Review
. 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 
Affiliations
  • PMID: 24829752
  •     128 References
  •     35 citations

Abstract

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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Mark E Dudley, James C Yang, +17 authors, Steven A Rosenberg.
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Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment.
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Curr Opin Immunol, 2010 Dec 28; 23(2). PMID: 21185705    Free PMC article.
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Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells.
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Sci Transl Med, 2013 Aug 30; 5(200). PMID: 23986400    Free PMC article.
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Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity.
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J Exp Med, 2010 Sep 08; 207(10). PMID: 20819927    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.
Lin Xu, Wei Xu, +3 authors, Sidong Xiong.
Cancer Biol Ther, 2008 Nov 26; 8(1). PMID: 19029829
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J Immunol, 1996 Feb 01; 156(3). PMID: 8557984
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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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Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor.
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Occurrence of malignancy in immunodeficiency diseases. A literature review.
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Clin Cancer Res, 2012 May 23; 18(14). PMID: 22615450
Immune modulation with interleukin-21.
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Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas.
Muhammad Baghdadi, Hiroko Nagao, +4 authors, Masahisa Jinushi.
Cancer Immunol Immunother, 2012 Nov 13; 62(4). PMID: 23143694
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Curr Opin Immunol, 2012 Jan 10; 24(2). PMID: 22226204
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Homeostatic proliferation plus regulatory T-cell depletion promotes potent rejection of B16 melanoma.
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Immunotherapy, 2012 Oct 11; 4(9). PMID: 23046239
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Nat Med, 2003 Sep 23; 9(10). PMID: 14502282
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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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Urologe A, 2015 Sep 10; 54(10). PMID: 26350358
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Naomi N Hunder, Herschel Wallen, +7 authors, Cassian Yee.
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Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma.
Roberta Mortarini, Adriano Piris, +10 authors, Andrea Anichini.
Cancer Res, 2003 May 17; 63(10). PMID: 12750277
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.
Stefani Spranger, Holly K Koblish, +3 authors, Thomas F Gajewski.
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PD-1 pathway inhibitors: the next generation of immunotherapy for advanced melanoma.
Jason J Luke, Patrick A Ott.
Oncotarget, 2015 Feb 17; 6(6). PMID: 25682878    Free PMC article.
Highly Cited. Review.
Biomarkers for glioma immunotherapy: the next generation.
Jennifer S Sims, Timothy H Ung, +2 authors, Jeffrey N Bruce.
J Neurooncol, 2015 Mar 01; 123(3). PMID: 25724916    Free PMC article.
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Immunotherapeutic approaches to ovarian cancer treatment.
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J Immunother Cancer, 2015 Mar 26; 3. PMID: 25806106    Free PMC article.
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Tumor antigen-targeting monoclonal antibody-based immunotherapy: Orchestrating combined strategies for the development of long-term antitumor immunity.
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Oncoimmunology, 2015 May 06; 3(9). PMID: 25941618    Free PMC article.
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Denileukin Diftitox (Ontak) as Maintenance Therapy for Peripheral T-Cell Lymphomas: Three Cases with Sustained Remission.
Alejandra C Fuentes, Ellen Szwed, +3 authors, Nam H Dang.
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Immunotherapy and Novel Combinations in Oncology: Current Landscape, Challenges, and Opportunities.
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The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications.
Panagiota Economopoulou, Christos Perisanidis, Evaggelos I Giotakis, Amanda Psyrri.
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High-throughput screening to enhance oncolytic virus immunotherapy.
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mRNA-transfected dendritic cell vaccine in combination with metronomic cyclophosphamide as treatment for patients with advanced malignant melanoma.
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Heterodimeric IL15 Treatment Enhances Tumor Infiltration, Persistence, and Effector Functions of Adoptively Transferred Tumor-specific T Cells in the Absence of Lymphodepletion.
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Effective Combination of Innate and Adaptive Immunotherapeutic Approaches in a Mouse Melanoma Model.
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Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses.
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Hallmarks of response to immune checkpoint blockade.
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Manipulation of Innate Immunity for Cancer Therapy in Dogs.
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Vet Sci, 2015 Dec 01; 2(4). PMID: 29061951    Free PMC article.
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Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment.
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Mechanisms of resistance to immune checkpoint inhibitors.
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Challenges and Opportunities in Dose Finding in Oncology and Immuno-oncology.
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Clin Transl Sci, 2018 Feb 03; 11(4). PMID: 29392871    Free PMC article.
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Immune Checkpoint Inhibitors in Advanced-Stage Non-small Cell Lung Cancer.
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Immunomodulatory activities of pixatimod: emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors.
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Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment.
Yang Zeng, Binghao Li, +9 authors, Mark C Poznansky.
FASEB J, 2019 Feb 26; 33(5). PMID: 30802149    Free PMC article.
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.
Are Conventional Type 1 Dendritic Cells Critical for Protective Antitumor Immunity and How?
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Front Immunol, 2019 Feb 28; 10. PMID: 30809220    Free PMC article.
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A network approach to developing immuno-oncology combinations in Canada.
V Higenell, R Fajzel, +11 authors, S Verma.
Curr Oncol, 2019 May 03; 26(2). PMID: 31043804    Free PMC article.
Novel strategies in immune checkpoint inhibitor drug development: How far are we from the paradigm shift?
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Monoclonal Antibody: A New Treatment Strategy against Multiple Myeloma.
Shih-Feng Cho, Liang Lin, +4 authors, Yu-Tzu Tai.
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Hybrid Fc-fused interleukin-7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy.
Ji-Hae Kim, Young-Min Kim, +11 authors, Seung-Woo Lee.
Clin Transl Immunology, 2020 Oct 01; 9(9). PMID: 32994996    Free PMC article.
Comparison study of different indoleamine-2,3 dioxygenase inhibitors from the perspective of pharmacodynamic effects.
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Int J Immunopathol Pharmacol, 2020 Sep 24; 34. PMID: 32962460    Free PMC article.
Treatment of Advanced Melanoma in 2020 and Beyond.
Russell W Jenkins, David E Fisher.
J Invest Dermatol, 2020 Apr 09; 141(1). PMID: 32268150    Free PMC article.
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Immunotherapies in ovarian cancer.
Elena García-Martínez, J Alejandro Pérez-Fidalgo.
EJC Suppl, 2020 Nov 27; 15. PMID: 33240447    Free PMC article.
Mechanisms of Resistance to Immune Checkpoint Blockade.
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Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy.
Laura Boyero, Amparo Sánchez-Gastaldo, +3 authors, Reyes Bernabé-Caro.
Cancers (Basel), 2020 Dec 17; 12(12). PMID: 33322522    Free PMC article.
Review.
A Novel Oral Arginase 1/2 Inhibitor Enhances the Antitumor Effect of PD-1 Inhibition in Murine Experimental Gliomas by Altering the Immunosuppressive Environment.
Paulina Pilanc, Kamil Wojnicki, +9 authors, Bozena Kaminska.
Front Oncol, 2021 Sep 11; 11. PMID: 34504786    Free PMC article.