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Introduction to Immunotherapy

Although successful immunotherapy in cancer treatment have garnered attention in the past decade, the concept of the immune system interaction with cancer cells can be traced back to over a century ago. Over the years, it has been accepted that the immune system plays an important role in tumor surveillance and regulation of tumor cells.

The immune system recognizes and regulates tumor cells in different methods. The main modality starts with malignant cells recognized as non-self antigens due to antigen major histocompatibility complex molecules on their cell surfaces. T-cell receptors interact and bind to cancer cell antigen receptors. With the costimulatory signals of the CD28 receptor on the T-cell surface with B7 ligand molecules of antigen presenting cells, T-cells are subsequently activated to mount an attack on tumor cells.

Cancer cells have learned to evade the immune system by manipulating the tumor microenvironment to permit itself to become undetected by T-cells and bypass checkpoints by the immune system.

In response to the methods of tumor evasion, several immunotherapy therapy agents have been developed, including checkpoint inhibitors, adoptive T-cell therapy, immunostimulatory cytokines, vaccines, and oncolytic viruses. The most popular and successful therapies in this group are checkpoint inhibitors and adoptive T-cell therapy with chimeric antigen receptor T-cell therapy. Immunotherapy acts to enhance the patient’s immune system to target cancer cells or to restore T-cell regulation inhibited by cancer cells.

Immune Checkpoint Inhibitors

Immune checkpoints allow the immune system to regulate responses to pathogens and self-antigens. Checkpoints are T-cell receptor binding to ligands on cell surfaces in order to regular the functions of the T-cell to perform its various activities.

The required costimulatory signal to activate T-cells is the T-cell receptor CD28 and B7 ligand interaction, which are regulated by inhibitory checkpoint receptor and ligand pairs. There are several checkpoint receptor and ligand pairs, but the ones that have gained the most interest are the cytotoxic T-lymphocyte associated protein (CTLA-4) and programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1).

CTLA-4 is expressed primarily on activated effector T-cells and regulatory T-cells. CTLA-4 interferes with costimulation of T-cells and act as a negative regulator. Cancer cells also express ligands for CTLA-4 and acts as a strong negative signal to the immune system, thus allowing cancer evasion.

The other critical checkpoint receptor and ligand pairs are PD-1 and PD-L1 or PD-L2, which are members of the B7 costimulatory family. Immune checkpoint inhibitors targeting the PD-1 pathway are of particular interest since the response rates across all tumor types average 20-30%.

Combination immune checkpoint inhibitor therapy also has shown promising results. The CTLA-4 and B7 interaction occurs prior to the PD-1/PD-L1 interaction. This combined immune checkpoint inhibitor therapy has shown a 50% response rate in melanoma where the response rate prior to immunotherapy was 10%. The agents approved by the U.S. Food and Drug Administration (FDA) for combination therapy use are ipilimumab and nivolumab.

Immune checkpoint inhibitors have become popular in the recent years due to the fact that its adverse effects are more tolerable than those of cytotoxic chemotherapy and the administration is simpler than other forms of immunotherapy.

Immune checkpoint inhibitors have the potential to cause adverse events in any organ system and are similar to autoimmune manifestations. In general, the most common adverse events associated with immune checkpoint inhibitors include fatigue, dermatologic, gastrointestinal, hepatotoxicity, and musculoskeletal.

Anti-CTLA-4 Therapy: Ipilimumab (Yervoy®)

Ipilimumab was the first agent to show overall survival benefit in melanoma patients. Unlike chemotherapy, treatment with ipilimumab typically increases the tumor burden initially followed by reduction of lesions. This mechanism of action may be related to T-cell infiltration around the tumors and not due to tumor progression.

Indication: Melanoma, renal cell carcinoma, colorectal cancer

Dosing: The dosing of ipilimumab is weight based, 1 mg/kg, 3 mg/kg, or 10 mg/kg depending on the indication. It is also administered every 3 weeks for a total of 4 doses.

Administration: Intravenous infusion over 90 minutes or 30 minutes depending on the indication.

In the event of severe toxicity, the dose of ipilimumab should be omitted in the adjuvant setting for melanoma rather than delayed. In the setting of metastatic melanoma, doses may be delayed due to toxicity.
When administered in combination with nivolumab, ipilimumab should be administered after nivolumab.

Adverse events: The most common adverse events associated with ipilimumab use includes fatigue, diarrhea, pruritus, rash, colitis, nausea, vomiting, headache, weight loss, pyrexia, decreased appetite, and insomnia.

Toxicities typically occur around the third or fourth cycle of ipilimumab.
The reintroduction of ipilimumab after patients experiencing severe toxicities should require careful deliberation as side effects may indicate disease response.
Vitiligo is an adverse event in which patches of skin loses pigmentation. This adverse event in the treatment of melanoma is considered to show response to therapy and a positive prognostic indicator due to the immune system targeting melanocytes.

Anti-PD-1 Therapy: Nivolumab (Opdivo®)

Indications: Melanoma, non-small cell lung cancer, small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck carcinoma, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma.

Nivolumab may be used in combination with ipilimumab for the treatment of melanoma, renal cell carcinoma, and colorectal cancer.

Dosing: The typical dose of nivolumab is a flat dose of 240 mg or 480 mg depending on the indication.

When used in combination with ipilimumab for melanoma, nivolumab is administered as 1 mg/kg for 4 doses. Flat dosing of nivolumab may be used after the initial 4 doses.

Administration: Nivolumab is administered as an intravenous infusion over 30 minutes for all indications. If using 240 mg nivolumab dosing, it may be administered every 2 weeks. However, if using the 480 mg dosing, it may be administered every 4 weeks.

Adverse events: The most common adverse events experienced with nivolumab include fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, and vomiting.

When used in combination with ipilimumab, the incidence of adverse events may be increased.

Anti-PD-1 Therapy: Pembrolizumab (Keytruda®)

Indications: Melanoma, non-small cell lung cancer, small cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, mediastinal large B-cell lymphoma, head and neck carcinoma, gastric carcinoma, esophageal carcinoma, cervical carcinoma, Merkel cell carcinoma, urothelial carcinoma, microsatellite instability-high cancer, hepatocellular carcinoma.

Pembrolizumab may be used in combination with chemotherapy or targeted therapy with axitinib.

Dosing: The typical dose of pembrolizumab is a flat dose of 200 mg for all indications.

Administration: Pembrolizumab is administered as an intravenous infusion over 30 minutes for all indications. It is typically administered every 3 weeks.

Adverse events: The most common adverse events experienced with pembrolizumab monotherapy include fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

Companion testing: Testing for tumor expression of PD-L1 is required prior to pembrolizumab use, especially in the first line setting. The scores for PD-L1 expression differ based on indication.

Anti-PD-1 Therapy: Cemiplimab-rwlc (Libtayo®)

Indications: Cutaneous squamous cell carcinoma

Dosing: The typical dose of cemiplimab is a flat dose of 350 mg.

Administration: Cemiplimab is administered as an intravenous infusion over 30 minutes. It is typically administered every 3 weeks.

Adverse events: The most common adverse events include fatigue, rash, and diarrhea.

The most serious and potentially fatal reactions that may occur with cemiplimab are similar to those in the same drug class.
These reactions include pneumonitis, colitis, hepatitis, endocrinopathies, renal dysfunction, and dermatologic reactions.
Other less common and serious reactions that may occur include neurological events, cardiovascular, ocular, gastrointestinal, and musculoskeletal.

Anti-PD-L1 Therapy: Atezolizumab (Tecentriq®)

Indications: Urothelial carcinoma, non-small cell lung cancer, breast cancer, small cell lung cancer.

Atezolizumab may be used as a single agent or in combination with bevacizumab, paclitaxel, and carboplatin.

Dosing: The typical dose of atezolizumab is a flat dose of 1200 mg. For triple negative breast cancer or maintenance therapy for small cell lung cancer, atezolizumab is dosed at 840 mg.

Administration: Atezolizumab is administered as an intravenous infusion over 60 minutes for the first infusion. If the first infusion was well tolerated by the patient, subsequent infusions may be shortened to 30 minutes. It is typically administered every 3 weeks.

Adverse events: The most common adverse events with atezolizumab monotherapy include fatigue, nausea, cough, dyspnea, and decreased appetite.

Companion testing: PD-L1 testing is required to be performed prior to administration of therapy. If the tumor expresses PD-L1 immune cells in >5% of the sample, atezolizumab may be used for treatment. PD-L1 testing is required for treatment in the first line setting.

Anti-PD-L1 Therapy: Durvalumab (ImfinziTM)

Indications: Urothelial carcinoma, non-small cell lung cancer

Dosing: Durvalumab is dosed based on the patient’s weight at a dose of 10 mg/kg. There are no dose reductions recommended if patients experience toxicity.

Administration: Durvalumab is administered as an intravenous infusion over 60 minutes. It is typically administered every 2 weeks.

Adverse events: The most common adverse events include fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, urinary tract infection, cough, pneumonitis, upper respiratory tract infection, dyspnea, and rash.

Companion testing: PD-L1 expression testing is available prior to use with durvalumab, although it is not required for treatment.

Anti-PD-L1 Therapy: Avelumab (Bavencio®)

Indications: Merkel cell carcinoma, renal cell carcinoma, urothelial carcinoma

Avelumab should be used in combination with axitinib for renal cell carcinoma.

Dosing: The typical dose of avelumab is a flat dose of 800 mg.

Administration: Avelumab is administered as an intravenous infusion over 60 minutes.

Premedication with acetaminophen and an antihistamine for the first 4 infusions is recommended. Patients may require premedications for subsequent infusions as well.
Avelumab is typically administered every 2 weeks.

Adverse events: The most common adverse events include fatigue, musculoskeletal pain, diarrhea, nausea, infusion related reactions, rash, decreased appetite, peripheral edema, and urinary tract infection.

Infusion reactions are typically rare with immune checkpoint inhibitors, however, it occurs at a much higher frequency with avelumab.

Companion testing: PD-L1 expression testing is available prior to use with avelumab, although it is not required for treatment.

Adoptive Cell Therapy

Adoptive cell therapy is a type of immunotherapy in which T-cells are isolated and directed towards tumor cells through the process of genetic engineering. The types of adoptive cell therapy include tumor autologous infiltrating lymphocytes (TILs) and chimeric antigen receptors (CAR) T-cells that have been genetically engineered. The T-cells are obtained from patients, isolated for cell activation, and then infused back into the patient to directly target tumor cells.

The most successful is CAR T-cells. This form of adoptive cell therapy uses T-cells that have been genetically engineered using the CRISPR/Cas9 method. After administration of lymphodepleting chemotherapy, CAR T-cells are reinfused back into the patient. Lymphodepleting chemotherapy administration prior to CAR T-cell therapy allows for subsequent expansion of CAR T-cells in vivo.

Since CAR T-cell therapy is a relatively novel approach to treating tumors, researchers are still refining the process of genetically altering T-cells to reduce the adverse events in patients.

Tisagenlecleucel and axicabtagen ciloleucel were the first two therapies approved to treat patients with acute lymphoblastic leukemia and diffuse-large B cell lymphoma. Both of these agents target CD19 cells.

CAR T-cell: Tisagenlecleucel (KymriahTM)

Indication: Patients under 25 years of age with B-cell precursor acute lymphoblastic leukemia, adult patients with large B-cell lymphoma.

Large B-cell lymphoma includes diffuse large B-cell lymphoma, high grade B-cell lymphoma, and diffuse large B-cell lymphoma arising from follicular lymphoma.

Administration: Tisagenlecleucel administration is complex and requires trained staff to administer and monitor for adverse events.

It is crucial that appropriate patient identification is performed prior to therapy administration.
Tisagenlecleucel should be administered intravenously after a lymphodepleting regimen in order for the CAR T-cells to expand and proliferate.
Premedication with acetaminophen and an H1-antihistamine is required to mitigate infusion reactions. Corticosteroids should be avoided since it may interfere with the effectiveness of tisagenlecleucel.
Subsequent bags of T-cells should only be thawed once the patient has tolerated the first bag of infusion.
Tocilizumab for adverse event treatment should be available prior to CAR T-cell administration.

Dosing: The dose of tisagenlecleucel is based on the patient’s weight.

Patients with acute lymphoblastic leukemia weighing 50 kg or less, a dose of 0.2 to 5.0 x 106 CAR positive T-cells per kg of body weight should be administered.
Patients with acute lymphoblastic leukemia above 50 kg, 0.1 to 2.5 x 108 CAR positive T-cells should be administered.
For patients with diffuse large B-cell lymphoma, 0.6 to 6.0 x 108 CAR positive T-cells should be administered.
A single dose of tisagenlecleucel may be contained in up to 3 cryopreserved infusion bags.

Adverse events: The most common adverse events associated with tisagenlecleucel therapy include cytokine release syndrome, infections, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, headache, hypogammaglobulinemia, decreased appetite, encephalopathy, bleeding episodes, tachycardia, viral infectious disorders, hypoxia, acute kidney injury, cough, and delirium.

CAR T-cell: Axicabtagene ciloleucel (YescartaTM)

Indication: Adult patients with large B-cell lymphoma

Large B-cell lymphoma includes diffuse large B-cell lymphoma, high grade B-cell lymphoma, and diffuse large B-cell lymphoma arising from follicular lymphoma.

Administration: Axicabtagene ciloleucel administration is complex and requires experienced medical staff to administer and monitor for adverse events.

It is crucial that appropriate patient identification is performed prior to therapy administration.
A lymphodepleting regimen of cyclophosphamide 500 mg/m2 and fludarabine 30 mg/m2 on the fifth, fourth, and third day should be administered prior to the infusion of axicabtagene ciloleucel.
Premedication with acetaminophen 650 mg PO and diphenhydramine 12.5 mg intravenous (IV) one hour prior to axicabtagene ciloleucel is required to mitigate the infusion reaction. Corticosteroids should be avoided since it may interfere with the effectiveness of axicabtagene ciloleucel.
Axicabtagene ciloleucel should be administered within 30 minutes and is only stable for up to 3 hours at room temperature.
Tocilizumab for adverse event treatment should be available prior to CAR T-cell administration.

Dosing: The dose of axicabtagene ciloleucel is based on the patient’s weight.

The optimal dose of axicabtagene ciloleucel is of 2 x 106 CAR positive T-cells per kg of body weight.
The maximum dose of axicabtagene ciloleucel is 2 x 108 CAR positive T-cells.

Adverse events: The most common adverse events associated with axicabtagene ciloleucel therapy include cytokine release syndrome, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

Monitoring: Daily monitoring for at least seven days after therapy administration is recommended.

Cytokines

Cytokines are small proteins that act as messengers involved in cell signaling. Cytokines allow immune cells to communicate to distant cells and respond against target antigens to control cell growth and activity in the immune system. Additionally, proinflammatory cytokines promote effector T-cell proliferation and activation.

Cytokines that are approved by the Food and Drug Administration (FDA) for cancer treatment include interferon (IFN) and interleukin-2 (IL-2) therapies.

Cytokine therapy has its drawbacks in cancer treatment. Using cytokine therapy does not stimulate the immune system to directly target the malignant cells, but to up-regulate and initiate an immune response. Additionally, the immune system will eventually activate the immunologic checkpoints to terminate the immune response. Cytokine administration has the potential for inducing severe adverse events including hypotension, adrenal insufficiency, respiratory failure, and neuropsychiatric issues.

Cytokines: Interferon alfa-2b (Intron®)

Description: Three different formulations for recombinant INFα exists: alfa-2a, alfa-2b, and alfa-2c. Interferon uses recombinant DNA in Escherichia coli to insert an interferon alfa-2b gene from human leukocytes.

Peginterferon alpha-2b (PEG-IntronTM) is a compound consisting of conjugate recombinant alfa interferon with monomethoxy polyethylene glycol (PEG). The pegylation of interferon therapy increases its half-life, while the mechanism of action remains the same.

Indication: Hairy cell leukemia, melanoma, follicular lymphoma, acquired immune deficiency syndrome (AIDS) related Kaposi’s sarcoma

Other indications of interferon therapy that are not related to cancer include chronic hepatitis B, chronic hepatitis C, and condylomata acuminata.

Administration: Intramuscular, subcutaneous, intralesional, intravenous

Intravenous administration of interferon therapy is only reserved in the induction phase of treatment for melanoma. The maintenance phase of melanoma may utilize the subcutaneous route.

Adverse events: Flu-like symptoms (fever, headache, chills, myalgia, fatigue), neutropenia, anorexia, vomiting, nausea, depression, diarrhea, alopecia, altered taste, vertigo

In patients with a history of pulmonary disease, diabetes mellitus prone to ketoacidosis, coagulation disorders, or cardiovascular disease, use interferon therapy with caution. Additional monitoring for these indications is beneficial due to the potentially for serious adverse events in this patient population.
Patients with a pre-existing psychiatric disorder should be educated about the risk of depression and suicidal behavior while on therapy. Psychiatric patients should be carefully monitored throughout the treatment duration and for 6 months after therapy discontinuation.

Cytokines: Aldesleukin (Proleukin®)

IL-2 is a glycoprotein mainly produced by antigen-activated T helper 1 CD4 T-cells. Due to the short half-life of IL-2, it must be administered as a high dose in order to have immune effects in tissues. High-dose (HD) IL-2 is a cytokine developed to target the tumor microenviroment. IL-2 acts as a T-cell growth factor during the initiation of the immune response. IL-2 and antibody protein complex recognizes peptides on the surface of tumor cells to aid the immune system in recognition and tumorigenesis. Additionally, HD IL-2 also plays a role in the termination of T-cell responses to maintain self-tolerance by activation induced cell death of overactive T-cells.

Indication: Currently, aldesleukin is approved for renal cell carcinoma and melanoma.

Patients are screened prior to HD IL-2 administration since HD IL-2 is only indicated for a small subset of patients.
The patient’s functional or performance status is the most important predictor of response as well as therapy tolerance.
Patients who have a high functional or performance status are the only patients selected for HD IL-2 therapy.

Administration: HD IL-2 is infused over 15 minutes.

The administration of HD IL-2 therapy requires inpatient hospitalization with cardiac and oxygen saturation monitoring.
Additionally, the staff should be trained in managing potential adverse events associated with HD IL-2. Additional training with administration of vasopressors is also necessary.

Dosing schedule: The dosing of HD IL-2 therapy is complicated since the administration is dependent on toxicities experienced.

A typical dose involves an IV bolus with a fixed weight based dose of 600,000 or 720,000 units/kg every 8 hours up to a maximum of 14 doses over the course of 5 days. Only a small number of patients receive all doses of therapy due to adverse events.
The planned 5 days of treatment is considered to be a cycle. One course of treatment consists of two cycles separated 1 to 2 weeks.
Most centers separate cycles by 1 week with a potential for extending the time of between cycles depending on patient recovery.
Typically, the first cycle is associated with a higher number of doses administered compared to the second cycle due to toxicity accumulation.
Additional courses of HD IL-2 therapy should be based on disease response.

Adverse events: Constitutional symptoms including fever, fatigue, headache, gastrointestinal symptoms, and myalgia occur in at least 80% of patients.

High doses produce severe systemic toxicities including vascular leak syndrome, pulmonary edema, hypotension, acute renal insufficiency and myocarditis.
The mechanism behind HD IL-2 adverse events is due to the binding of IL-2 to IL-2Rα expressing endothelial cells, which subsequently induces acute vasodilation and vascular leak syndrome.
With the amount of fluid administration expected during the cycle of HD IL-2 to counteract hypotension, patients are expected to gain 5% to 10% of their body weight during the week of therapy administration.
Other less common adverse events of cytokine therapy include transaminases, thrombocytopenia, leukopenia, neutropenia, and neuropsychiatric issues.
Toxicities are cumulative with worsening adverse events with successive doses during the cycle.
The severity of adverse events peaks 4 to 6 hours after a bolus of IL-2. Holding a dose is the main method of management with prolonged toxicity from a previous dose. There are no dose reduction recommendations.
Therapy with HD IL-2 should be discontinued when the patient experiences severe adverse events. Once IL-2 therapy is discontinued, typically patients will recover rapidly despite accumulation of adverse events.

Discharge Instructions After HD IL-2 Therapy

Patients will likely experience severe fatigue and should not drive for several days.

Diuretics may be prescribed upon discharge due to fluid shifts.

Anti-hypertensive medications can be resumed 48 hours after discharge and discontinued 48 hours prior to the next cycle of IL-2 therapy. Beta-blockers should be held during therapy and not restarted in between cycles.

If hyperthyroidism or hypothyroidism occurs with IL-2 therapy, thyroid replacement therapy should be initiated and euthyroidism achieved prior to resuming HD IL-2 therapy.

Iodinated contrast agents should be avoided prior to retreatment with IL-2 therapy due to iodinated contrast media potentially causing skin and systemic reactions similar to HD IL-2 in previously treated patients.

Delayed effects of capillary leak syndrome may occur and affect the cardiopulmonary systems. Patients should slowly ease into physical activity again.

Cancer Vaccine

The focus of tumor vaccines has been on tumor peptide antigens and major histocompatibility complex antigen presentation.

Vaccination uses the adaptive immune system for its effectiveness, requiring the host to generate a response. After exposure to the vaccine, typically B-cells and T-cells respond by producing antibodies or generating a response with the production of cytokines after exposure to antigen presenting cells. One type of antigen presenting cells is a dendritic cell, which has been utilized as a cancer vaccine.

The goal of tumor vaccines is to try to expose patients to tumor antigens in order to elicit an immune response against tumor specific cells. Tumor specific antibodies and T-cells generate this desired immune response.

The only cancer vaccine approved by the FDA is sipuleucel-T. However, the intravesicular use of the BCG vaccine used for the treatment of urothelial carcinoma has shown benefit.

Cancer Vaccine: Sipuleucel-T (Provenge®)

Sipuleucel-T is an autologous vaccine that uses dendritic cells. Patients undergo leukapheresis to obtain dendritic cells. Dendritic cells are then exposed to a fusion protein of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The GM-CSF acts as an antigen presenting cell to stimulate the immune system. There is an incubation period to allow the dendritic cells to recognize PAP. These cells are reinfused back into the patient. Dendritic cells subsequently activate T lymphocytes through major histocompatibility complex to target tumor cells.

Indication: Castration-resistant prostate cancer

Dose: A single dose of vaccine contains at least 50 million autologous CD54+ cells activated with PAP-GM-CSF.

Patients receive a total of 3 doses.
If a dose is missed, leukapheresis is required to be performed again in order for the patient to continue therapy and complete treatment.
Leukapheresis may be performed at any medical entity, however, the manipulation of cells to be infused back to the patient is only performed at the drug manufacturer.

Administration: Administration of sipuleucel-T will require trained healthcare personnel with experience in cellular therapy administration.

Sipuleucel-T should not be left at room temperature for more than 3 hours.
Sipuleucel-T is administered every 2 weeks.
Premedication with acetaminophen and diphenhydramine is necessary.
Each dose is administered over a 60 minute infusion.

Adverse events: Chills, fatigue, fever, back pain, nausea, joint aches, headaches, citrate toxicity, paresthesia, vomiting, anemia, constipation, oral paresthesia, pain in extremities, dizziness, muscle aches, asthenia, and diarrhea

Post-marketing experience of sipuleucel-T showed that 62.6% of adverse events reported were serious. The most common adverse events reported were chills, fever, back pain, fatigue, arthralgia, headache, and nausea.
Adverse events occurred within the first few days of treatment and improved in 1 to 2 days.

Consideration for Use: Clinical trial data with sipuleucel-T demonstrated a 4.1 month median overall survival benefit compared to placebo. Additionally, the quality of life has been reported to be superior to the comparative therapy of docetaxel, however, treatment with sipuleucel-T and the management of its adverse events are more costly.

Oncolytic Viruses

Virotherapy falls into two categories. One is a virus that infects cancer cells and induces expression of viral antigens on the surface of cancer cells to make them more visible to the immune system, resulting in a better immune response stimulation with cytokine production. The second method is with the use of oncolytic viruses, which is the more successful method.

Oncolytic viruses consist of either native or engineered viruses that lack virulence against normal cells but capable of selectively replicating in cancer cells to cause tumor cell lysis and overtaking the tumor apoptosis pathway. The tumor lysing process also stimulates the immune system to respond with increased cytokine production.

Talimogene laherparepvec or T-VEC is a genetically modified herpes simplex-1 virus consisting of two excised genes with the virulence factor removed and one gene added to express GM-CSF. The purpose of GM-CSF in tumor cell destruction is multifold. GM-CSF plays a role in the recruitment of antigen presenting cells to the sites of malignant cells. Additionally, dendritic cell function and cytotoxic T-cell activities are also enhanced to direct a response towards tumor associated antigens.

Oncolytic Virus: Talimogene laherparepvec (Imlygic ®)

Indication: Melanoma

More specifically, T-VEC is approved for regionally advanced melanoma that cannot be surgically removed.
T-VEC is the only FDA approved agent in its class.

Administration: Intralesionally

Injection of T-VEC into the tumor site has been associated with necrosis and apoptosis of tumor cells with observable response.
T-VEC may be repeated 3 weeks after the initial dose. All subsequent doses are administered at every 2 weeks interval for a total of 6 months or until no treatable lesions remain.
Although T-VEC is administered locally, it produces both local and systemic responses.

Dose: The dose of T-VE varies with the size of the tumor lesion with a dose range of 0.5 mL to 4 mL of 106 – 108 pfu/mL in phosphate-buffered saline. The lesion sizes ranges from 0.5 cm to >5 cm.

0.5 – 1.5 cm tumors: administer 0.5 mL
1.5 – 2.5 cm tumors: administer 1 mL
2.5 – 5 cm tumors: administer 2 mL
>5 cm tumors: administer 4 mL

Adverse events: The most common adverse events consist of fatigue, chills, pyrexia, nausea, influenza-like illness, and injection site pain.

Future directions: The use of T-VEC therapy has not been shown to improve overall survival in melanoma patients. Additionally, it is not beneficial for patients with visceral metastases. There is potential for combination therapy with T-VEC and other modes of immunotherapy in the future. It has been hypothesized with promising results shown in preclinical data, the effectiveness of combination therapy with T-VEC. T-VEC use with immune checkpoint inhibitors, ipilimumab and nivolumab are of special interest. Full and complete result of the clinical trials are still pending.

Pharmacoeconomic Considerations

The cost of cancer treatment has increased significantly over the past decade and is higher than other chronic medical conditions. It is estimated that the cost of cancer treatment in the United States will reach two hundred and six billion dollars in 2020.

Immune checkpoint inhibitors for melanoma have demonstrated a higher response rate and better progression free survival, albeit, with a higher cost. Results from studies that evaluated the cost effectiveness of sequencing immune checkpoint inhibitors for melanoma found that the most cost effective method for stage 3 or 4 BRAF wild-type melanoma was to use an anti-PD-1 agent as monotherapy followed by ipilimumab if there is not a desired response.

Cost analysis studies have found that identifying the appropriate patient for treatment is one of the key factors in reducing cost. Additionally, for non-small cell lung cancer, the most cost effective method in utilizing ant-PD-1/PD-L1 agents is in the second line setting.

With more biosimilars entering the market, there is a potential for decreased cost. However, the method in manufacturing these novel immunotherapy modalities are quite time and labor intensive that the reduction in cost of therapy may be very minimal.

Future Directions

Immunotherapy is intertwined in the past, present, and future of cancer treatment. Now that there are multiple immunotherapy agents approved, the future of immunotherapy looks at combination therapy for advancement in patient outcomes.

There are a few regimens that are FDA approved for use with combination immunotherapy. For example, targeted therapy using axitinib in combination with immunotherapy using pembrolizumab for renal cell carcinoma has shown positive results. Different immunotherapy agents have also been combined. The most significant one of impact is the combination of ipilimumab, a CTLA-4 inhibitor, with nivolumab, a PD-1 inhibitor.

Additionally, there have also been FDA approvals for PD-1/PD-L1 blockade in combination with chemotherapy for the indications of small cell lung cancer, non-small cell lung cancer, and head and neck squamous cell carcinoma. There are also over one hundred ongoing studies investigating the use of PD-1/PD-L1 inhibitors with chemotherapy.

Research into combination therapy with immunotherapy with immune checkpoint inhibitors and radiotherapy has shown a lack of significance in overall survival. However, multiple immunotherapy modalities with radiotherapy may show positive results.

Conclusion

Immunotherapy has gained traction over the last decade and it appears that it is here to stay. Immunotherapy has become incorporated into the treatment algorithms of many malignancies and rapidly expanding their indications.

Multiple modalities of immunotherapy include immune checkpoint inhibition, adoptive cell therapy, cytokine therapy, cancer vaccine, and oncolytic viral therapy. Of these modalities, the most successful have been immune checkpoint inhibition, leading to first line indications for malignancies.

Immunotherapy has changed the way clinicians view cancer treatment as it has provided improved survival rates for indications where extending overall survival was not previously achieved, especially in the treatment of melanoma.

As researchers gain further insight into the interaction between the immune system, the possibilities into the future of immunotherapy treatment is endless as combination therapy is the next frontier of immunotherapy.

Active Learning

Cancer Immunotherapy: A Brief Review of the History, Possibilities, and Challenges Ahead: The history of immunotherapy is long with many trials and tribulations that date back to over one hundred years ago. Through the years, the knowledge of the immune system and the tumor microenvironment has increased, which has led to the development of many different immunotherapy agents to target malignant cells. With the use of immunotherapy comes the complexity of adverse effect management and toxicities. https://jcmtjournal.com/article/view/2275/1732

Advances in Cancer Immunotherapy 2019 – Latest Trends: Immunotherapy is a novel modality of treatment, which has come with its own unique adverse events. Further questions have been raised about different modes of therapy with immunotherapy, such as targeted therapy, chemotherapy, radiation therapy, and peri-operative use. There are currently several ongoing clinical trials investigating the use of combination therapy with immune checkpoint inhibitors and chemotherapy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585101/

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