

Vaccines to help treat cancer

ØCancer treatment vaccines work differently then those used to prevent viruses

ØThey attempt to get the immune system to mount an attack against cancer cells in the body.

ØInstead of preventing disease, they are meant to get the immune system to attack a disease that already exists

ØSipuleucel-T (Provenge®) This is the only vaccine approved in the US to treat cancer so far. It’s used to treat advanced prostate cancer that is no longer being helped by hormone therapy.

(American Cancer Society www.cancer.org; Barber, 2018; Bayer et al., 2018; Conn, 2018)

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CAR T-Cell Therapies

ØCAR T-cell therapy is a promising new way to get immune cells called T cells (a type of white blood cell) to fight cancer by changing them in the lab so they can find and destroy cancer cells

ØCAR T-cell therapies are sometimes referred to as a type of gene or cell therapy, or an adoptive cell transfer therapy

ØApproved CAR T-cell Therapies§ Acute Lymphoblastic Leukemia in children and young adults§ Recurrent Large B-Cell Lymphoma

ØCAR T- Cell therapy side effects- Due to cytokine release syndrome and can be life threatening§ High fever, Hypotension, Neurotoxicity, Weakened immune system , Renal dysfunction

(American Cancer Society www.cancer.org; Barber, 2018; Bayer et al., 2018; Conn, 2018)

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Cytokine Release Syndrome Symptoms and Their Treatment

ØCapillary Leakage Syndrome and Pulmonary Edema• Methylprednisolone• Oxygen, • Intubation

ØCoagulopathy • Fresh frozen plasma, • Cryoprecipitate• Platelets

ØFever, Myalgia, Headache, Anorexia, Nausea and Vomiting• Acetaminophen• Narcotics, • Total parental nutrition, • Antiemetics

ØHypotension• IV fluids• Vasoactive medications• Tociluzumab

ØRenal Dysfunction• Renal dosing of medications• Dialysis

(Smith & Venella, 2017; Warren, 2018)

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Non-specific Cancer Immunotherapies and AdjuvantsCytokines

ØCytokines are chemicals made by some immune system cells. They are crucial in controlling the growth and activity of other immune system cells and blood cells

ØCytokines are injected, either under the skin, into a muscle, or into a vein

InterleukinsØInterleukins are a group of cytokines that act as chemical signals between white

blood cells.

InterferonsØInterferons are chemicals that help the body resist virus infections and cancers. The

types of interferon (IFN)� IFN-alfa, IFN-beta, IFN-gamma

ØOnly IFN-alfa is used to treat cancer. It boosts the ability of certain immune cells to attack cancer cells. It may also slow the growth of cancer cells directly, as well as the blood vessels that tumors need to grow.

(American Cancer Society ( www.cancer.org); Barber, 2018; Bayer et al., 2018; Chodon et al., 2015; Conn, 2018

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Immune-Related Adverse Events (irAEs)

ØAdverse events are dependent on the type of anti- CTLA-4, PD-1 or PD L1 disease being treated and if it is being used as a Single agent or in combination

ØImmune-related adverse events usually develop within the first few weeks to months after treatment initiation

ØImmune-related adverse events can present at any time, including after cessation of immune checkpoint blockade therapy, and may fluctuate over time

Ø Several studies have indicated that with both anti–CTLA-4 and anti–PD-1 therapy, dermatologic toxicity occurs early

ØMost studies indicate that prolonged treatment does not result in an increased cumulative incidence of immune-related adverse events

ØIt is unknown whether immune checkpoint blockade creates later-term toxicity risk (i.e., many years after the initiation of therapy)

(Mistry et al., 2017; Postow et al., 2018)

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Figure 1. Organs Affected by Immune Checkpoint Blockade.

MA Postow et al. N Engl J Med 2018;378:158-168.

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Multiple System Immune-Related Adverse Effects (irAEs)

irAE Median Onset

Presenting symptoms

Diagnostic tests

Dermatologic toxicity

5 weeks pruritus, mucositis, rash,

vitiligo

• R/O viral or bacterial infection

• R/O nutritional deficit or other medication effect

• R/Ocomplications from cancer or co-morbidities

• Labs-CBC, CMPThyroid panel, cortisol level, etc.

• MRI, CT scan, lumbar puncture as indicated

GI toxicity/Enterocolitis

6-8 weeks Diarrhea abdominal pain, rectal bleeding

GI Toxicity-Hepatitis

8-12 weeks Asymptomatic elevation of AST, ALT, and bilirubin

Endocrinopathy 6-11 weeks Nonspecific: fatigue, weight

change, depression elevated glucose,

hypotensionRheumatologic

Toxicity1 month Muscle and joint

stiffness and painPneumonitis 2-5 months Cough, upper

respiratory symptoms, chest

painNeurotoxicity 10-14 weeks Central and

peripheral deficits Nephrotoxicity 15 weeks Asymptomatic

elevation in creatinine

(Conn, Y. 2018)

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The mechanisms that result in immune-related adverse events are still being elucidated. Some potential mechanisms include increasing T-cell activity against antigens that are present

Figure 2. Possible Mechanisms Underlying Immune-Related Adverse Events.

MA Postow et al. N Engl J Med 2018;378:158-168.

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Using CTCAE for Immunotherapy The Common Terminology Criteria for Adverse Events (CTCAE)

ØTool for reporting adverse events of cancer treatments which has been in use in different ways since the 1980s

ØStandardized way to report adverse events by assigning uniformed terminology and a grading system to note the severity

ØRegulated and updated by the National Cancer Institute • Latest update in November 2017- added terminology to assist in reporting irAEs of

immunotherapy

ØThe tool consists of a list of adverse event terms commonly encountered during cancer treatment

ØMonitors safety data for reporting to regulatory bodes

ØProvides safety standards for oncology research and nursing (Reiner., 2018)

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Treatment of Immune-Related Adverse Events (irAEs)

Treatment of irAEs is dependent on the type and grade level of symptoms

Grade Levels§ Grade 1- managed with supportive care§ Grade 2 - may require high dose oral or IV steroids § Grade 3 to 4 - may require high dose IV steroids and referral to specialists

Types of symptoms ØDermatologic ( 50% of patients)

§ Grade 1- 2 (mild rash covering 10%-30%of the body)§ Grade 3 (rash covering >30%, needs oral or IV steroids, hold treatment)§ Grade 4 (blistering ulceration, will need hospitalization, steroids and referral)

ØGastrointestinal (30% for any grade and 10% for grade 3 to 4)§ Grade 1 ( <4 stools per day)- symptomatic treatment§ Grade 2 ( 4-6 stools per day)- may need to hold therapy and begin systemic steroids § Grade 3 to 4 ( > 7 stools per day )- IV steroids and stop medication

(Mistry et al., 2017; Postow et al., 2018)

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Treatment of Immune-Related Adverse Events (irAEs)

Ø Pulmonary (occurs in less than 1% of patients )§ If Pneumonitis is suspected imaging should be done§ Grade 1 and 2- Immunotherapy should be held and high dose oral steroid should be

started § Grade 3 to 4- Admitted to hospital and started on high dose IV steroids and stop

immunotherapy

Ø Endocrine ( hypothyroidism and hypothyroidism occur 5%-20%)§ Patients may be asymptomatic but present with fatigue§ Thyroid panel should be done§ Treatment varies and dependent on labs and symptoms § May have to hold or stop medication

Ø Hepatic § Hepatitis occurs in 5%-10% of patients on Ipilimumab, nivolumab, and pembrolizumab§ Grade 2 symptoms should receive steroid an treatment placed on hold§ Grade 3 or 4 requires IV steroids and checkpoint inhibitor stopped and may need

referral to specialist if inadequate response to steroid after 72 hours

(Mistry et al., 2017; Postow et al., 2018)

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Treatment of Immune-Related Adverse Events (irAEs)

Ø Hold immune checkpoint inhibitors for most grade 2 toxicities and consider resuming when symptoms and/or lab values revert ≤ grade 1. Corticosteroids, (initial dose of 0.5–1 mg/kg/day of prednisone or equivalent) may be administered.

Ø Hold immune checkpoint inhibitors is for grade 3 toxicities and initiate high dose corticosteroids (prednisone 1–2 mg/kg/day or methylprednisolone IV 1–2 mg/kg/day). Corticosteroids should be tapered over the course of at least 4-6 weeks. If symptoms do not improve with 48-72 hours of high dose corticosteroid, infliximab may be offered for some toxicities.

Ø When symptoms and/or laboratory values revert grade 1 or less, re-challenging the patient may be offered; however caution is advised especially in those patients with early-onset irAEs. Dose adjustments are not recommended.

Ø In general, grade 4 toxicities warrant permanent discontinuation of immune checkpoint inhibitors, with the exception of endocrinopathies that have been controlled by hormone replacement.

www.asco.org/supportive-care-guidelines ©American Society of Clinical Oncology and National Comprehensive Cancer Network 2018. All rights reserved.

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Patient and Clinician CommunicationØAs immunotherapeutic treatment for cancer continues to evolve with single agents and in

new combinations, it is imperative that patients and family caregivers receive timely and up-to-date education about immunotherapies, their mechanism of action, and the clinical profile of possible irAEs.

ØPatient and caregiver education should occur prior to initiating therapy and continue throughout treatment and survivorship.

ØPatients should be encouraged to alert all health care providers that they are receiving or have received an immunotherapeutic agent and to report any changes in health status to each provider.

ØConsistent assessment and documentation at each encounter will also enable the clinical team to note changes that may occur over time.

ØClose monitoring throughout treatment is important as minimal changes in a patient’s baseline status may indicate an early irAE.

www.asco.org/supportive-care-guidelines ©American Society of Clinical Oncology and National Comprehensive Cancer Network 2018.

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Pediatric Oncology- Immunotherapy ØImmunotherapy offers a promising approach for many pediatric

malignancies especially for those that have failed standard treatments

ØThere are fours immunotherapies currently being used and/or studied for pediatric cancer treatment

Monoclonal antibodies

ØFew approved and most still in clinical trials ØDinutuximab and Rituximab

CAR-T Cell Therapy

ØCART-19 is approved for relapsed and refractory B-cell Leukemia positive for the CD19 antigen

(Warren, 2018)

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Pediatric Oncology- Immunotherapy (cont.)

Immune Checkpoint Inhibitors

ØCurrently there are numerous phase 1 and 2 trials ØNot approved in the pediatric population ØSingle use drugs as only approved in adultsØCombination therapies coupling CTLA-4 and PD-1 are also showing

potential in pediatric cancer treatment

Cancer Vaccine

ØAlthough promising have a long way to go before FDA approval ØMost likely to be used as adjunct therapy due to limited efficacy in

monotherapyØCurrent trials- Neuroblastoma, ALL and AML

(Warren, 2018)

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Current Approved Pediatric Immunotherapy ØCAR-T-19

� CAR anti-CD19 � Used to treat CD19-positive relapsed leukemia � Important to instruct family to call for any fever, monitor patient for signs

of CRS, and patients with B-cell aplasia will require monthly IVIG

ØDinutuximab• MAB, chimeric, anti- GD2• Used to treat neuroblastoma and osteosarcoma • Pain management prior to and during treatment, acetaminophen every 4-6

hours during infusion, Benadryl to prevent hypersensitivity reactions, Daily weights and close observation

ØRituximab• MAB, chimeric, anti- CD20 • Used to treat leukemia and lymphoma • Monitor patients for B-cell aplasia and may require long term IVIG

ØToclizumab• MAB, human, anti-interleukin 6• Used to treat CRS after CAR T cell therapy• Monitor patient for neutropenia

(Bartholomew et al., 2016, Bayer et al., 2017; Ceppi et al., 2017;Wayne et al., 2018 ; Warren, 2018)

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Pediatric Immunotherapy in Research ØBlinatumamab• Bispecific MAB, chimeric, CD3 and anti-CD19 • Used to treat leukemia and lymphoma • Monitor for severe side effects including CRS, seizures, encephalopathy,

and tumor lysis syndromeØNivolumab • Immune checkpoint inhibitor, anti-PD-1• Used to treat Hodgkin lymphoma • Monitor for irAEs (cardiac toxicity, hypertension, and progressive multifocal

leukoencephalopathy) ØPemrolizumab• Immune checkpoint inhibitor, anti-PD-1 • Used to treat glioblastoma, medulloblastoma, and also used off label after

CAR T therapy ( with evidence of B-cell in the periphery • Monitor for irAEs (vitiligo )

Ø Iplimumab• Immune checkpoint inhibitor, anti-CTLA-4• Used to treat solid tumors • Monitor for irAEs ( neurotoxicity, hematologic toxicity, and progressive

multifocal leukoencephalopathy (Bartholomew et al., 2016, Bayer et al., 2017; Ceppi et al., 2017; Wayne et al., 2018 ; Warren, 2018)

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References • Barber, F. D. (2018). Recent Developments in Oncology Immunotherapy, Adverse Effects Part 2. The

Journal for Nurse Practitioners, 14(4), 259-266. doi:10.1016/j.nurpra.2017.11.012

• Bartholomew, J., Washington, T., Bergeron, S., Nielson, D., Saggio, J., & Quirk, L. (2016). Dinutuximab: A novel immunotherapy in the treatment of pediatric patients with high-risk neuroblastoma. Journal of Pediatric Oncology Nursing, 34, 5–12.

• Bayer, V., Amaya, B., Baniewicz, D., Callahan, C., Marsh, L., & Mccoy, A. (2017). Cancer Immunotherapy: An Evidence-Based Overview and Implications for Practice. Clinical Journal of Oncology Nursing, 21(2), 13-21. doi:10.1188/17.cjon.s2.13-21.

• Bramer, et al. (2018). Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology practice guidelines, Journal of Clinical Oncology 36, 1-54

• Cancer Institute: www.cnacer.org

• Capitani, C.M., Otto, M., DeSantes, K.B., & Sondel, P.M.(2014). Immunotherapy in pediatric malignancies; current status and future perspectives, Future Oncology, 10(9), 1659-1678

• Ceppi, F., Beck-Popovic, M., Bourquin, J.-P., & Renella, R. (2017). Opportunities and challenges in the immunological therapy of pediatric malignancy: A concise snapshot. European Journal of Pediatrics, 176, 1163–1172. https://doi.org/10.1007/s00431-017-2982-0

• Conn, Y. (2018). Recent Developments in Oncology Immunotherapy, Implications for NPs Part 1. The Journal for Nurse Practitioners, 14(4). doi:10.1016/j.nurpra.2017.12.013

• Chodon, T/. Koya, R., &Odunsi, K, (2015). Active Immunotherapy of cancer. Immunological Investigations, 44(8),817-836. doi:10.3109/08820139.2015.1096684

• Kabir, T.F., Chauhan, A., Anthony, l.. & Hildebrandt, G.C. (2018). Immune checkpoint inhibitors in pediatric solid tumors: Status in 2018. Oschner Journal, 18, 370-376.

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References• Majzner, R.G., Heitzeneder, S., & Mackall, C.L (2017) Harnessing the immunotherapy revolution for

the treatment of childhood cancers. Cancer Cell Perspectives 31, 476-485.

• Mistry, H., Forbes, S., & Fowler, N. (2017). Toxicity Management: Development of a Novel and Immune-Mediated Adverse Events Algorithm. Clinical Journal of Oncology Nursing, 21(2), 53-59. doi:10.1188/17.cjon.s2.53-59

• National Cancer Institute; Biological Therapies for Cancer: Fact Sheet Retrieved from: http://www.cancer.gov/abput-cancer/treatment/types/immunotherapy/bio-therapies-fact-sheet

• Postow, M., Sidlow, R., Hellams, M.D. (2018). Immune-related adverse events associated with immune checkpoint inhibitors. N ENGL J MED, 378(2), 158-168.

• Ribas, A, (2015). Releasing the brakes on cancer immunotherapy. N ENGL J MED, 373, 1490-1492

• Riener, J (2018,). Although immunotherapy is changing the face of cancer care, it is not exempt from side effects, ONS Voice, August, 2018.

• Shoushtari, A., MD, Wolchok, J., MD, & Hellman, M., MD. (2018). Principles of cancer immunotherapy (M. Atkins MD & M. Ross MD, Eds.). Waltham, MA: Up To Date.

• Smith, L.T., & Venella, K. (2017). Cytokine release syndrome: Inpatient care for side effects of CAR T-cell therapy. Clinical Journal of Oncology Nursing, 21(Suppl.), 29–34. https://doi.org/10.1188/17.CJON.S2.29-34

• Warren, C.B. (2018) Immunotherapy in pediatric oncology: A review of therapy types and nursing implications. CJON, 22(6), 649-655.

• Wayne, A.S., Capitini, C.M., & Mackall, C.L. (2010). Immunotherapy of childhood cancer: From biologic understanding to clinical application. Current Opinion in Pediatrics, 22, 2–11.https://doi.org/10.1097/MOP.0b013e3283350d3e

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