. 2013 Jan; 1:16.
doi: 10.1186/2051-1426-1-16.

Rational combinations of immunotherapeutics that target discrete pathways

Stefani Spranger 1 Thomas Gajewski 2 
  • PMID: 24829752
  •     128 References
  •     35 citations


An effective anti-tumor immune response requires the coordinated action of the innate and adaptive phases of the immune system. Critical processes include the activation of dendritic cells to present antigens, produce cytokines including type I interferons, and express multiple costimulatory ligands; induction of a productive T cell response within lymph nodes; migration of activated T cells to the tumor microenvironment in response to chemokines and homing receptor expression; and having effector T cells gain access to antigen-expressing tumor cells and maintain sufficient functionality to destroy them. However, tumors can become adept at escaping the immune response, developing multiple mechanisms to disrupt key processes. In general, tumors can be assigned into two different, major groups depending on whether the tumor there is an 'inflamed' or 'non-inflamed' tumor microenvironment. Improvements in our understanding of the interactions between the immune system and cancer have resulted in the development of various strategies to improve the immune-mediated control of tumors in both sub-groups. Categories of major immunotherapeutic intervention include methods to increase the frequency of tumor antigen-specific effector T cells in the circulation, strategies to block or uncouple a range of immune suppressive mechanisms within the tumor microenvironment, and tactics to induce de novo immune inflammation within the tumor microenvironment. The latter may be particularly important for eliciting immune recognition of non-inflamed tumor phenotypes. The premise put forth in this review is that synergistic therapeutic effects in vivo may be derived from combination therapies taken from distinct "bins" based on these mechanisms of action. Early data in both preclinical and some clinical studies provide support for this model. We also suggest that optimal application of these combinations may be aided by appropriate patient selection based on predictive biomarkers.

Keywords: CTLA-4; Cancer; Denileukin diftitox; Immunotherapy; Indoleamine-2,3,-dioxygenase; Interferon; PD-1; PD-L1; Regulatory T cell; Tumor-associated antigen.

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Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment.
Thomas F Gajewski, Mercedes Fuertes, +2 authors, Justin Kline.
Curr Opin Immunol, 2010 Dec 28; 23(2). PMID: 21185705    Free PMC article.
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TLR ligands in the local treatment of established intracerebral murine gliomas.
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J Immunol, 2008 Nov 05; 181(10). PMID: 18981089
Depletion of CD4(+)CD25(high) regulatory T cells from tumor infiltrating lymphocytes predominantly induces Th1 type immune response in vivo which inhibits tumor growth in adoptive immunotherapy.
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Cancer Biol Ther, 2008 Nov 26; 8(1). PMID: 19029829
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J Immunol, 2002 Aug 24; 169(5). PMID: 12193750
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MAGE A3 antigen-specific cancer immunotherapeutic.
Nir Peled, Ana B Oton, Fred R Hirsch, Paul Bunn.
Immunotherapy, 2009 Jan 01; 1(1). PMID: 20635969
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[Therapy of untreated local advanced or metastatic renal cell carcinoma. Phase III, randomized, open-label study of nivolumab combined with ipilimumab versus sunitinib monotherapy in subjects with previously untreated, local advanced or metastatic renal cell carcinoma (CheckMate 214 - AN 36/15 of the AUO)].
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Roberta Mortarini, Adriano Piris, +10 authors, Andrea Anichini.
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Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment.
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PD-1 pathway inhibitors: the next generation of immunotherapy for advanced melanoma.
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Biomarkers for glioma immunotherapy: the next generation.
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J Neurooncol, 2015 Mar 01; 123(3). PMID: 25724916    Free PMC article.
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The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications.
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Challenges and Opportunities in Dose Finding in Oncology and Immuno-oncology.
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Elena García-Martínez, J Alejandro Pérez-Fidalgo.
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