Pharmacologic Modulation of Human Immunity in the Era of Immuno-oncology: Something Old, Something New

REVIEW

Pharmacologic Modulation of Human Immunity in the Era of Immuno-oncology: Something Old, Something New Anagha Bangalore Kumar, MBBS; Rachel Maus, PhD; and Svetomir N. Markovic, MD, PhD Abstract The concept of exploiting the immune system to treat cancer forms the basis of immuno-oncology. Since its birth in the late 1800s, immuno-oncology, or cancer immunotherapy, has come a long way. With better understanding of the complex relationship between tumor and the immune system, we have been able to explore and develop various modalities of anticancer therapies. In this review, we summarize the main strategies of immunotherapy that are available today: monoclonal antibodies, anticancer vaccines, cytokines, and adoptive T-cell therapy. We also highlight the unique set of adverse effects associated with modern immunotherapy and propose nonsteroidal immunomodulators and anticytokine antibodies as treatment options for toxicities. The future of immuno-oncology is discussed, including combination therapy, drug-antibody conjugates, epigenetic drugs, using nanoparticles for drug delivery, new antigen discovery, and developing biomarkers to assess treatment responses. A data search was conducted using PubMed and included studies published through November 1, 2017. Search terms used include cancer immunotherapy, pembrolizumab, ipilimumab, nivolumab, PD-1 inhibitors, PD-L1 inhibitors, checkpoint inhibitors, anticancer vaccines, TVEC, and adoptive cell therapy. ª 2018 Mayo Foundation for Medical Education and Research

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n recent times, immunotherapy has emerged as a promising treatment option in medicine. Immunotherapy modifies the immune system by augmentation or suppression of immune responses to obtain a desired effect. As such, immunomodulators have found applications in various fields of medicine, such as dermatology, rheumatology, immunology, and oncology. This review summarizes the various uses of immunotherapy in oncology, discusses practical considerations, and proposes possible applications in the future. The immune system and cancer have a complex relationship such that advanced cancer causes immune suppression, and an immunosuppressed state can predispose to cancer. Tumors use various mechanisms to evade antitumor responses. When the immune system recognizes a tumor, it destroys the cells it can from the tumor. This forms the elimination phase, also called the phase of immune surveillance. The tumor cells that escape the initial immunosurveillance enter the phase of

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equilibrium, during which these cells undergo mutations to evade immune response. These tumor cells are said to undergo “cancer immunoediting,” during which they are continuously groomed with properties/mutations to bypass immune-based killing. By the time tumor cells enter the escape phase they have accumulated enough mutations to elude the immune system and grow unchallenged.1 Most of the time, tumor cells downregulate major histocompatibility complex expression, thus reducing their presentation to the immune system. Tumors also use the “brakes” of the immune system, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyteeassociated protein 4 (CTLA-4), to turn down immune responses.2,3 Some tumors attract myeloid-derived suppressor cells and interfere with their maturation, thus reducing antitumor immunity. Also, regulatory T cells dampen immune responses against tumors.4 The idea of harnessing the immune response to fight cancer dates back to the times of Dr William Coley. Since then we have made many

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From the Department of Medical Oncology, Mayo Clinic, Rochester, MN.

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ARTICLE HIGHLIGHTS d

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The various modalities of immuno-oncology are monoclonal antibodies, anticancer vaccines, cytokines, and adoptive T-cell therapy. Immunotherapy is associated with a unique range of adverse effects involving the skin, gastrointestinal system, endocrine organs, respiratory system, bones, and joints. Immune-related adverse effects are managed with corticosteroids and additional immunosuppression (biologicals) depending on the grade of toxicity. Combinations of checkpoint inhibitors with other checkpoint inhibitors/chemotherapeutic agents/epigenetic drugs are being increasingly experimented with in the clinic.

attempts to use our immune system in immunooncology. ERA OF ANTIBODIES It was only in the 1970s that monoclonal antibodies for specific targets were developed. Monoclonal antibodies bind to the antigens expressed on the tumor cells and bring about their action. They exert antitumoral responses by 1 of these mechanisms:(1) direct cytotoxicity by inducing apoptosis or downregulating signals of cell survival; (2) delivery of cytotoxic and radiotherapeutic agents; (3) antibodydependent cell-mediated cytotoxicity and complement-dependent cytotoxicity; (4) targeting growth factors and vasculature, thereby preventing tumor growth; or (5) targeting the supporting junctions with stromal cells or microenvironment.5-7 IMMUNE CHECKPOINT BLOCKADE A member of the CD28:B7 immunoglobulin family, CTLA-4 functions as an immune checkpoint. On binding to B7 present on the antigen-presenting cells, CTLA-4 downregulates T-cell activation.8 It plays an important role in preventing autoimmunity by preventing excessive T-cell activation. Figure 1 explains the action of CTLA inhibitors. Ipilimumab is an antieCTLA-4 antibody that causes blockade of CTLA-4, resulting in prolonged T-cell activation, proliferation, and antitumor response. 2

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Ipilimumab in Melanoma In 2011, the Food and Drug Administration (FDA) approved ipilimumab, a CTLA-4 inhibitor, as first-line therapy for metastatic melanoma based on phase 3 trials. In the phase 3 trial conducted by Hodi et al,9 676 patients with melanoma were enrolled: 403 received ipilimumab 3 mg/kg plus glycoprotein 100 peptide vaccine, 136 received only the vaccine, and 137 patients received only ipilimumab. The median overall survival (OS) of patients in the ipilimumab group was 10 months vs 6.4 months in those who received only the vaccine. There was no difference in the OS between the 2 ipilimumab groups.9 Another phase 3 trial consisting of 502 patients compared ipilimumab 10 mg/kg plus dacarbazine vs placebo plus dacarbazine. The OS was increased in the ipilimumab group compared with the placebo group (11.2 vs 9.1 months).10 After the success of adjuvant ipilimumab in a metastatic setting, a trial was conducted comparing adjuvant ipilimumab 10 mg/kg with placebo in patients with resected stage III melanoma. Adjuvant ipilimumab was associated with increased relapse-free survival (RFS) (hazard ratio, 0.75; median RFS, 26.1 vs 17.1 months). These results subsequently led to the FDA approval of the drug in an adjuvant setting.11 Ipilimumab in Renal Cell Carcinoma Another study assessed the combination of nivolumab and ipilimumab vs sunitinib in more than 1000 patients with previously untreated advanced or metastatic renal cell carcinoma (RCC). The objective response (OR) and progression-free survival (PFS) rates were higher in the combination immunotherapy group in patients with intermediate or poor risk. However, in patients at favorable risk, the OR and PFS rates were higher in patients who received sunitinib.12 Ipilimumab in Hematologic Malignancies The efficacy of ipilimumab was studied in patients with hematologic malignancies who had relapsed after an allogenic transplant. Patients were initially treated with 3 mg/kg every 3 weeks, and then the dose was escalated to 10 mg/kg every 3 weeks. Of the 28 patients who were assessed, 11 had lymphoma. Although no XXX 2018;nn(n):1-20

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response was seen in patients receiving low-dose ipilimumab, of 22 patients who received a dose of 10 mg/kg, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had a decreased tumor burden.13 Ipilimumab in Prostate Cancer In a randomized phase 3 trial enrolling 799 patients, ipilimumab was compared with placebo after radiotherapy in patients with metastatic castrationresistant prostate cancer that had progressed after docetaxel chemotherapy. There was no significant difference in OS in both groups; however, ipilimumab displayed antitumor activity that warrants further investigation.14 Ipilimumab in Lung Cancer A recent phase 3 trial reported that the addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous nonesmall cell lung cancer (NSCLC).15 PROGRAMMED CELL DEATH INHIBITORS Programmed cell death 1 is an immune checkpoint belonging to the CD28/CTLA-4 receptor family. It binds to 2 known ligands: programmed death ligand-1 (PD-L1) and PD-L2. Once PD-1 binds to PD-L1, it downregulates T-cell functioning. Inhibitors of PD-1 and PDL1 are being used in various malignancies.16,17 Figure 2 explains the action of antiePD-1 and antiePD-L1 blockers. Table 1 summarizes the FDA-approved checkpoint inhibitor monoclonal antibodies. PD-1 Inhibitors in Melanoma In a phase 3 trial, pembrolizumab was compared in 2 different doses with ipilimumab. There were 834 patients with melanoma enrolled in the study and divided in a 1:1:1 ratio into groups receiving pembrolizumab 10 mg/kg every 2 weeks or 3 weeks and ipilimumab 3 mg/kg every 3 weeks. The 6-month PFS rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for the ipilimumab group. Efficacy was similar in the 2 pembrolizumab groups; the OR rate was 33% with pembrolizumab and 12% with ipilimumab.18 Nivolumab is another FDA-approved antiePD-1 antibody. In a phase 3 trial of patients with metastatic melanoma, nivolumab Mayo Clin Proc. n XXX 2018;nn(n):1-20 www.mayoclinicproceedings.org

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FIGURE 1. The action of cytotoxic T-lymphocyteeassociated protein (CTLA) inhibitors. Ipilimumab is an antieCTLA-4 antibody that causes blockade of CTLA-4, resulting in prolonged T-cell activation, proliferation, and antitumor response.

was compared with chemotherapy (investigators’ choice). The OR rate was 32% in the nivolumab group compared with 11% in the chemotherapy group.19 In another phase 3 trial, nivolumab alone was compared with nivolumab plus ipilimumab and ipilimumab alone. The OR rate with nivolumab was 43.7%, with combination therapy was 57.6%, and with ipilimumab monotherapy was 19%.20 In 2015, the combination of nivolumab and ipilimumab was approved for advanced melanoma. PD-1/PD L-1 Inhibitors in Lung Cancer Reck et al,21 in a randomized controlled phase 3 trial, compared the efficacy of pembrolizumab with that of chemotherapy. Of 305 patients with NSCLC included in the study, 154 received pembrolizumab 200 mg for 3 weeks or chemotherapy. The group taking pembrolizumab had significantly longer PFS (10.3 months vs 6 months). In the pembrolizumab group, there were fewer grade 3 adverse reactions and a higher overall response rate.21 Based on these results, the FDA approved pembrolizumab as a frontline PD-1 inhibitor for NSCLC. Pembrolizumab was tested on patients with previously treated NSCLC with PD-L1 expression on at least 1% of tumor cells. These

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with epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations before receiving atezolizumab. This approval was based on the results of 2 international trials (OAK and POPLAR) testing more than 1100 patients. Atezolizumab was safe and efficacious, with a 4.2-month improved survival in patients in the OAK trial and a 2.9-month improved survival in the POPLAR trial.25,26

FIGURE 2. The action of antieprogrammed cell death 1 (PD-1) and antieprogrammed death ligand-1 (PD-L1) blockers.

patients were randomized to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel every 3 weeks. The median OS was significantly longer for patients receiving pembrolizumab (10.4 months in the 2 mg/kg group and 12.7 months in the 10 mg/kg group vs 8.5 months in the docetaxel group). Overall, this trial found that pembrolizumab was relatively well tolerated and effective in patients with previously treated NSCLC with PD-L1 expression. The 22C3 clone of PD-L1 detection by immunohistochemical analysis was also approved as a diagnostic test to identify tumors with PD-L1 expression.22 In 2015, nivolumab was approved for nonsquamous NSCLC after a phase 3 trial that found an increase of 3.2 months in OS and a 17% improvement in 2-year survival for patients with metastatic squamous NSCLC who had progressed while receiving platinumbased chemotherapy.23 In another randomized study, nivolumab had superior clinical benefit to docetaxel in patients with nonsquamous NSCLC. The FDA approved nivolumab for nonsquamous NSCLC and also a complementary test for PD-L1 by immunohistochemical analysis to guide physicians for nivolumab treatment.24 Atezolizumab is a PD-L1 inhibitor approved for the treatment of patients with metastatic NSCLC whose disease progressed during or after platinum-containing chemotherapy. Patients 4

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PD-1/PD L-1 Inhibitors in Genitourinary Malignancies Atezolizumab, an antiePD-L1 inhibitor, was proved to be safe and effective in advanced urothelial carcinoma. Compared with chemotherapy, the response was rapid and durable, and these results lead to accelerated FDA approval of the drug in metastatic urothelial carcinoma.39 However, atezolizumab was not associated with significantly longer OS than was chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1.40 In a large phase 2 study, nivolumab was tried on 270 patients with locally advanced or metastatic urothelial carcinoma who had progressed while receiving platinum-based chemotherapy. The OR was 19.6%, and, based on this study, nivolumab was granted accelerated approval for use in locally advanced or metastatic urothelial carcinoma who progress during or after platinum-based chemotherapy for metastatic disease or those who have disease progression within 1 year of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.28 Seventeen patients with castration-resistant prostate cancer were treated with nivolumab in an early-phase trial, but no objective response was noted.41 Durvalumab was approved for locally advanced or metastatic urothelial carcinoma who progressed during or after treatment with platinum-based chemotherapy or those who progressed within 1 year of neoadjuvant or adjuvant therapy with platinum-based chemotherapy based on a trial of 191 patients who had an OR rate of 18% and median OS of 18.2 months.27 Avelumab was found to be safe and efficacious in 44 patients with metastatic urothelial XXX 2018;nn(n):1-20

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Drug name

Target

Atezolizumab (Tecentriq; PD-L1 inhibitor, marketed by Genentech) humanized

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Avelumab (Bavencio; EMD Serono)

PDL-1 inhibitor, human

Durvalumab (Imfinzi; AstraZeneca)

PD-L1 inhibitor, human

Ipilimumab (Yervoy; Bristol-Myers Squibb)

CTLA-4, human

Nivolumab (Opdivo; Bristol-Myers Squibb)

PD-1 checkpoint inhibitor, human

Immunologic relevance

FDA-approved indication (year)

Locally advanced/metastatic bladder cancer progressing during/after platinum-based chemotherapy or within 12 mo of chemotherapy (2016) Metastatic NSCLC progressing during/after platinum-based chemotherapy; for patients with EGFR or ALK mutations whose cancer is progressing while receiving therapy for the mutation (2016) Initial treatment of locally advanced/metastatic bladder cancer in patients ineligible for cisplatin chemotherapy or within 12 mo of chemotherapy (2017) First- or second-line therapy for metastatic PD-L1 binding to PD-1 releases inhibitory Merkel cell carcinoma (2017) stimuli for T-cell activation, proliferation, Locally advanced/metastatic bladder cancer that and survival progressed during/after platinum-based chemotherapy or within 12 mo of neoadjuvant treatment (2017) Locally advanced/metastatic bladder PD-L1 binding to PD-1 releases inhibitory cancer progressing during/after stimuli for T-cell activation, proliferation, platinum-based chemotherapy or and survival within 12 mo of chemotherapy (2017) CTLA-4 protein is present on T cells, functions Adjuvant (after surgery) therapy for stage III melanoma (2015) as an immune checkpoint; when bound to Unresectable melanoma and no BRAF V600 mutation, CD80/CD86 on antigen-presenting cells, it combined with nivolumab (2015) acts as an off switch and downregulates T-cell Metastatic melanoma (2011) activation and proliferation Metastatic melanoma or unresectable melanoma PD-1 acts as an immune checkpoint; PD-L1 after ipilimumab or BRAF inhibitor (2014) binding to PD-1 releases inhibitory stimuli for Unresectable/metastatic melanoma without BRAF T-cell activation, proliferation, and survival V600 mutation, combined with ipilimumab (2015) Metastatic squamous NSCLC during/after platinumbased chemotherapy (2015) Metastatic NSCLC progressing during/after platinumbased chemotherapy; for patients with EGFR or ALK mutations whose cancer is progressing while receiving therapy for the mutation (2016) Advanced renal cell carcinoma after antiangiogenic therapy (2015) Unresectable metastatic melanoma, combined with PD-L1 binding to PD-1 releases inhibitory stimuli for T-cell activation, proliferation, and survival

Adverse effects Immune-related effects, nausea, fatigue, infections

Immune-related adverse effects, nausea, rash

Fatigue, musculoskeletal pain, constipation, swelling of extremities Immunologic adverse effects, diarrhea, demyelination

Immune-mediated inflammation of lungs, colon, liver, kidney, rash

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TABLE 1. Summary of the FDA-Approved Checkpoint Inhibitor Monoclonal Antibodies10,11,18-38

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Pembrolizumab (Keytruda; Merck)

Target

n

PD-1 checkpoint inhibitor, humanized

Immunologic relevance

FDA-approved indication (year)

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Immune-related inflammation of endocrine organs, lungs, kidney, rash, fatigue, infections

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ipilimumab with or without a BRAF mutation (2016) Metastatic melanoma with a BRAF V600 mutation or melanoma that cannot be removed surgically (2016) Relapsed/progressing classical Hodgkin lymphoma after autologous hematopoietic stem cell transplant þ brentuximab vedotin or after 3 systemic therapies (2016) Recurrent/metastatic HNSCC progressing during/after platinum-based chemotherapy (2017) Locally advanced/metastatic bladder cancer progressing during/after platinum-based chemotherapy or within 12 mo of chemotherapy(2017). Advanced hepatocellular carcinoma that had progressed on or was intolerant of sorafenib (2017) Metastatic NSCLC expressing PD-L1 and progressing PD-1 acts as an immune checkpoint; PD-L1 during/after platinum-based chemotherapy; for patients binding to PD-1 releases inhibitory stimuli for with EGFR or ALK mutations whose cancer is progressing T-cell activation, proliferation, and survival while receiving therapy for the mutation (2015) Advanced/unresectable refractory melanoma (2014) Initial treatment of unresectable/metastatic melanoma (2015) Recurrent/metastatic HNSCC progressing during/after platinum-based chemotherapy (2016) Initial treatment of metastatic NSCLC with PD-L1 expression and no EGFR/ALK mutation (2016) Classical Hodgkin lymphoma not responding to therapy or relapsed after more therapies (2017) Initial treatment of metastatic nonsquamous NSCLC combined with pemetrexed and carboplatin, with or without PD-L1 expression (2017) Initial treatment of locally advanced/metastatic bladder cancer in patients ineligible for cisplatin-based chemotherapy (2017) Locally advanced/metastatic bladder cancer progressing

Adverse effects

during/after platinum-based chemotherapy or within 12 mo of chemotherapy (2017) Any unresectable/metastatic solid tumor with certain genetic marker and disease progression after previous treatment and for colorectal cancer progressing after fluoropyrimidine, oxaliplatin þ irinotecan (2017) Locally advanced/metastatic gastric or gastroesophageal junction cancer with positive PD-L1 expression (2017)

ALK ¼ anaplastic lymphoma kinase; CTLA-4 ¼ cytotoxic T-lymphocyteeassociated protein 4; EGFR ¼ epidermal growth factor receptor; FDA ¼ Food and Drug Administration; HNSCC ¼ head and neck squamous cell carcinoma; NSCLC ¼ nonesmall cell lung cancer; PD-1 ¼ programmed cell death 1; PD-L1 ¼ programmed death ligand-1.

Drug name

TABLE 1. Continued

Target

Immunologic relevance

FDA-approved indication (year)

Adverse effects

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carcinoma with an OR rate of 18.2% and median OS of 13.7 months. This lead to accelerated approval of the drug in locally advanced or metastatic urothelial carcinoma who progressed during or after treatment with platinum-based chemotherapy or those who progressed within 1 year of neoadjuvant or adjuvant therapy with platinum-based chemotherapy.29 Pembrolizumab has been studied in patients ineligible for cisplatin, with successful results leading to FDA approval for use in this cohort. Three hundred seventy-four patients were enrolled in the study, and the OR rate was 29%. In a phase 3 trial on 542 patients who had recurred or progressed while receiving platinum-based chemotherapy, the OR and median OS rates were increased in the pembrolizumab group compared with the chemotherapy group. This lead to accelerated approval of the drug in locally advanced or metastatic urothelial carcinoma in patients who progressed during or after treatment with platinum-based chemotherapy or those who progressed within 1 year of neoadjuvant or adjuvant therapy with platinum-based chemotherapy.30 A large multicenter trial assessed 821 patients with advanced RCC who progressed after at least 1 antiangiogenic therapy. These patients were randomized to receive nivolumab or everolimus. The OR and median OS rates were superior in patients receiving nivolumab vs everolimus (25% vs 5% and 25 months vs 19.6 months), leading to FDA approval of the drug for use in advanced RCC who progressed after at least 1 antiangiogenic therapy.31

PD-1 Inhibitors in Lymphoma Nivolumab has been FDA approved for the treatment of relapsed or refractory classic Hodgkin lymphoma that has progressed after autologous stem cell transplant and posttransplant brentuximab vedotin. The approval was based on 2 trials in which nivolumab had a good response rate and tolerability profile.32 Pembrolizumab was approved for the treatment of relapsed or refractory classic Hodgkin lymphoma after failure of at least 3 previous lines of therapy. The approval was based on a phase 2 trial in which 210 patients (69%) experienced a response.33,34

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TABLE 2. Monoclonal Antibodies Approved for Treatment of Cancer44-61 Name

Target, source

Indication

Ado-trastuzumab HER2, conjugated with drug emtansine (Drug causes inhibition of HER2 signaling, ADCC)

Alemtuzumab Bevacizumab

CD52, humanized (Drug causes ADCC, CMC and induces apoptosis) VEGFA, recombinant humanized (Drug inhibits VEGF signaling)

Blinatumomab

CD19 (ADCC)

Brentuximab

CD30 chimeric, conjugated with the drug auristatin E (Antibody delivers cytotoxic drug)

Cetuximab

EGFR, chimeric (Inhibition of EGFR signaling, ADCC)

Daratumumab

CD38 (ADCC, CDC)

Denosumab

RANKL, human (Inhibition of RANKL signaling)

Dinutuximab

Glycolipid GD2 (ADCC, CDC)

Elotuzumab

CD319 (SLAMF7-directed)

Ibritumomab

CD20 murine, conjugated with yttrium90 or indium111 (Delivers radioisotope yttrium90)

Necitumumab

EGFR (Inhibition of EGFR signaling, ADCC)

As a single agent, for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either received previous therapy for metastatic disease or developed disease recurrence during or within 6 mo of completing adjuvant therapy. Single agent for the treatment of B-cell CLL Metastatic colorectal cancer when used with standard chemotherapy treatment (as first-line treatment) and with 5-fluorouracilebased therapy for second-line metastatic colorectal cancer First-line advanced nonsquamous NSCLC combined with carboplatin/ paclitaxel chemotherapy Metastatic renal cell carcinoma Glioblastoma multiforme Philadelphia chromosomeenegative relapsed or refractory B-cell precursor acute lymphoblastic leukemia Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of 2 previous multiagent chemotherapy regimens in patients who are not autologous stem cell transplant candidates Systemic anaplastic large cell lymphoma after failure of 1 previous multiagent chemotherapy regimen Combined with radiotherapy for treating head and neck squamous cell carcinoma or as a single agent in patients who have had previous platinum-based therapy Combined with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received 1 previous therapy As monotherapy, for the treatment of patients with multiple myeloma who have received 3 previous lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to it. Prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. Treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity Combined with granulocyte-macrophage colony-stimulating factor, IL2, and 13-cis-retinoic acid, for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to previous first-line multiagent, multimodality therapy Combined with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received 1-3 previous therapies. Relapsed or refractory, low-grade or follicular B-cell non-Hodgkin lymphoma Patients with previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy Combined with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous NSCLC Continued on next page

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TABLE 2. Continued Name

Target, source

Obinutuzumab

CD20 humanized (Drug causes ADCC, CMC and induces apoptosis)

Ofatumumab

CD20, human (ADCC, CMC)

Olaratumab

Platelet-derived growth factor receptor-a

Panitumumab

EGFR, human (Antibody inhibits EGFR signaling)

Pertuzumab

HER2, humanized (Inhibits HER2 signaling)

Ramucirumab

VEGFR2 (Drug inhibits VEGF signaling)

Indication Combined with chlorambucil, for the treatment of patients with previously untreated CLL Combined with bendamustine followed by Gazyva monotherapy, for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen Combined with chemotherapy followed by Gazyva monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma Combined with chlorambucil, for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate Combined with fludarabine and cyclophosphamide for the treatment of patients with relapsed CLL For extended treatment of patients who are in complete or partial response after 2 lines of therapy for recurrent or progressive CLL For the treatment of patients with CLL refractory to fludarabine and alemtuzumab Combined with doxorubicin, for the treatment of adult patients with soft-tissue sarcoma with a histologic subtype for which an anthracycline-containing regimen is appropriate and that is not amenable to curative treatment with radiotherapy or surgery. Metastatic colorectal carcinoma with disease progression on or after fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy regimens Use in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive metastatic breast cancer who have not received previous anti-HER2 therapy or chemotherapy for metastatic disease. Use in combination with trastuzumab and chemotherapy as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either >2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer Adjuvant treatment of patients with HER2-positive early breast cancer at high risk for recurrence As a single agent or combined with paclitaxel, for treatment of advanced gastric or gastroesophageal junction adenocarcinoma, with disease progression on or after previous fluoropyrimidine- or platinum-containing chemotherapy Combined with docetaxel, for treatment of metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations before receiving Cyramza. Combined with FOLFIRI, for the treatment of metastatic colorectal cancer with disease progression on or after previous therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine Continued on next page

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TABLE 2. Continued Name

Target, source

Rituximab

CD20, chimeric (Drug causes ADCC, CMC, induces apoptosis)

Trastuzumab

HER2/neu, humanized (Inhibits HER2 signaling)

Indication NHL CLL FL Relapsed or refractory, FL as a single agent Previously untreated FL, combined with first-line chemotherapy and, in patients achieving a complete or partial response to rituximab combined with chemotherapy, as single-agent maintenance therapy Nonprogressing (including stable disease), FL as a single agent after firstline cyclophosphamide, vincristine, and prednisone chemotherapy Treatment of HER2-overexpressing breast cancer Treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma

ADCC ¼ antibody-dependent cell-mediated cytotoxicity; ALK ¼ anaplastic lymphoma kinase; CDC ¼ complement-dependent cytotoxicity; CLL ¼ chronic lymphocytic leukemia; CMC ¼ complement-mediated cytotoxicity; EGFR ¼ epidermal growth factor receptor; FDA ¼ Food and Drug Administration; FL ¼ follicular lymphoma; NHL ¼ non-Hodgkin lymphoma; NSCLC ¼ nonesmall cell lung cancer; RANKL ¼ receptor activator of nuclear factor-kB; VEGF ¼ vascular endothelial growth factor.

PD-1 Inhibitors in Gastric Cancer The FDA recently approved pembrolizumab for use in locally advanced or metastatic gastric or gastroesophageal junction cancer with positive PD-L1 expression based on a phase 2 trial of 259 patients who had progressed while receiving at least 2 chemotherapy regimens. These patients had a response rate of 13.3%, and pembrolizumab was tolerated well.42

PD-1 Inhibitors in Hepatobiliary Cancer Nivolumab was approved for use in patients with advanced hepatocellular carcinoma who had progressed on or were intolerant of sorafenib. This approval followed the results of a trial that found that nivolumab was well tolerated and that the OR rate was 20% in patients with hepatocellular carcinoma.35

PD-1 Inhibitors in Colorectal Cancer Pembrolizumab was evaluated in a phase 2 study of 28 patients with colorectal cancer with DNA mismatch repair (MMR) abnormalities and 25 patients with proficient MMR. Whereas the OR rate was 50% in the DNA MMR group, it was 0% in those with proficient MMR. The FDA granted accelerated approval of pembrolizumab for use in patients with advanced microsatellite instability or DNA MMR metastatic colorectal carcinoma 10

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who progressed while receiving conventional chemotherapy.36 PD-1 Inhibitors in Head and Neck Squamous Cell Carcinoma Pembrolizumab was approved for use in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) progressing during/ after platinum-based chemotherapy. In a trial enrolling 174 patients with HNSCC, the OR rate was reported to be 16%, and 59% of patients were alive after 6 months.43 Nivolumab was evaluated in 361 patients with HNSCC. These patients were randomized to receive either nivolumab or single-agent therapy of the investigators’ choice. The OS rate was significantly longer in those receiving nivolumab (7.5 months vs 5.1 months), and the OR rate was also higher in the nivolumab group (13.3% vs 5.8%). Nivolumab was granted FDA approval based on these results.37 PD-1 Inhibitors in Merkel Cell Carcinoma Avelumab was granted approval for use in Merkel cell carcinoma after a trial enrolling 88 patients reported an OR in 28 patients and 69% OS at 6 months.38 OTHER MONOCLONAL ANTIBODIES APPROVED FOR CANCER THERAPY Monoclonal antibodies approved for treatment in cancer are summarized in Table 2. Rituximab XXX 2018;nn(n):1-20

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TABLE 3. Unique Set of Immune-Related Adverse Effects Surfaced With Use of Immune Checkpoint Inhibitors64-72 Immune-related adverse effect

Grade 1

Grade 2

Diarrhea

Manage conservatively

Hepatitis

Careful monitoring Hold therapy, start corticosteroids, of LFTs weekly monitor LFTs twice weekly until grade 1 or lower; can rechallenge with immunotherapy after corticosteroid tapering and continued LFT monitoring Conservative with Oral corticosteroid antihistamines, Withhold treatment until rash improves to grade 1 and topical corticosteroid tapering has been corticosteroids done to a dose of 10 mg of prednisone or equivalent Continue therapy Withhold treatment for grade 2 and higher, begin corticosteroids and with frequent carefully monitor for worsening of monitoring and frequent imaging respiratory status and hypoxia. Hospitalize patients with abnormal oxygen saturation and start highdose IV corticosteroids. Those who do not improve may require bronchoscopy. Patients with grade 2 once corticosteroids are tapered to 10 mg of prednisone can be challenged with immunotherapy Weekly monitoring Withhold treatment, start of renal corticosteroids 0.5 mg/kg; parameters Grade 2 and higher require referral to nephrologist Observe closely Withhold treatment

Dermatologic

Pulmonary toxicity

Renal toxicity

Neurologic toxicity Rheumatologic toxicity Ocular

Thyroid dysfunction

Hold treatment until patients return to grade 1

Grade 3

Grade 4

Corticosteroid refractory Corticosteroids at any Discontinue treatment for grade 3 or grade, grade 3 or higher: higher with this exception: as assessed by antieCTLA-4 agents have higher gastroenterologist, flexible rates of diarrhea, patients who sigmoidoscopy/ recovered to below grade 2 and colonoscopy, may need discontinued corticosteroids can be biologicals rechallenged with antiePD-1 therapy Grade 3 or higher or corticosteroidrefractory hepatitis: referral to hepatologist

Grade 3 or higher, withhold treatment Evaluate blisterlike lesions, mucosal lesions, and patients Start higher doses of corticosteroids, with fever to rule out refer to dermatologist StevensJohnson syndrome, toxic epidermal necrolysis Grade 3 or 4 should not receive further immunotherapy; consider need for additional immunosuppression

Grade 3 and higher, permanently discontinue treatment

Corticosteroids, consult rheumatology, Mild symptoms: assess need for other biologicals manage conservatively Mild symptoms: Topical corticosteroid drops, lubricating drops intraocular injection, refer to ophthalmologist Severe symptoms: hospitalize, IV Asymptomatic, no Symptomatic hypothyroidism: corticosteroids levothyroxine intervention needed: monitor Symptomatic hyperthyroidism: endocrinology consult, start only b-blocker

CTLA-4 ¼ cytotoxic T-lymphocyteeassociated protein 4; IV ¼ intravenous; LFT ¼ liver function test; PD-1 ¼ programmed cell death 1.

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was one of the first antibodies to be used in the treatment of cancer. Combined with fludarabine and cyclophosphamide, it has achieved longer periods of survival in lymphoma. Studies have found that when added to the standard regimen for B-cell lymphoma, 70% of patients achieved complete remission vs 40% to those who received standard treatment only.62 Trastuzumab blocks human epidermal growth factor receptor 2 signaling required for the growth of cancerous cells. When trastuzumab is added to the standard chemotherapeutic regimen, it increases disease-free survival by 10%.63 As more patients are being treated with immunotherapy, there will be more patients who are at risk for toxicities due to these drugs. The incidence of these adverse effects varies depending on the agent used. Table 3 summarizes the commonly seen adverse effects of checkpoint inhibitors and their management according to the grade of adverse effect. The most commonly seen adverse effects involve the skin, colon, endocrine organs, and liver. As mentioned in Table 3, most of the immunerelated adverse effects are treated with corticosteroids. There are several FDA-approved drugs in the market to treat immune-related diseases, such as rheumatoid arthritis, ulcerative colitis, and Crohn disease. These drugs would specifically target the immunologic consequences of immunotherapeutic agents without interfering with their anticancer activity. We propose that these drugs could be used to address the immune-related adverse effects of newer immunotherapeutic agents. Infliximab (tumor necrosis factor [TNF]-a inhibitor) was used in the clinic successfully to treat severe or corticosteroid-refractory colitis due to immunotherapy.64-66 A recent case series reported successful treatment of checkpoint-related colitis with vedolizumab (integrin inhibitor).67 Similarly, another case series reported the use of tocilizumab (interleukin [IL]-6 inhibitor) in immunotherapyinduced arthritis.68 Studies reported that many patients needed additional immunosuppression (TNF-a inhibitors, azathioprine, mycophenolate mofetil, tacrolimus) after corticosteroids to manage immune-related adverse effects.69-72 It would be interesting to try other TNF-a inhibitors, IL inhibitors, and integrin inhibitors to manage immune-related adverse 12

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effects. Table 4 describes the biological agents that are used for immune-related diseases and their possible use in treating immune-related consequences of cancer immunotherapy. ADOPTIVE CELL THERAPY Adoptive cell therapy (ACT) aims to fight cancer with the use of lymphocytes, usually a mixture of CD8 and CD4 cells. Theoretically it is an ideal modality of cancer treatment because T cells develop tumor-specific immune response, retain memory, and can launch a robust response. Lymphocytes are isolated from the patient’s blood, tumor, and draining lymph nodes. They are then cultured, expanded ex vivo, and infused back into the patient’s bloodstream. Figure 3 describes the concept of ACT. Some of the different types of ACT are tumor-infiltrating lymphocytes (TILs), antigen-specific autologous T-cell clones, donor antitumor lymphocytes, and, more recently, genetically engineered human lymphocytes.80 In a landmark publication, 86 patients with melanoma were treated with either TIL or high-dose IL-2 over 5 years. The OR in the TIL group was 36%, and 5 patients had a complete response.81 Several trials in patients with melanoma have reported a sustained durable response with TIL, especially when it is preceded by a lymphodepletion conditioning regimen. The phase of lymphodepletion eliminates immunosuppressive cells such as regulatory T cells and increases the availability of local cytokines.82,83 Rosenberg et al84 enrolled 93 patients with metastatic melanoma refractory to standard therapy. The patients were exposed to cytotoxic chemotherapy that causes lymphodepletion. The OR ranged from 49% to 72%. Complete regression of tumor was seen in 20 patients. The response was more favorable in patients with greater lymphodepletion.84 Although ACT relies on endogenous T-cell repertoire, recent advances in biotechnology allow induction of tumor-specific T-cell receptors or chimeric antigen receptors (CARs). The CARs exhibit high-affinity major histocompatibility complex independent recognition of any antigen.85 In CAR T-cell (CAR-T) therapy, T cells of patients with B-cell tumors are transfected with anti-CD19 and, thus, they gain the capacity to recognize B cells in all stages of development. The recently developed XXX 2018;nn(n):1-20

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TABLE 4. Biological Agents That Are Used for Immune-Related Diseases and Their Possible Use in Treating Immune-Related Consequences of Cancer Immunotherapy73-79

Drug name

Target

FDA-approved indication

IL-1

Cryopyrin-associated periodic syndromes, including familial cold autoinflammatory syndrome and Muckle-Wells syndrome in adults and children 12 y, gout Neonatal-onset multisystem inflammatory disease, moderate-severe rheumatoid arthritis Moderate-severe plaque psoriasis Psoriasis Psoriasis, psoriatic arthritis, ankylosing spondylitis Rheumatoid arthritis Cytokine release syndrome, rheumatoid arthritis, systemic juvenile idiopathic arthritis, temporal arthritis Cryopyrin-associated periodic syndromes, tumor necrosis factor receptoreassociated periodic syndrome, hyperimmunoglobulin D syndrome/ mevalonate kinase deficiency, and familial Mediterranean fever Crohn disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and chronic severe plaque psoriasis Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn disease Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis Rheumatoid arthritis Crohn disease Crohn disease and ulcerative colitis After organ transplant

Rilonacept (Arcalyst)

Anakinra (Kineret)

IL-1 receptor

Brodalumab (Siliq) Ixekizumab (Taltz) Secukinumab (Cosentyx) Sarilumab (Kevzara) Tocilizumab (Actemra)

IL-17 IL-17 IL-17 IL-6 receptor IL-6 receptor

Canakinumab (Ilaris)

IL-1b

Infliximab (Remicade)

TNF-a inhibitor

Adalimumab (Humira)

TNF-a inhibitor

Etanercept (Enbrel)

TNF-a inhibitor

Golimumab (Simponi)

TNF-a inhibitor

Certolizumab (Cimzia) Natalizumab (Tysabri) Vedolizumab (Entyvio) Mycophenolate mofetil (CellCept)

TNF-a inhibitor a4 integrin integrin a4b7 Inosine monophosphate dehydrogenase inhibitor

Tacrolimus (Prograf, Advagraf)

Inhibits production of IL-2

After organ transplant, atopic dermatitis

Cyclophosphamide (Endoxan)

Alkylating agent

Nephrotic syndrome

Azathioprine (Azasan)

Antimetabolite

Rheumatoid arthritis, after renal transplantation

Immune-related adverse effect that could be potentially targeted Arthritis

Arthritis Arthritis Arthritis Arthritis Arthritis Arthritis

Arthritis

Colitis, arthritis

Arthritis, colitis

Arthritis, skin rash Arthritis Arthritis Colitis Colitis Hepatotoxicity, pneumonitis, cardiac toxicity Hepatotoxicity, cardiac toxicity Renal toxicities, pneumonitis Arthritis

FDA ¼ Food and Drug Administration; IL ¼ interleukin; TNF ¼ tumor necrosis factor.

CAR-Ts are designed to have an extracellular domain that recognizes CD19 and an intracellular domain that stimulates production of cytokines.86 The first CAR-T was approved recently. This FDA approval was based on the results of an open-label, multicenter, Mayo Clin Proc. n XXX 2018;nn(n):1-20 www.mayoclinicproceedings.org

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single-arm, phase 2 trial in which 68 patients with acute lymphoblastic leukemia were infused with CAR-T, and results were assessed in 63 patients. The results showed a dramatic complete response in 83% of patients within 3 months of infusion. The median duration of

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FIGURE 3. The concept of adoptive cell therapy.

response was not reached. The most common adverse reactions were cytokine release syndrome, hypogammaglobulinemia, infections, pyrexia, and decreased appetite.87 ACT carries a risk of infection and is expensive and timeconsuming.88 Identifying the ideal tumor antigen, the cost, and the difficulty of the procedure have made this modality less popular. CYTOKINES Interferons (IFNs) possess antiviral and immunomodulatory properties.89 High-dose IFN-a is approved for hairy cell leukemia, malignant melanoma, FL, and Kaposi sarcoma. It was first tried in hairy cell leukemia and other lymphoproliferative and myeloproliferative neoplasms. Applying recombinant DNA technology, we have been able to produce recombinant IFN-a2b. Also, conjugation with polyethylene glycol (PEG) reduces toxicity of IFN. Efficacy is not altered by these modifications, but adverse effects are reduced. Treatment with IFN is associated with fever, flulike symptoms, chills, headaches, local reactions, and, rarely, hypotension, arrhythmia, confusion, and gastrointestinal distress. Use of PEG-IFN-a2b in high-risk melanoma is approved by the FDA. This approval was based on a large trial involving 1256 patients after surgical resection. The patients

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were randomized 1:1 in the PEG-IFN group and the other observation group. The PEG-IFN, 6 mg/kg per week, was administered subcutaneously for 8 doses, followed by 3 mg/ kg per week for up to 252 weeks. The median RFS times were 34.8 months in the group receiving PEG-IFN and 25.5 months in the observation group.90 Interleukin-2 is one of the key cytokines in the immune system with various effects mainly related to T-cell activation. It enhances cellular immunity through increasing white cells, eosinophils, and multiple cytokines. Aldesleukin, a recombinant IL-2, is a potent immunostimulator.91 High-dose IL-2 is indicated in metastatic renal cell carcinoma and melanoma. Highdose IL-2 was used in 255 patients with metastatic RCC, and the overall response rate was observed to be 14%.92 Similarly, 270 patients with metastatic melanoma had an OR rate of 16%.93 A recent analysis including 170 patients with metastatic melanoma and 192 patients with metastatic RCC treated with high-dose IL-2 was reported. In patients with melanoma, complete response was observed in 5%, partial response in 10%, stable disease in 22%, and progressive disease in 63%. The median OS for these patients was 19.6 months, and in patients with metastatic RCC the median OS was 41 months.94 Some of the adverse effects associated with IL-2 are capillary leak syndrome, hypotension, infections, and local reactions.95 VACCINES After decades of hard work and struggle, anticancer vaccines are now a reality. The FDA has approved vaccines to fight melanoma and prostate cancer. Numerous newer vaccines are being developed every day for different cancers. One of the toughest challenges in developing a vaccine is finding the ideal antigen. An ideal vaccine target antigen should be specifically expressed on tumor tissue, processed as peptide major histocompatibility complex class 1 complexes and easy to produce and administer. An anticancer vaccine should be able to stimulate dendritic cell (DC) maturation and promote the production of tumorspecific, CD8þ cytotoxic T cells.96

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Initially, short peptide vaccines were used as target antigens. Unfortunately, they could not be developed as vaccines in the clinic due to poor pharmacokinetic properties and poor efficacy. Then, recombinant proteins were created. Melanoma antigen family A3 is an antigen expressed on melanoma, NSCLC, and various hematologic malignancies.97 It, however, was not efficacious when tried in clinical trials. Cell-based vaccines were then tried as cancer vaccine antigens.98 An example of a whole tumor cell vaccine modified to produce cytokines is GVAX, which was tried in pancreatic cancer, but phase 3 was halted due to lack of vaccine efficacy.99 The DCs are antigen-presenting cells that play a vital role in triggering an immune response. One school of thought suggested that the use of high quantities of antigens targeting the DCs could be used to break the tolerance developed by cancer cells.98 To prepare DC vaccines, DCs are collected from the patient’s blood, treated with tumor antigens and maturation stimuli, and then reinfused back into the patient.100 Sipuleucel-T is a DC vaccine combined with prostatic acid phosphatase protein and granulocyte-macrophage colony-stimulating factor (GM-CSF). Studies have found a 4month increase in median survival in prostate cancer due to this vaccine. It has been approved for use in prostate cancer by the FDA since 2010.101 Preventive vaccines used in cancer immunology are human papilloma virus vaccine to prevent human papilloma viruseassociated cancers and hepatitis B virus vaccine to prevent hepatocellular carcinoma.102,103 Some vaccines have been tried but have not yielded successful results in clinical studies. Prostvac is a vaccine targeting prostatespecific antigen that was explored in the treatment of prostate cancer.104,105 Stimuvax is a vaccine containing CD4 and CD8 epitopes for proteoglycan expressed on several tumors. In a phase 2 trial, patients who received both the vaccine and best supportive care had median survival of 4.2 months higher than those who received best supportive care alone.106 BiovaxID is a personalized vaccine developed from the patient’s tissue

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biopsy that has given mixed results in follicular carcinoma.107,108 ONCOLYTIC VIRUS THERAPY Oncolytic viruses promote antitumor responses by infecting the tumor cell and initiating specific antitumor immunity.109 Scientists have used viral genome to reduce its pathogenicity and augment antitumor responses. Covalent conjugation of the viral coat with PEG can prevent the host immune response from developing an antiviral response.110 Genetic engineering also allows expression of desired cytokines to increase immune response.111 After the virus infects the tumor cells, it causes cell lysis, releasing tumor cell antigens. A sustained, specific CD8þ T-cellemediated response is developed against these tumor antigens. Talimogene laherparepvec (T-VEC) is a genetically modified oncolytic herpes simplex virus type-1. The genes for neuronal development are deleted and the coding sequence for GM-CSF is added to it.112 A phase 3 randomized controlled trial enrolling 439 patients with metastatic melanoma evaluated the efficacy of T-VEC. The patients were randomized into 2 arms at a ratio of 2:1 receiving T-VEC and GM-CSF, respectively. Better and durable responses were noted in patients of the T-VEC group. There were minimal adverse effects such as, fever, fatigue, nausea, and local site reaction.113 The FDA approved T-VEC to treat advanced melanoma in October 2015. Also, T-VEC has been tried in combination with other treatment strategies. A phase 1 trial of T-VEC combined with ipilimumab in melanoma had an OR rate of 50%, and 44% of patients had durable responses at 6 months.114 Talimogene laherparepvec was combined with chemoradiation for patients with HNSCC. At median follow-up of 29 months, locoregional control was 100% and RFS was 76%.115 FUTURE TRENDS IN IMMUNOTHERAPY For most patients, monotherapy is not entirely effective and there is a need to have a combination of drugs. Although CTLA-4 and PD-1 work on different signaling pathways, both facilitate T-cell activation. Thus, the combination of antiePD-1 and antieCTLA-4 has

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shown synergy in the clinic.98 In a recent randomized controlled phase 3 trial, the efficacy of monotherapy with either nivolumab or ipilimumab was compared with their combination, showing a greater response in the combination group.116 Although this combination increased antitumor immunity, it also added to the immunologic adverse effects. Because it is a novel combination, the longterm consequences are still unknown.117 Recently, the combination of chemoimmunotherapy is catching the attention of investigators. Chemotherapy can sensitize the tumor to immunotherapy in many ways.118 Recently, the combination of pembrolizumab and chemotherapy (pemetrexed and carboplatin) was granted FDA approval for NSCLC. Vascular endothelial growth factor inhibitors have been tried in combination with immunotherapy. Hodi et al119 used antieCTLA-4 inhibitors and bevacizumab and reported increased median OS of 25 months. Unfortunately, the inflammatory adverse effects were increased.119 A myriad of possible combinations exist along with checkpoint blockers as the main stem. Not just combining but appropriate timing of different therapies is essential for optimal results. A biomarker predicting the response to therapy would be a useful tool before initiating immunotherapy. It would help to identify the population that would benefit from treatment and prevent unnecessary cost and adverse effects in those who would not.120 Higher mutational load was found to have a direct effect on response to therapy.23,121 Similar studies showed that lymphocytes infiltrate improved survival.118 Expression of PD-L1 on tumors was a useful predictor for response to antiePD-1/PD-L1 therapy.41 Furthermore, epigenetic drugs have been used to improve cancer immunoresponsivity. Epigenetic drugs such as DNA methyltransferases and histone deacetylases modify the expression of genes and reverse immune suppression through various mechanisms. Epigenetic drugs increase the expression of tumorassociated antigens, and the host immune system works with these drugs to better recognize tumors. These drugs also enhance the efficacy of checkpoint inhibitors when used in

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combination with them.122 These drugs have been tried in combination with other agents for NSCLC, melanoma, and prostate and colon cancers in various clinical trials. Drugantibody conjugates consist of recombinant monoclonal antibodies covalently bound to cytotoxic chemicals via linkers. Modifications in linkages and warheads have led to improved drug delivery systems. After tumor cell lysis from drug antibody conjugates, more tumor antigens might be expressed to facilitate T-cell responses against the tumor. Preclinical studies have identified that antibody drug conjugates not only have cytotoxic effects but also stimulate the immune system. A strong synergistic effect is seen in combination with PD-1/PD-L1 inhibitors.123 Nanoparticles have been used in various areas of medicine and science. Nanoparticles such as liposomes, dendrimers, micelles, polymer nanoparticles, nanotubes, and inorganic nanoparticles can all be used to deliver the desired agent. This method ensures optimal drug delivery and higher efficacy. Researchers are applying nanotechnology to cancer immunology to develop nanocarriers for vaccines and chemo-immunotherapies.124 Tumorspecific antigens can be identified by techniques such as serological analysis of expression cDNA libraries (SEREX). Newly discovered antigens could be used as potential targets of immunotherapy.125

CONCLUSION Over the years, our understanding of the immune system has greatly increased. Today, there are multiple approaches in cancer immunology, such as monoclonal antibodies, cytokines, vaccines, and ACT. Checkpoint inhibitors have revolutionized the field of immuno-oncology; however, they are associated with a range of unique immune-related adverse effects involving the skin, gastrointestinal system, lungs, endocrine system, and respiratory system. It is important to know about these adverse effects and management strategies of these adverse effects. Despite incredible progress in the field of immuno-oncology, there are still challenges that we face.

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Abbreviations and Acronyms: ACT = adoptive cell therapy; ADCC = antibody-dependent cell-mediated cytotoxicity; ALK = anaplastic lymphoma kinase; CAR = chimeric antigen receptor; CDC = complement-dependent cytotoxicity; CLL = chronic lymphocytic leukemia; CMC = complement-mediated cytotoxicity; CTLA-4 = cytotoxic Tlymphocyteeassociated protein 4; DC = dendritic cell; EGFR = epidermal growth factor receptor; FDA = Food and Drug Administration; FL = follicular lymphoma; GM-CSF = granulocyte-macrophage colony-stimulating factor; HER2 = human epidermal growth factor receptor 2; HNSCC = head and neck squamous cell carcinoma; IFN = interferon; IL = interleukin; IV = intravenous; LFT = liver function test; MMR = mismatch repair; NHL = non-Hodgkin lymphoma; NSCLC = nonesmall cell lung cancer; OR = objective response; OS = overall survival; PD-1 = programmed cell death 1; PD-L1 = programmed death ligand-1; PEG = polyethylene glycol; PFS = progression-free survival; RANKL = receptor activator of nuclear factor-kB; RCC = renal cell carcinoma; RFS = relapse-free survival; TIL = tumor-infiltrating lymphocyte; TNF = tumor necrosis factor; T-VEC = talimogene laherparepvec; VEGF = vascular endothelial growth factor Grant Support: The work was supported by grant T32 GM008685-19 (A.B.K.) from the National Institutes of Health. Potential Competing Interests: The authors report no competing interests. Correspondence: Address to Svetomir N. Markovic, MD, PhD, Department of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (markovic.svetomir@ mayo.edu).

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