Gastrointestinal cancers are a group of highly aggressive malignancies, and novel therapeutic strategies with higher clinical efficacy are being actively sought. \u27Immunotherapy\u27 is now emerging as one such promising strategy for the treatment of these tumors. This article briefly reviews the recent advances that utilize targeting of immune checkpoint pathways, in the management of gastrointestinal malignancies

Goel, Gaurav

Sun, Weijing

English

University of Kentucky

University of KentuckyUKnowledgeInternal Medicine Faculty Publications Internal Medicine7-16-2015Advances in the Management of GastrointestinalCancers—An Upcoming Role of ImmuneCheckpoint BlockadeGaurav GoelUniversity of Kentucky, gaurav.goel@uky.eduWeijing SunUniversity of PittsburghRight click to open a feedback form in a new tab to let us know how this document benefits you.Follow this and additional works at: https://uknowledge.uky.edu/internalmedicine_facpubPart of the Medicine and Health Sciences CommonsThis Article is brought to you for free and open access by the Internal Medicine at UKnowledge. It has been accepted for inclusion in Internal MedicineFaculty Publications by an authorized administrator of UKnowledge. For more information, please contact UKnowledge@lsv.uky.edu.Repository CitationGoel, Gaurav and Sun, Weijing, "Advances in the Management of Gastrointestinal Cancers—An Upcoming Role of ImmuneCheckpoint Blockade" (2015). Internal Medicine Faculty Publications. 77.https://uknowledge.uky.edu/internalmedicine_facpub/77Advances in the Management of Gastrointestinal Cancers—An Upcoming Role of Immune Checkpoint BlockadeNotes/Citation InformationPublished in Journal of Hematology & Oncology, v. 8, article 86, p. 1-4.© 2015 Goel and Sun.This is an Open Access article distributed under the terms of the Creative Commons Attribution License(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons PublicDomain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the datamade available in this article, unless otherwise stated.Digital Object Identifier (DOI)http://dx.doi.org/10.1186/s13045-015-0185-6This article is available at UKnowledge: https://uknowledge.uky.edu/internalmedicine_facpub/77REVIEW Open AccessAdvances in the management ofgastrointestinal cancers—an upcomingrole of immune checkpoint blockadeGaurav Goel1 and Weijing Sun2*AbstractGastrointestinal cancers are a group of highly aggressive malignancies, and novel therapeutic strategies withhigher clinical efficacy are being actively sought. ‘Immunotherapy’ is now emerging as one such promisingstrategy for the treatment of these tumors. This article briefly reviews the recent advances that utilize targeting ofimmune checkpoint pathways, in the management of gastrointestinal malignancies.Keywords: Checkpoint inhibitors, Gastrointestinal cancers, Immunotherapy, Pembrolizumab, Nivolumab, PD-1,PD-L1, BiomarkersIntroductionGastrointestinal (GI) cancers are a group of highly ag-gressive malignancies and a major public health problemworldwide. In the USA alone, 291,000 new cases areestimated to be diagnosed, and approximately 149,000patients will die from these cancers in 2015 [1]. Thecurrently approved treatments for these tumors result inonly modest improvement in overall survival (OS), espe-cially when dealing with advanced disease. Consequently,novel therapeutic strategies with higher efficacy arebeing actively sought.Immunotherapy is a relatively new and evolving fieldof cancer therapeutics that has already demonstrateddurable responses in solid tumors including melanoma,non-small cell lung cancer, and renal cancer and is asso-ciated with encouraging activity in hematologic malig-nancies as well [2, 3]. In contrast, the progress madetowards development of effective antitumor immunetherapies for GI cancers has been relatively slow. GI ma-lignancies usually lack naturally occurring effector T cellresponses and have been traditionally considered to bepoorly immunogenic. With the identification of newimmune-based targets including immune checkpoints,immunotherapy is now beginning to emerge as a prom-ising therapeutic strategy [4, 5]. This article highlightsthe recent immunotherapeutic advances that werewitnessed in the field of GI malignancies.Immune checkpoint blockadeIt is now well established that tumors evade the host im-mune response using a multitude of mechanisms, includ-ing expansion of immunosuppressive cells (regulatory T[Treg] cells, myeloid-derived suppressor cells [MDSCs]) inthe tumor microenvironment, elaboration of various cyto-kines and chemokines (transforming growth factor-β[TGF-β], interleukin [IL]-10, indoleamine 2,3-dioxygenase[IDO]), and co-inhibitory signaling pathways mediated viaimmune checkpoints (cytotoxic T lymphocyte-associatedprotein-4 [CTLA-4], programmed cell death-1 [PD-1],T cell immunoglobulin- and mucin-domain-containingmolecule-3 [TIM-3], and lymphocyte activation gene 3[LAG3]) [6]. Together, these contribute to the develop-ment of resistance to immune effectors.Immune checkpoint blockade strategy is now beingactively evaluated in the management of GI malignan-cies including esophageal, gastric, colorectal, and livercancers. PD-1, which is a co-inhibitory receptor expressedon the surface of activated T cells, B cells, and myeloidcells, interacts with its ligands (PD-L1 and PD-L2) to pre-vent T cell functioning. Antibody mediated blockade of* Correspondence: sunw@upmc.edu2Division of Hematology-Oncology, Department of Medicine, University ofPittsburgh Cancer Institute, University of Pittsburgh School of Medicine, 5150Centre Avenue, Pittsburgh, PA 15232, USAFull list of author information is available at the end of the articleJOURNAL OF HEMATOLOGY& ONCOLOGY© 2015 Goel and Sun. This is an Open Access article distributed under the terms of the Creative Commons Attribution License(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Goel and Sun Journal of Hematology & Oncology  (2015) 8:86 DOI 10.1186/s13045-015-0185-6PD-1 or PD-L1 results in inhibition of this checkpoint,leading to T cell functional activation and enhanced anti-tumor activity. Emerging data suggest encouraging activityof PD-1 axis blockade in the management of GI cancers.Gastric and esophageal carcinomaThe Cancer Genome Atlas (TCGA) project performedcomprehensive molecular characterization of gastricadenocarcinoma and identified four major molecular sub-types, namely, Epstein-Barr virus (EBV)-infected tumors,microsatellite instability (MSI) tumors, genomically stabletumors, and chromosomally unstable tumors [7]. In theEBV subgroup, there was amplification at 9p24.1 leadingto upregulation of PD-L1 and PD-L2, which indicates apotential role of PD-1 axis blockade in treatment of thesepatients.KEYNOTE-012 is a multi-center, multi-cohort, non-randomized phase Ib trial evaluating the safety and effi-cacy of anti-PD-1 antibody pembrolizumab (MK-3475) inpatients with previously treated, PD-L1-positive, advancedcancers (NCT01848834) [8]. Patients were classified asPD-L1 positive based on ≥1 % of tumor cells demonstrat-ing expression of PD-L1 marker, or any positive stainingin the tumor stroma. In the gastric cancer cohort, 39patients who were previously treated for their metastaticdiseases have been enrolled. The observed median dur-ation of response (DoR) was 24 weeks. The 6-month pro-gression free survival (PFS) and OS rates were 24 and69 %, respectively. PD-L1 expression level was found tocorrelate with the objective response rate (ORR; P = 0.10).In this study cohort, four patients experienced grades 3–5drug-related adverse events (DRAEs), which included per-ipheral sensory neuropathy, fatigue, decreased appetite,hypoxia, and pneumonitis. In another similar multi-cohort, phase Ib trial (KEYNOTE-028) of pembrolizumabmonotherapy for PD-L1-positive advanced solid tumors,23 patients with either squamous cell carcinoma (SCC;74 %) or adenocarcinoma (22 %) of the esophagus or gas-troesophageal junction (GEJ) have been treated at the timeof interim analysis (NCT02054806) [9]. The ORR was30 % (40 % for adenocarcinoma, 29 % for SCC). The me-dian DoR was 40 weeks, with 6 of 7 responses ongoing atcutoff. DRAEs were observed in 39 %, including grade 3toxicity (lymphopenia, decreased appetite, liver disorder,pruritic rash) in 17 % (n = 4) of the patients.In summary, the available results from KEYNOTE-012and KEYNOTE-028 demonstrate a promising clinical ac-tivity of pembrolizumab monotherapy in heavily pre-treated, PD-L1-positive, advanced gastric and esophagealcarcinoma, respectively.Colorectal cancerMSI tumors are characterized by epigenetic silencing ormutations of DNA mismatch repair (MMR) genes, leadingto the formation of variable length DNA microsatellites.The high mutational load in MSI tumors creates manytumor-specific neoantigens, some of which are recognizedas foreign by T cells, and this contributes to the lympho-cytic reaction frequently observed in these tumors [10].MSI colorectal cancers (CRCs) comprise approximately15 % of the total sporadic CRCs, and these tumors havebeen shown to upregulate expression of immune check-points including PD-1, PD-L1, CTLA-4, LAG-3, and IDOin tumor infiltrating lymphocytes (TILs), stroma or tumorinvasive front compartments [11].A phase II study evaluated the clinical activity of pem-brolizumab monotherapy in patients with previouslytreated, progressive metastatic tumors, with and withoutMMR deficiency (NCT01876511) [12]. The patients wereenrolled in three cohorts, MMR-deficient CRC (n = 11),MMR-proficient CRC (n = 21), and MMR-deficient non-colorectal tumor cohort (n = 9). The study met its co-primary endpoints of immune-related ORR (irORR) andimmune-related PFS (irPFS) at 20 weeks, for both theMMR-deficient cohorts. The irORR and irPFS were 40and 78 % for MMR-deficient CRC, 0 and 11 % in theMMR-proficient CRC cohort. Response rates (RR) anddisease control rates (DCR) were 40 and 90 % in MMR-deficient CRC, 0 and 11 % in MMR-proficient CRCcohort. Median PFS and OS were not reached in theMMR-deficient CRC group but was 2.2 and 5.0 months inthe MMR-proficient CRC cohort (hazard ratio [HR] forPFS = 0.103; 95 % confidence interval [CI], 0.029 to 0.373;P = 0.001 and HR for OS = 0.216; 95 % CI, 0.047 to 1.000;P = 0.05). These results provide promising evidence tosuggest that MMR status predicts clinical benefit from im-mune checkpoint blockade in advanced CRC.Hepatocellular carcinomaThe liver is characterized by the presence of an im-munosuppressive microenvironment and expression ofPD-L1 on sinusoidal endothelial and Kupffer cells. Anti-PD-1 blockade strategy has demonstrated manageabletoxicity profile and preliminary evidence of efficacy in arecently reported study involving advanced hepatocellularcarcinoma (HCC) patients [13]. This multiple ascending-dose phase I/II study evaluated the safety and antitumorefficacy of nivolumab in patients with pretreated orsorafenib-intolerant advanced HCC (NCT01658878).Patients with Child-Pugh score ≤B7 were enrolled in threeindependent parallel cohorts, namely, uninfected, HCV-infected, and HBV-infected cohorts. DRAEs occurred in32 patients (68 %; 19 % grades 3–4) and included elevationof lipase, amylase, aspartate aminotransferase (AST) andalanine aminotransferase (ALT), rash, anemia, and fatigue.No maximum tolerated dose (MTD) was identified in anycohort. At the time of the interim analysis in March 2015,response was evaluable in 42 patients and included twoGoel and Sun Journal of Hematology & Oncology  (2015) 8:86 Page 2 of 4complete responders (CR; 5 %) and six partial responders(PR; 14 %). Objective clinical responses were observed inboth uninfected and viral-associated HCC. The OS ratewas 70 % at 9 months and 62 % at 12 months. Responseswere ongoing in six of eight patients at the time of interimanalysis. Patient enrollment is continuing in the dose ex-pansion phase of the study.Pancreatic cancerCheckpoint pathways are also being evaluated as immu-notherapeutic targets for the treatment of pancreaticcancer. However, due to an immunologically quiescentmicroenvironment associated with these tumors, noneof the examined approaches have demonstrated a clinic-ally meaningful benefit till date [14]. CD40 activationcan reverse immune suppression and drive antitumor Tcell responses. Agonist CD40 antibody has been used incombination with gemcitabine in a phase I study toshrink pancreatic ductal adenocarcinoma by stimulatingtumor macrophages against pancreatic cancer stroma[15]. Single agent ipilimumab was evaluated in a phase IItrial of advanced pancreatic cancer and failed to demon-strate an appreciable antitumor activity [16]. The com-bination of ipilimumab with gemcitabine in advancedpancreatic cancer is currently under phase Ib evalu-ation (NCT01473940). A phase Ib/II trial is studyingthe safety and immunological effect of neoadjuvantchemoradiation therapy (CRT) added to pembrolizu-mab in resectable or borderline resectable pancreaticcancer (NCT02305186). Other strategies that are beingevaluated include combination of vaccine (GVAX, CRS-207) with antibody against CTLA-4 (NCT01896869) orPD-1 (NCT02243371).Future directions, challenges, and conclusionThe potential of immunotherapy as a treatment modalityfor GI malignancies has finally become a reality. How-ever, the clinical benefit from these agents is restrictedto only a subset of patients, at least at the present time.Moreover, these immune-modulating therapies are oftenassociated with immune-mediated toxicities. Conse-quently, biomarkers are needed to refine patient selec-tion for optimum clinical benefit and minimize toxicity[17].PD-L1 positivity has been used to select patient popu-lation in KEYNOTE trials. Experience from a series ofclinical trials across a variety of tumor types suggeststhat although PD-L1 positivity is associated with agreater likelihood of response from anti-PD-1 or anti-PD-L1 agents, the benefit is not restricted to the PD-L1-positive population exclusively [18]. Currently, the evalu-ation and validation of PD-L1 positivity as a predictivebiomarker suffers from several limitations including lackof standardized definition for PD-L1 positivity, lack ofuniformity in antibody clone used for immunohistochem-istry staining across studies, and discordance between pri-mary tumor and metastatic lesions [18].The presence of MSI is a potential genetic biomarkershown to have a predictive value in the study presentedby Le and colleagues [12]. Considering the fact that ma-jority of GI tumors are microsatellite stable (MSS) andtherefore immunogenically quiescent, additional ap-proaches that utilize combination of immune checkpointinhibitors with T cell-inducing strategies such as use ofvaccines, chemotherapy, targeted agents, or radiotherapyneed to be evaluated to continually improve upon theexisting responses.To conclude, immune therapy using checkpoint block-ade has added a new treatment paradigm in the manage-ment of GI malignancies. Further evaluation with futureclinical trials that enroll larger patient cohorts and studycombinatorial approaches is strongly warranted.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsGG drafted the manuscript and revised it critically for important intellectualcontent. WS revised the manuscript critically for important intellectualcontent. Both authors read and approved the final manuscript.Author details1Division of Medical Oncology, Department of Medicine, University ofKentucky Markey Cancer Center, Lexington, KY 40536, USA. 2Division ofHematology-Oncology, Department of Medicine, University of PittsburghCancer Institute, University of Pittsburgh School of Medicine, 5150 CentreAvenue, Pittsburgh, PA 15232, USA.Received: 30 June 2015 Accepted: 8 July 2015References1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin.2015;65:5–29.2. Shi L, Chen S, Yang L, Li Y. The role of PD-1 and PD-L1 in T-cell immunesuppression in patients with hematological malignancies. J Hematol Oncol.2013;6:74.3. Han EQ, Li XL, Wang CR, Li TF, Han SY. Chimeric antigen receptor-engineered Tcells for cancer immunotherapy: progress and challenges. J Hematol Oncol.2013;6:47.4. Li Z, Chen L, Rubinstein MP. Cancer immunotherapy: are we there yet? ExpHematol Oncol. 2013;2:33.5. Ehrlich D, Wang B, Lu W, Dowling P, Yuan R. Intratumoral anti-HuDimmunotoxin therapy for small cell lung cancer and neuroblastoma. JHematol Oncol. 2014;7:91.6. Goel G, Sun W. Cancer immunotherapy in clinical practice–the past, present,and future. Chin J Cancer. 2014;33:445–57.7. Comprehensive molecular characterization of gastric adenocarcinoma.Nature 2014, 513:202–209.8. Bang YJ, Chung HC, Shankaran V, Geva R, Catenacci DVT, Gupta S, et al.Relationship between PD-L1 expression and clinical outcomes in patientswith advanced gastric cancer treated with the anti-PD-1 monoclonal anti-body pembrolizumab (MK-3475) in KEYNOTE-012. J Clin Oncol 2015,33(suppl):abstr 4001.9. Doi T, Piha-Paul SA, Jalal SI, Mai-Dang H, Yuan S, Koshiji M, et al.Pembrolizumab (MK-3475) for patients (pts) with advanced esophagealcarcinoma: preliminary results from KEYNOTE-028. J Clin Oncol 2015,33(suppl):abstr 4010.Goel and Sun Journal of Hematology & Oncology  (2015) 8:86 Page 3 of 410. Smyrk TC, Watson P, Kaul K, Lynch HT. Tumor-infiltrating lymphocytes are amarker for microsatellite instability in colorectal carcinoma. Cancer.2001;91:2417–22.11. Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al.The vigorous immune microenvironment of microsatellite instable coloncancer is balanced by multiple counter-inhibitory checkpoints. CancerDiscov. 2015;5:43–51.12. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1blockade in tumors with mismatch-repair deficiency. N Engl J Med.2015;372:3509–20.13. El-Khoueiry AB, Melero I, Crocenzi TS, Welling TH, Yau TC, Yeo W, et al.Phase I/II safety and antitumor activity of nivolumab in patients withadvanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol 2015,33(suppl):abstr LBA101.14. Goel G, Sun W. Novel approaches in the management of pancreatic ductaladenocarcinoma: potential promises for the future. J Hematol Oncol.2015;8:44.15. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W,et al. CD40 agonists alter tumor stroma and show efficacy againstpancreatic carcinoma in mice and humans. Science. 2011;331:1612–6.16. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2trial of single agent ipilimumab (anti-CTLA-4) for locally advanced ormetastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828–33.17. Smith AD, Roda D, Yap TA. Strategies for modern biomarker and drugdevelopment in oncology. J Hematol Oncol. 2014;7:70.18. Mahoney KM, Atkins MB. Prognostic and predictive markers for the newimmunotherapies. Oncology (Williston Park). 2014;28 Suppl 3:39–48.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitGoel and Sun Journal of Hematology & Oncology  (2015) 8:86 Page 4 of 4

Advances in the Management of Gastrointestinal Cancers—An Upcoming Role of Immune Checkpoint Blockade

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Advances in the Management of Gastrointestinal Cancers—An Upcoming Role of Immune Checkpoint Blockade

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