The promise of immunotherapy in head and neck squamous cell carcinoma: combinatorial immunotherapy approaches

The immune system plays a fundamental role in preventing cancer development by recognising and eliminating tumour cells. The recent success in the field of immunotherapy has confirmed the potential to exploit the immune response as a cancer treatment. Head and neck squamous cell carcinoma (HNSCC) is a malignancy characterized by dismal prognosis and high mortality rate; low survival outcomes in combination with significant toxicity of current treatment strategies highlight the necessity for novel therapeutic modalities. HNSCC is a favourable disease for immunotherapy, as immune escape plays a key role in tumour initiation and progression. T-cell checkpoint inhibitors targeting programmed cell death protein-1 have emerged as novel immunotherapy agents showing remarkable efficacy in HNSCC. However, only a minority of patients derive benefit for single-agent immunotherapies. In this regard, combinatorial immunotherapy approaches represent an alternative strategy that might increase the number of patients who respond to immunotherapy. Focusing on HNSCC, this review will summarise novel combinations of immune checkpoint blockade with other immunotherapy treatment modalities.

[1]  M. Burnet Cancer—A Biological Approach , 1957, British medical journal.

[2]  W. Coley The Classic: The Treatment of Malignant Tumors by Repeated Inoculations of Erysipelas , 1991 .

[3]  P. Linsley,et al.  CTLA-4 is a second receptor for the B cell activation antigen B7 , 1991, The Journal of experimental medicine.

[4]  T. Honjo,et al.  Induced expression of PD‐1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. , 1992, The EMBO journal.

[5]  G. Freeman,et al.  Uncovering of functional alternative CTLA-4 counter-receptor in B7-deficient mice. , 1993, Science.

[6]  F. Ramsdell,et al.  Identification of OX40 ligand and preliminary characterization of its activities on OX40 receptor. , 1994, Circulatory shock.

[7]  P. Linsley,et al.  Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. , 1994, Immunity.

[8]  P. Linsley,et al.  CTLA-4 can function as a negative regulator of T cell activation. , 1994, Immunity.

[9]  J. Allison,et al.  CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation , 1995, The Journal of experimental medicine.

[10]  H. Griesser,et al.  Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4 , 1995, Science.

[11]  J. Bluestone,et al.  Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. , 1995, Immunity.

[12]  K. Bennett,et al.  Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. , 1996, Immunity.

[13]  T. Honjo,et al.  Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. , 1996, International immunology.

[14]  P. Linsley,et al.  Covalent Dimerization of CD28/CTLA-4 and Oligomerization of CD80/CD86 Regulate T Cell Costimulatory Interactions* , 1996, The Journal of Biological Chemistry.

[15]  J. Bluestone,et al.  CTLA-4 ligation blocks CD28-dependent T cell activation [published erratum appears in J Exp Med 1996 Jul 1;184(1):301] , 1996, The Journal of experimental medicine.

[16]  J. Allison,et al.  CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells , 1996, The Journal of experimental medicine.

[17]  D. Munn,et al.  Inhibition of  T Cell Proliferation by Macrophage Tryptophan Catabolism , 1999, The Journal of experimental medicine.

[18]  G. Zhu,et al.  B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion , 1999, Nature Medicine.

[19]  T. Honjo,et al.  Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. , 1999, Immunity.

[20]  J. Allison,et al.  CTLA-4-Mediated inhibition of early events of T cell proliferation. , 1999, Journal of immunology.

[21]  G. Alvord,et al.  Engagement of the OX-40 Receptor In Vivo Enhances Antitumor Immunity1 , 2000, The Journal of Immunology.

[22]  G. Freeman,et al.  Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation , 2000, The Journal of experimental medicine.

[23]  F. Khuri,et al.  Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene-deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial. , 2000, Cancer research.

[24]  S. Dzik B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin 10 secretion , 2000 .

[25]  J. Madrenas,et al.  CTLA-4 (CD152) Can Inhibit T Cell Activation by Two Different Mechanisms Depending on Its Level of Cell Surface Expression1 , 2000, The Journal of Immunology.

[26]  T. Okazaki,et al.  Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. , 2001, Science.

[27]  G. Freeman,et al.  PD-L2 is a second ligand for PD-1 and inhibits T cell activation , 2001, Nature Immunology.

[28]  Sujung Park,et al.  4-1BB Promotes the Survival of CD8+ T Lymphocytes by Increasing Expression of Bcl-xL and Bfl-11 , 2002, The Journal of Immunology.

[29]  J. Shimizu,et al.  Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance , 2002, Nature Immunology.

[30]  Tatyana Chernova,et al.  Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease , 2002, Nature.

[31]  Lieping Chen,et al.  Cutting Edge: Expression of Functional CD137 Receptor by Dendritic Cells1 , 2002, The Journal of Immunology.

[32]  I. Wang,et al.  Program Death-1 Engagement Upon TCR Activation Has Distinct Effects on Costimulation and Cytokine-Driven Proliferation: Attenuation of ICOS, IL-4, and IL-21, But Not CD28, IL-7, and IL-15 Responses , 2003, The Journal of Immunology.

[33]  B. Kwon,et al.  4-1BB cross-linking enhances the survival and cell cycle progression of CD4 T lymphocytes. , 2003, Cellular immunology.

[34]  Yoshimasa Tanaka,et al.  Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice , 2003, Nature Medicine.

[35]  Yang Zhang,et al.  [Phase II clinical study of intratumoral H101, an E1B deleted adenovirus, in combination with chemotherapy in patients with cancer]. , 2003, Ai zheng = Aizheng = Chinese journal of cancer.

[36]  C. June,et al.  SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation1 , 2004, The Journal of Immunology.

[37]  Zihai Li,et al.  4-1BB and OX40 Dual Costimulation Synergistically Stimulate Primary Specific CD8 T Cells for Robust Effector Function1 , 2004, The Journal of Immunology.

[38]  金丸 史子 Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25[+] regulatory CD4[+] T cells , 2004 .

[39]  A. Houghton,et al.  Concomitant Tumor Immunity to a Poorly Immunogenic Melanoma Is Prevented by Regulatory T Cells , 2004, The Journal of experimental medicine.

[40]  A. Lanfranco,et al.  CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms , 2004, Molecular and Cellular Biology.

[41]  T. Nomura,et al.  Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells , 2005, The Journal of experimental medicine.

[42]  P. Lollini,et al.  Vaccination with dendritic cells pulsed with apoptotic tumors in combination with anti‐OX40 and anti‐4‐1BB monoclonal antibodies induces T cell–mediated protective immunity in Her‐2/neu transgenic mice , 2005, International journal of cancer.

[43]  P. Saunders,et al.  PD‐L2:PD‐1 involvement in T cell proliferation, cytokine production, and integrin‐mediated adhesion , 2005, European journal of immunology.

[44]  B. Baban,et al.  GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. , 2005, Immunity.

[45]  M. Colombo,et al.  Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. , 2005, Blood.

[46]  Paul Garside,et al.  Reversal of the TCR Stop Signal by CTLA-4 , 2006, Science.

[47]  G. Freeman,et al.  Restoring function in exhausted CD8 T cells during chronic viral infection , 2006, Nature.

[48]  D. Rimm,et al.  Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  Philip J. R. Goulder,et al.  PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression , 2006, Nature.

[50]  C. Riccardi,et al.  Glucocorticoid-Induced TNFR-Related Protein Lowers the Threshold of CD28 Costimulation in CD8+ T Cells1 , 2007, The Journal of Immunology.

[51]  J. Kirkwood,et al.  Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA) , 2008 .

[52]  T. So,et al.  The significance of OX40 and OX40L to T‐cell biology and immune disease , 2009, Immunological reviews.

[53]  A. Psyrri,et al.  E6 and e7 gene silencing and transformed phenotype of human papillomavirus 16-positive oropharyngeal cancer cells. , 2009, Journal of the National Cancer Institute.

[54]  J. Kirkwood,et al.  Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients , 2010, The Journal of experimental medicine.

[55]  J. Allison,et al.  PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors , 2010, Proceedings of the National Academy of Sciences.

[56]  D. Schadendorf,et al.  Improved survival with ipilimumab in patients with metastatic melanoma. , 2010, The New England journal of medicine.

[57]  J. Wolchok,et al.  Agonist Anti-GITR Monoclonal Antibody Induces Melanoma Tumor Immunity in Mice by Altering Regulatory T Cell Stability and Intra-Tumor Accumulation , 2010, PloS one.

[58]  G. Freeman,et al.  Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection , 2010, Proceedings of the National Academy of Sciences.

[59]  Todd M. Allen,et al.  Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. , 2010, The Journal of clinical investigation.

[60]  J. Wolchok,et al.  Anti-GITR antibodies--potential clinical applications for tumor immunotherapy. , 2010, Current opinion in investigational drugs.

[61]  J. Allison,et al.  Two Distinct Mechanisms of Augmented Antitumor Activity by Modulation of Immunostimulatory/Inhibitory Signals , 2010, Clinical Cancer Research.

[62]  A. Carè,et al.  A non‐redundant role for OX40 in the competitive fitness of Treg in response to IL‐2 , 2010, European journal of immunology.

[63]  Jenna M. Sullivan,et al.  Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity , 2010, The Journal of experimental medicine.

[64]  J. Allison,et al.  Combination CTLA-4 Blockade and 4-1BB Activation Enhances Tumor Rejection by Increasing T-Cell Infiltration, Proliferation, and Cytokine Production , 2011, PloS one.

[65]  George Coukos,et al.  Cancer immunotherapy comes of age , 2011, Nature.

[66]  M. Smyth,et al.  Prospects for TIM3-Targeted Antitumor Immunotherapy. , 2011, Cancer research.

[67]  K. Campbell,et al.  Structure/function of human killer cell immunoglobulin‐like receptors: lessons from polymorphisms, evolution, crystal structures and mutations , 2011, Immunology.

[68]  Antoni Ribas,et al.  Tumor immunotherapy directed at PD-1. , 2012, The New England journal of medicine.

[69]  Drew M. Pardoll,et al.  The blockade of immune checkpoints in cancer immunotherapy , 2012, Nature Reviews Cancer.

[70]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[71]  I. Ganly,et al.  Ten years of progress in head and neck cancers. , 2012, Journal of the National Comprehensive Cancer Network : JNCCN.

[72]  M. Suntharalingam,et al.  inducTION of mage‐A3 and HPV‐16 immunity by Trojan vaccines in patients with head and neck carcinoma , 2012, Head & neck.

[73]  J. Wolchok,et al.  Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4 , 2013, The Journal of experimental medicine.

[74]  Lei Lu,et al.  Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs , 2014, Journal of Translational Medicine.

[75]  C. Horak,et al.  Nivolumab plus ipilimumab in advanced melanoma. , 2013, The New England journal of medicine.

[76]  William L. Redmond,et al.  Combined Targeting of Costimulatory (OX40) and Coinhibitory (CTLA-4) Pathways Elicits Potent Effector T Cells Capable of Driving Robust Antitumor Immunity , 2013, Cancer Immunology Research.

[77]  B. Fox,et al.  OX40 is a potent immune-stimulating target in late-stage cancer patients. , 2013, Cancer research.

[78]  D. Bartlett,et al.  Oncolytic viruses as therapeutic cancer vaccines , 2013, Molecular Cancer.

[79]  R. Emerson,et al.  PD-1 blockade induces responses by inhibiting adaptive immune resistance , 2014, Nature.

[80]  Shulan Zhang,et al.  PD-1 Blockade and OX40 Triggering Synergistically Protects against Tumor Growth in a Murine Model of Ovarian Cancer , 2014, PloS one.

[81]  H. Kohrt,et al.  Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients , 2014, Nature.

[82]  J. Wolchok,et al.  Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[83]  J. Taube,et al.  Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy , 2014, Clinical Cancer Research.

[84]  G. Gibney,et al.  Preliminary results from a phase 1/2 study of INCB024360 combined with ipilimumab (ipi) in patients (pts) with melanoma. , 2014 .

[85]  M. Herlyn,et al.  Nivolumab in combination with ipilimumab for the treatment of melanoma , 2015, Expert review of anticancer therapy.

[86]  David C. Smith,et al.  Preliminary results from a Phase I/II study of epacadostat (incb024360) in combination with pembrolizumab in patients with selected advanced cancers , 2015, Journal of Immunotherapy for Cancer.

[87]  J. Lunceford,et al.  Pembrolizumab for the treatment of non-small-cell lung cancer. , 2015, The New England journal of medicine.

[88]  A. Ravaud,et al.  Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. , 2015, The New England journal of medicine.

[89]  J. Larkin,et al.  Pembrolizumab versus Ipilimumab in Advanced Melanoma. , 2015, The New England journal of medicine.

[90]  Troy Guthrie,et al.  Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[91]  J. Wolchok,et al.  Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo , 2015, The Journal of Immunology.

[92]  G. Linette,et al.  Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. , 2015, The New England journal of medicine.

[93]  M. Millenson,et al.  PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. , 2015, The New England journal of medicine.

[94]  B. Fox,et al.  OX40 signaling in head and neck squamous cell carcinoma: Overcoming immunosuppression in the tumor microenvironment. , 2016, Oral oncology.

[95]  J. Lunceford,et al.  Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. , 2016, The Lancet. Oncology.

[96]  E. Diamandis,et al.  Cancer immunotherapy: the beginning of the end of cancer? , 2016, BMC Medicine.

[97]  J. Radford Nivolumab for recurrent squamous-cell carcinoma of the head and neck , 2016, BDJ.

[98]  D. Deschler,et al.  Novel Immunotherapeutic Approaches for Head and Neck Squamous Cell Carcinoma , 2016, Cancers.

[99]  A. Ribas,et al.  Combination cancer immunotherapies tailored to the tumour microenvironment , 2016, Nature Reviews Clinical Oncology.