Journal Article
. 2016 Jul; 13(2):171-93.
doi: 10.20892/j.issn.2095-3941.2016.0015.

Immuno-oncology combinations: raising the tail of the survival curve

Samuel J Harris 1 Jessica Brown 1 Juanita Lopez 1 Timothy A Yap 2 
Affiliations
  • PMID: 27458526
  •     122 References
  •     36 citations

Abstract

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer, immune checkpoint inhibitors also appear to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.

Keywords: CTLA4; Combination drug therapy; PD-1; PD-L1; biomarkers; clinical trials; immunotherapy; oncology.

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James Larkin, Vanna Chiarion-Sileni, +28 authors, Jedd D Wolchok.
N Engl J Med, 2015 Jun 02; 373(1). PMID: 26027431    Free PMC article.
Highly Cited.
Overcoming T cell exhaustion in infection and cancer.
Kristen E Pauken, E John Wherry.
Trends Immunol, 2015 Mar 24; 36(4). PMID: 25797516    Free PMC article.
Highly Cited. Review.
Genetic basis for clinical response to CTLA-4 blockade in melanoma.
Alexandra Snyder, Vladimir Makarov, +18 authors, Timothy A Chan.
N Engl J Med, 2014 Nov 20; 371(23). PMID: 25409260    Free PMC article.
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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.
Dung T Le, Jennifer N Uram, +32 authors, Luis A Diaz.
N Engl J Med, 2015 Jun 02; 372(26). PMID: 26028255    Free PMC article.
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Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.
Antoni Ribas, Richard Kefford, +21 authors, Axel Hauschild.
J Clin Oncol, 2013 Jan 09; 31(5). PMID: 23295794    Free PMC article.
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Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
Philip W Kantoff, Celestia S Higano, +11 authors, IMPACT Study Investigators.
N Engl J Med, 2010 Sep 08; 363(5). PMID: 20818862
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New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape.
Deepak Mittal, Matthew M Gubin, Robert D Schreiber, Mark J Smyth.
Curr Opin Immunol, 2014 Feb 18; 27. PMID: 24531241    Free PMC article.
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MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy.
James Finke, Jennifer Ko, +3 authors, Peter Cohen.
Int Immunopharmacol, 2011 Feb 15; 11(7). PMID: 21315783    Free PMC article.
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Clinical Application of Anti-CCR4 Monoclonal Antibody.
Ryuzo Ueda.
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Michael A Postow, Margaret K Callahan, +18 authors, Jedd D Wolchok.
N Engl J Med, 2012 Mar 09; 366(10). PMID: 22397654    Free PMC article.
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Bevacizumab plus ipilimumab in patients with metastatic melanoma.
F Stephen Hodi, Donald Lawrence, +20 authors, David McDermott.
Cancer Immunol Res, 2014 May 20; 2(7). PMID: 24838938    Free PMC article.
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Combined Immune Checkpoint Blockade.
Charles G Drake.
Semin Oncol, 2015 Sep 01; 42(4). PMID: 26320068
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Xiangjiao Meng, Zhaoqin Huang, +2 authors, Jinming Yu.
Cancer Treat Rev, 2015 Nov 22; 41(10). PMID: 26589760
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Chemokine receptor-specific antibodies in cancer immunotherapy: achievements and challenges.
Maria Vela, Mariana Aris, +2 authors, Leonor Kremer.
Front Immunol, 2015 Feb 18; 6. PMID: 25688243    Free PMC article.
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Immune-checkpoint blockade: the springboard for immuno-combination therapy.
A M Ibrahim, Y Wang, N R Lemoine.
Gene Ther, 2015 Nov 06; 22(11). PMID: 26537748
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
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The evolution of checkpoint blockade as a cancer therapy: what's here, what's next?
Daniel Sanghoon Shin, Antoni Ribas.
Curr Opin Immunol, 2015 Jan 27; 33. PMID: 25621841
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Next-Generation Antibody-Drug Conjugates (ADCs) for Cancer Therapy.
Jagath Reddy Junutula, Hans-Peter Gerber.
ACS Med Chem Lett, 2016 Nov 25; 7(11). PMID: 27882192    Free PMC article.
From targeting the tumor to targeting the immune system: Transversal challenges in oncology with the inhibition of the PD-1/PD-L1 axis.
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Novel insights into mesothelioma biology and implications for therapy.
Timothy A Yap, Joachim G Aerts, Sanjay Popat, Dean A Fennell.
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Current progress in innovative engineered antibodies.
William R Strohl.
Protein Cell, 2017 Aug 20; 9(1). PMID: 28822103    Free PMC article.
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Combining DNA damaging therapeutics with immunotherapy: more haste, less speed.
Jessica S Brown, Raghav Sundar, Juanita Lopez.
Br J Cancer, 2017 Nov 11; 118(3). PMID: 29123260    Free PMC article.
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Smoldering myocarditis following immune checkpoint blockade.
Timothy G Norwood, Brian C Westbrook, +6 authors, Robert M Conry.
J Immunother Cancer, 2017 Nov 22; 5(1). PMID: 29157297    Free PMC article.
Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors.
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PD-L1 expression in medulloblastoma: an evaluation by subgroup.
Allison M Martin, Christopher J Nirschl, +19 authors, Michael Lim.
Oncotarget, 2018 May 04; 9(27). PMID: 29721192    Free PMC article.
First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.
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J Transl Med, 2018 May 31; 16(1). PMID: 29843811    Free PMC article.
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Algorithm for the treatment of advanced or metastatic squamous non-small-cell lung cancer: an evidence-based overview.
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Checkpoint blockade-based immunotherapy in the context of tumor microenvironment: Opportunities and challenges.
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Cancer Med, 2018 Aug 09; 7(9). PMID: 30088347    Free PMC article.
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Durvalumab in NSCLC: latest evidence and clinical potential.
Nerea Muñoz-Unceta, Isabel Burgueño, Elizabeth Jiménez, Luis Paz-Ares.
Ther Adv Med Oncol, 2018 Oct 23; 10. PMID: 30344651    Free PMC article.
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The Antitumor Activity of Combinations of Cytotoxic Chemotherapy and Immune Checkpoint Inhibitors Is Model-Dependent.
Chloé Grasselly, Morgane Denis, +7 authors, Charles Dumontet.
Front Immunol, 2018 Oct 26; 9. PMID: 30356816    Free PMC article.
Breast Cancer Chemo-immunotherapy through Liposomal Delivery of an Immunogenic Cell Death Stimulus Plus Interference in the IDO-1 Pathway.
Jianqin Lu, Xiangsheng Liu, +6 authors, Andre E Nel.
ACS Nano, 2018 Nov 30; 12(11). PMID: 30481959    Free PMC article.
Combination checkpoint inhibitor therapy induces multiple immune major related adverse events in the treatment of vaginal melanoma: A cautionary case report.
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Gynecol Oncol Rep, 2019 Nov 19; 30. PMID: 31737773    Free PMC article.
Amplifying Outcomes: Checkpoint Inhibitor Combinations in First-Line Non-Small Cell Lung Cancer.
Barbara Melosky, Rosalyn Juergens, +5 authors, Quincy Chu.
Oncologist, 2019 May 30; 25(1). PMID: 31138727    Free PMC article.
Relationship between protein biomarkers of chemotherapy response and microsatellite status, tumor mutational burden and PD-L1 expression in cancer patients.
Mina Nikanjam, David Arguello, +3 authors, Razelle Kurzrock.
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A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients.
Ida Netterberg, Chi-Chung Li, +5 authors, Lena E Friberg.
Clin Pharmacol Ther, 2018 Jul 31; 105(2). PMID: 30058723    Free PMC article.
Prognostic and Predictive Immunohistochemistry-Based Biomarkers in Cancer and Immunotherapy.
Emanuelle M Rizk, Robyn D Gartrell, +4 authors, Yvonne M Saenger.
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Interaction of host immunity with HER2-targeted treatment and tumor heterogeneity in HER2-positive breast cancer.
Gaia Griguolo, Tomás Pascual, +2 authors, Aleix Prat.
J Immunother Cancer, 2019 Mar 30; 7(1). PMID: 30922362    Free PMC article.
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Safety, Tolerability, and Potential Clinical Activity of a Glucocorticoid-Induced TNF Receptor-Related Protein Agonist Alone or in Combination With Nivolumab for Patients With Advanced Solid Tumors: A Phase 1/2a Dose-Escalation and Cohort-Expansion Clinical Trial.
Kimberley M Heinhuis, Matteo Carlino, +17 authors, Lillian L Siu.
JAMA Oncol, 2019 Nov 08; 6(1). PMID: 31697308    Free PMC article.
CinéBreast-factors influencing the time to first metastatic recurrence in breast cancer: Analysis of real-life data from the French ESME MBC database.
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Compound-therapy based on cancer-immunity cycle: promising prospects for antitumor regimens.
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Relationship between Progression-free Survival and Overall Survival in Randomized Clinical Trials of Targeted and Biologic Agents in Oncology.
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The New Immunotherapy Combinations in the Treatment of Advanced Non-Small Cell Lung Cancer: Reality and Perspectives.
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Curr Clin Pharmacol, 2019 Aug 11; 15(1). PMID: 31400270    Free PMC article.
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Positive progress: current and evolving role of immune checkpoint inhibitors in metastatic triple-negative breast cancer.
Christine E Simmons, Christine Brezden-Masley, +2 authors, Anil Abraham Joy.
Ther Adv Med Oncol, 2020 Oct 06; 12. PMID: 33014143    Free PMC article.
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A Systems Biology Workflow for Drug and Vaccine Repurposing: Identifying Small-Molecule BCG Mimics to Reduce or Prevent COVID-19 Mortality.
Rima Hajjo, Alexander Tropsha.
Pharm Res, 2020 Oct 08; 37(11). PMID: 33025261    Free PMC article.
Clinical development of targeted and immune based anti-cancer therapies.
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Effect of Treatment with the PD-1/PD-L1 Inhibitors on Key Health Outcomes of Cancer Patients.
Kyung-In Joung, Jong Hwa Song, +4 authors, Dong Churl Suh.
BioDrugs, 2020 Dec 18; 35(1). PMID: 33331991
Nasal mucosal melanoma as a cause of epistaxis.
Ruqaiyah Behranwala, Bhagya Harindi Loku Waduge, Bervin Teo.
BMJ Case Rep, 2019 Jul 16; 12(7). PMID: 31302615    Free PMC article.
Clinical complete response after nivolumab administered as a third-line treatment for unresectable advanced gastric cancer with peritoneal dissemination: A case report.
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Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study.
Robin Kate Kelley, Bruno Sangro, +21 authors, Ghassan K Abou-Alfa.
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Computational immune infiltration analysis of pediatric high-grade gliomas (pHGGs) reveals differences in immunosuppression and prognosis by tumor location.
Cavan P Bailey, Ruiping Wang, +3 authors, Joya Chandra.
Comput Syst Oncol, 2021 Nov 02; 1(3). PMID: 34723252    Free PMC article.
Immuno-oncology trends: preclinical models, biomarkers, and clinical development.
Maryland Rosenfeld Franklin, Suso Platero, +2 authors, Steven Anderson.
J Immunother Cancer, 2022 Jan 14; 10(1). PMID: 35022192    Free PMC article.
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Clinical trial data and emerging strategies: HER2-positive breast cancer.
Sonia Pernas, Sara M Tolaney.
Breast Cancer Res Treat, 2022 Apr 10; 193(2). PMID: 35397080
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The pro-tumorigenic host response to cancer therapies.
Yuval Shaked.
Nat Rev Cancer, 2019 Oct 28; 19(12). PMID: 31645711
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