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 
  • PMID: 27458526
  •     122 References
  •     36 citations


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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Trends Immunol, 2015 Mar 24; 36(4). PMID: 25797516    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.
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Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
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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.
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Bevacizumab plus ipilimumab in patients with metastatic melanoma.
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Combined Immune Checkpoint Blockade.
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Semin Oncol, 2015 Sep 01; 42(4). PMID: 26320068
Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy.
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.
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Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
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The evolution of checkpoint blockade as a cancer therapy: what's here, what's next?
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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.
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Current progress in innovative engineered antibodies.
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Combining DNA damaging therapeutics with immunotherapy: more haste, less speed.
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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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Durvalumab in NSCLC: latest evidence and clinical potential.
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The Antitumor Activity of Combinations of Cytotoxic Chemotherapy and Immune Checkpoint Inhibitors Is Model-Dependent.
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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.
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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.
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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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Positive progress: current and evolving role of immune checkpoint inhibitors in metastatic triple-negative breast cancer.
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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.
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Nasal mucosal melanoma as a cause of epistaxis.
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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.
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Computational immune infiltration analysis of pediatric high-grade gliomas (pHGGs) reveals differences in immunosuppression and prognosis by tumor location.
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Clinical trial data and emerging strategies: HER2-positive breast cancer.
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