The future of cancer treatment: immunomodulation, CARs and combination immunotherapy (original) (raw)

• Coley, W. B. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc. R. Soc. Med. 3, 1–48 (1910).
  CAS PubMed PubMed Central Google Scholar
• Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2014).
  PubMed Google Scholar
• Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).
  CAS PubMed Google Scholar
• Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
  CAS PubMed PubMed Central Google Scholar
• Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).
  CAS PubMed Google Scholar
• Rizvi, N. A. et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet. Oncol. 16, 257–265 (2015).
  CAS PubMed PubMed Central Google Scholar
• Pedicord, V. A., Montalvo, W., Leiner, I. M. & Allison, J. P. Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc. Natl Acad. Sci. USA 108, 266–271 (2011).
  CAS PubMed Google Scholar
• Schadendorf, D. et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J. Clin. Oncol. 33, 1889–1894 (2015).
  CAS PubMed PubMed Central Google Scholar
• Chapman, P. B., D'Angelo, S. P. & Wolchok, J. D. Rapid eradication of a bulky melanoma mass with one dose of immunotherapy. N. Engl. J. Med. 372, 2073–2074 (2015).
  PubMed Google Scholar
• Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).
  PubMed PubMed Central Google Scholar
• Wilgenhof, S. et al. Single-center experience with ipilimumab in an expanded access program for patients with pretreated advanced melanoma. J. Immunother. 36, 215–222 (2013).
  CAS PubMed Google Scholar
• Kitano, S. et al. Computational algorithm-driven evaluation of monocytic myeloid-derived suppressor cell frequency for prediction of clinical outcomes. Cancer Immunol. Res. 2, 812–821 (2014).
  CAS PubMed PubMed Central Google Scholar
• Hannani, D. et al. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25. Cell Res. 25, 208–224 (2015).
  CAS PubMed PubMed Central Google Scholar
• Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
  CAS PubMed PubMed Central Google Scholar
• Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
  PubMed PubMed Central Google Scholar
• Van Allen, E. M. et al. Genomic correlates of response to CTLA4 blockade in metastatic melanoma. Science 350, 207–211 (2015).
  CAS PubMed PubMed Central Google Scholar
• Bonifaz, L. et al. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J. Exp. Med. 196, 1627–1638 (2002).
  CAS PubMed PubMed Central Google Scholar
• Walunas, T. L. et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405–413 (1994).
  CAS PubMed Google Scholar
• Krummel, M. F. & Allison, J. P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182, 459–465 (1995).
  CAS PubMed Google Scholar
• Tivol, E. A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995).
  CAS PubMed Google Scholar
• Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995).
  CAS PubMed Google Scholar
• Matheu, M. P. et al. Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nat. Commun. 6, 6219 (2015).
  CAS PubMed Google Scholar
• Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008).
  CAS PubMed Google Scholar
• Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 192, 303–310 (2000).
  CAS PubMed PubMed Central Google Scholar
• Read, S., Malmström, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).
  CAS PubMed PubMed Central Google Scholar
• Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).
  CAS PubMed PubMed Central Google Scholar
• Selby, M. J. et al. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1, 32–42 (2013).
  CAS PubMed Google Scholar
• Phan, G. Q. et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 100, 8372–8377 (2003).
  CAS PubMed PubMed Central Google Scholar
• Gregor, P. D. et al. CTLA-4 blockade in combination with xenogeneic DNA vaccines enhances T-cell responses, tumor immunity and autoimmunity to self antigens in animal and cellular model systems. Vaccine 22, 1700–1708 (2004).
  CAS PubMed Google Scholar
• Quezada, S. A. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J. Clin. Invest. 116, 1935–1945 (2006).
  CAS PubMed PubMed Central Google Scholar
• Weber, J. S., Kähler, K. C. & Hauschild, A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30, 2691–2697 (2012).
  CAS PubMed Google Scholar
• Wolchok, J. D. et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet. Oncol. 11, 155–164 (2010).
  CAS PubMed Google Scholar
• Wolchok, J. D. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 15, 7412–7420 (2009).
  CAS PubMed Google Scholar
• Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).
  CAS PubMed Google Scholar
• Yang, J. C. et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J. Immunother. 30, 825–830 (2007).
  CAS PubMed PubMed Central Google Scholar
• Royal, R. E. et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).
  CAS PubMed PubMed Central Google Scholar
• Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).
  CAS PubMed PubMed Central Google Scholar
• Zamarin, D. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl. Med. 6, 226ra32–226ra32 (2014).
  PubMed PubMed Central Google Scholar
• Waitz, R., Fassò, M. & Allison, J. P. CTLA-4 blockade synergizes with cryoablation to mediate tumor rejection. Oncoimmunology 1, 544–546 (2014).
  Google Scholar
• Chemnitz, J. M. 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 activation. J. Immunol. 173, 945–954 (2004).
  CAS PubMed Google Scholar
• Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25, 9543–9553 (2005).
  CAS PubMed PubMed Central Google Scholar
• Park, J.-J. et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 116, 1291–1298 (2010).
  CAS PubMed PubMed Central Google Scholar
• Paterson, A. M. et al. The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J. Immunol. 187, 1097–1105 (2011).
  CAS PubMed Google Scholar
• Nishimura, H. et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291, 319–322 (2001).
  CAS PubMed Google Scholar
• Nishimura, H. et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999).
  CAS PubMed Google Scholar
• Okazaki, T. & Honjo, T. PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19, 813–824 (2007).
  CAS PubMed Google Scholar
• Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).
  PubMed PubMed Central Google Scholar
• Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–134 (2015).
  CAS PubMed PubMed Central Google Scholar
• U.S. Food and Drug Administation. FDA expands approved use of Opdivo in advanced lung cancer. [online], (2014).
• U.S. Food and Drug Administation. FDA approves Keytruda for advanced non-small cell lung cancer. [online], (2015).
• Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
  CAS PubMed PubMed Central Google Scholar
• Brahmer, J. R. et al. Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): survival and clinical activity by subgroup analysis [abstract]. J. Clin. Oncol. 32 (Suppl.), 8112 (2014).
  Google Scholar
• Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).
  CAS PubMed Google Scholar
• Ansell, S. M. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311–319 (2014).
  PubMed PubMed Central Google Scholar
• Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
  CAS PubMed PubMed Central Google Scholar
• Huard, B. et al. Cellular expression and tissue distribution of the human LAG-3-encoded protein, an MHC class II ligand. Immunogenetics 39, 213–217 (1994).
  CAS PubMed Google Scholar
• Huard, B. et al. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)–Ig fusion proteins. Eur. J. Immunol. 25, 2718–2721 (1995).
  CAS PubMed Google Scholar
• Huang, C.-T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004).
  CAS PubMed Google Scholar
• Okamura, T. et al. CD4+CD25−LAG3+ regulatory T cells controlled by the transcription factor Egr-2. Proc. Natl Acad. Sci. USA 106, 13974–13979 (2009).
  CAS PubMed PubMed Central Google Scholar
• Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).
  CAS PubMed Google Scholar
• Butler, N. S. et al. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat. Immunol. 13, 188–195 (2012).
  CAS Google Scholar
• Woo, S.-R. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 72, 917–927 (2012).
  CAS PubMed Google Scholar
• Triebel, F., Hacene, K. & Pichon, M.-F. A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors. Cancer Lett. 235, 147–153 (2006).
  CAS PubMed Google Scholar
• Brignone, C. et al. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin. Cancer Res. 15, 6225–6231 (2009).
  CAS PubMed Google Scholar
• US National Library of Science. ClinicalTrials.gov [online], (2016).
• Jin, H.-T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl Acad. Sci. USA 107, 14733–14738 (2010).
  CAS PubMed PubMed Central Google Scholar
• Zhu, C. et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 6, 1245–1252 (2005).
  CAS PubMed Google Scholar
• Chiba, S. et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 13, 832–842 (2012).
  CAS PubMed PubMed Central Google Scholar
• Nakayama, M. et al. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood 113, 3821–3830 (2009).
  CAS PubMed Google Scholar
• Huang, Y.-H. et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature 517, 386–390 (2015).
  CAS PubMed Google Scholar
• Ngiow, S. F. et al. Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors. Cancer Res. 71, 3540–3551 (2011).
  CAS PubMed Google Scholar
• Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187–2194 (2010).
  CAS PubMed PubMed Central Google Scholar
• Fourcade, J. et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175–2186 (2010).
  CAS PubMed PubMed Central Google Scholar
• Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923–937 (2014).
  CAS PubMed Google Scholar
• Lozano, E., Dominguez-Villar, M., Kuchroo, V. & Hafler, D. A. The TIGIT/CD226 axis regulates human T cell function. J. Immunol. 188, 3869–3875 (2012).
  CAS PubMed Google Scholar
• Kurtulus, S. et al. Mechanisms of TIGIT-driven immune suppression in cancer. J. Immunother. Cancer 2, O13 (2014).
  PubMed Central Google Scholar
• Khalil, D. N. et al. The new era of cancer immunotherapy: manipulating T-cell activity to overcome malignancy. Adv. Cancer Res. 128, 1–68 (2015).
  CAS PubMed Google Scholar
• Bartkowiak, T. & Curran, M. A. 4-1BB agonists: multi-potent potentiators of tumor immunity. Front. Oncol. 5, 117 (2015).
  PubMed PubMed Central Google Scholar
• Lee, H.-W. et al. 4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1. J. Immunol. 169, 4882–4888 (2002).
  PubMed Google Scholar
• Stärck, L., Scholz, C., Dörken, B. & Daniel, P. T. Costimulation by CD137/4-1BB inhibits T cell apoptosis and induces Bcl-xL and c-FLIPshort via phosphatidylinositol 3-kinase and AKT/protein kinase B. Eur. J. Immunol. 35, 1257–1266 (2005).
  PubMed Google Scholar
• Shuford, W. W. et al. 4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses. J. Exp. Med. 186, 47–55 (1997).
  CAS PubMed PubMed Central Google Scholar
• Vinay, D. S. & Kwon, B. S. 4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy. BMB Rep. 47, 122–129 (2014).
  PubMed PubMed Central Google Scholar
• Curran, M. A. et al. Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS ONE 6, e19499 (2011).
  CAS PubMed PubMed Central Google Scholar
• Uno, T. et al. Eradication of established tumors in mice by a combination antibody-based therapy. Nat. Med. 12, 693–698 (2006).
  CAS PubMed Google Scholar
• Tirapu, I. et al. Improving efficacy of interleukin-12-transfected dendritic cells injected into murine colon cancer with anti-CD137 monoclonal antibodies and alloantigens. Int. J. Cancer 110, 51–60 (2004).
  CAS PubMed Google Scholar
• Shi, W. & Siemann, D. W. Augmented antitumor effects of radiation therapy by 4-1BB antibody (BMS-469492) treatment. Anticancer Res. 26, 3445–3453 (2006).
  CAS PubMed Google Scholar
• Molckovsky, A. & Siu, L. L. First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American Society of Clinical Oncology meeting. J. Hematol. Oncol. 1, 20 (2008).
  PubMed PubMed Central Google Scholar
• Garber, K. Beyond ipilimumab: new approaches target the immunological synapse. J. Natl Cancer Inst. 103, 1079–1082 (2011).
  CAS PubMed Google Scholar
• US National Library of Science. ClinicalTrials.gov [online], (2016).
• James, A. M., Cohen, A. D. & Campbell, K. S. Combination immune therapies to enhance anti-tumor responses by NK cells. Front. Immunol. 4, 481 (2013).
  Google Scholar
• Kohrt, H. E. et al. Targeting CD137 enhances the efficacy of cetuximab. J. Clin. Invest. 124, 2668–2682 (2014).
  CAS PubMed PubMed Central Google Scholar
• Schaer, D. A., Cohen, A. D. & Wolchok, J. D. Anti-GITR antibodies — potential clinical applications for tumor immunotherapy. Curr. Opin. Investig. Drugs 11, 1378–1386 (2010).
  CAS PubMed Google Scholar
• Kanamaru, F. et al. Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells. J. Immunol. 172, 7306–7314 (2004).
  CAS PubMed Google Scholar
• Ronchetti, S. et al. Glucocorticoid-induced TNFR-related protein lowers the threshold of CD28 costimulation in CD8+ T cells. J. Immunol. 179, 5916–5926 (2007).
  CAS PubMed Google Scholar
• Valzasina, B. 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. Blood 105, 2845–2851 (2005).
  CAS PubMed Google Scholar
• Mitsui, J. et al. Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. Clin. Cancer Res. 16, 2781–2791 (2010).
  CAS PubMed Google Scholar
• Bulliard, Y. et al. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210, 1685–1693 (2013).
  CAS PubMed PubMed Central Google Scholar
• Cohen, A. D. et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS ONE 5, e10436 (2010).
  PubMed PubMed Central Google Scholar
• Schaer, D. A. et al. GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability. Cancer Immunol. Res. 1, 320–331 (2013).
  CAS PubMed Google Scholar
• US National Library of Science. ClinicalTrials.gov[online], (2015).
• US National Library of Science. ClinicalTrials.gov[online],(2015).
• Eliopoulos, A. G. & Young, L. S. The role of the CD40 pathway in the pathogenesis and treatment of cancer. Curr. Opin. Pharmacol. 4, 360–367 (2004).
  CAS PubMed Google Scholar
• Van Kooten, C. & Banchereau, J. CD40–CD40 ligand. J. Leukoc. Biol. 67, 2–17 (2000).
  CAS PubMed Google Scholar
• Kawabe, T. et al. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1, 167–178 (1994).
  CAS PubMed Google Scholar
• Burington, B. et al. CD40 pathway activation status predicts response to CD40 therapy in diffuse large B cell lymphoma. Sci. Transl. Med. 3, 74ra22 (2011).
  PubMed Google Scholar
• Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).
  CAS PubMed PubMed Central Google Scholar
• Baumann, R. et al. Functional expression of CD134 by neutrophils. Eur. J. Immunol. 34, 2268–2275 (2004).
  CAS PubMed Google Scholar
• Rogers, P. R. et al. OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells. Immunity 15, 445–455 (2001).
  CAS PubMed Google Scholar
• Arestides, R. S. S. et al. Costimulatory molecule OX40L is critical for both Th1 and Th2 responses in allergic inflammation. Eur. J. Immunol. 32, 2874–2880 (2002).
  CAS PubMed Google Scholar
• Griseri, T., Asquith, M., Thompson, C. & Powrie, F. OX40 is required for regulatory T cell-mediated control of colitis. J. Exp. Med. 207, 699–709 (2010).
  CAS PubMed PubMed Central Google Scholar
• Hirschhorn-Cymerman, D. et al. OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. J. Exp. Med. 206, 1103–1116 (2009).
  CAS PubMed PubMed Central Google Scholar
• Pan, P.-Y. et al. OX40 ligation enhances primary and memory cytotoxic T lymphocyte responses in an immunotherapy for hepatic colon metastases. Mol. Ther. 6, 528–536 (2002).
  CAS PubMed Google Scholar
• Curti, B. D. et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 73, 7189–7198 (2013).
  CAS PubMed PubMed Central Google Scholar
• US National Library of Science. ClinicalTrials.gov[online], (2015).
• US National Library of Science. ClinicalTrials.gov[online], (2015).
• US National Library of Science. ClinicalTrials.gov[online], (2015).
• US National Library of Science. ClinicalTrials.gov[online], (2015).
• Naidoo, J., Page, D. B. & Wolchok, J. D. Immune modulation for cancer therapy. Br. J. Cancer 111, 2214–2219 (2014).
  CAS PubMed PubMed Central Google Scholar
• Gross, G., Waks, T. & Eshhar, Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl Acad. Sci. USA 86, 10024–10028 (1989).
  CAS PubMed PubMed Central Google Scholar
• Brentjens, R. J. et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat. Med. 9, 279–286 (2003).
  CAS PubMed Google Scholar
• Brentjens, R. J. et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin. Cancer Res. 13, 5426–5435 (2007).
  CAS PubMed Google Scholar
• Davila, M. L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra25 (2014).
  PubMed PubMed Central Google Scholar
• Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676–684 (2004).
  CAS PubMed Google Scholar
• Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
  PubMed PubMed Central Google Scholar
• Hombach, A. A. et al. OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells. Oncoimmunology 1, 458–466 (2012).
  PubMed PubMed Central Google Scholar
• Guedan, S. et al. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 124, 1070–1080 (2014).
  CAS PubMed PubMed Central Google Scholar
• US National Library of Science. ClinicalTrials.gov[online], (2015).
• Pegram, H. J. et al. Tumor-targeted T cells modified tosecrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119, 4133–4141 (2012).
  CAS PubMed PubMed Central Google Scholar
• Zhao, Z. et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28, 415–428 (2015).
  CAS PubMed PubMed Central Google Scholar
• Curran, K. J. et al. Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol. Ther. 23, 769–778 (2015).
  CAS PubMed PubMed Central Google Scholar
• Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2014).
  PubMed PubMed Central Google Scholar
• Fielding, A. K. et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 109, 944–950 (2007).
  CAS PubMed Google Scholar
• Pegram, H. J., Smith, E. L., Rafiq, S. & Brentjens, R. J. CAR therapy for hematological cancers: can success seen in the treatment of B-cell acute lymphoblastic leukemia be applied to other hematological malignancies? Immunotherapy 7, 545–561 (2015).
  CAS PubMed Google Scholar
• Park, J. H. et al. CD19-Targeted 19-28z CAR modified autologous T cells induce high rates of complete remission and durable responses in adult patients with relapsed, refractory B-cell ALL. Blood 124, 382 (2014).
  Google Scholar
• Park, J. H. et al. Efficacy and safety of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed or refractory B-ALL. J. Clin. Oncol. 33, 7010 (2015).
  Google Scholar
• Grupp, S. A. et al. T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) have long term persistence and induce durable remissions in children with relapsed, refractory ALL. Blood 124, 380 (2014).
  Google Scholar
• Grupp, S. A. Immunotherapy for childhood leukemia. Presented at the 2015 ASCO Annual Meeting (2015).
• Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).
  CAS PubMed PubMed Central Google Scholar
• Turtle, C. et al. Immunotherapy with CD19-specific chimeric antigen receptor (CAR)-modified T cells of defined subset composition. J. Clin. Oncol. 33, 3006 (2015).
  Google Scholar
• Kebriaei, P. et al. Adoptive therapy using sleeping beauty gene transfer system and artificial antigen presenting cells to manufacture T cells expressing CD19-specific chimeric antigen receptor. Blood 124, 311 (2014).
  Google Scholar
• Porter, D. L. et al. Randomized, phase II dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. Blood 124, 1982 (2014).
  Google Scholar
• Beatty, G. L. et al. Safety and antitumor activity of chimeric antigen receptor modified T cells in patients with chemotherapy refractory metastatic pancreatic cancer [abstract]. J. Clin. Oncol. 33 (Suppl.), 3007 (2015).
  Google Scholar
• Howlader, N. et al. SEER Cancer Statistics Review, 1975–2012. National Cancer Institute [online], (2015).
• Aspinall, R. & Andrew, D. Thymic involution in aging. J. Clin. Immunol. 20, 250–256 (2000).
  CAS PubMed Google Scholar
• Goronzy, J. J., Li, G., Yu, M. & Weyand, C. M. Signaling pathways in aged T cells — a reflection of T cell differentiation, cell senescence and host environment. Semin. Immunol. 24, 365–372 (2012).
  CAS PubMed PubMed Central Google Scholar
• Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity? Nat. Rev. Immunol. 3, 609–620 (2003).
  CAS PubMed Google Scholar
• Brentjens, R. J. et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118, 4817–4828 (2011).
  CAS PubMed PubMed Central Google Scholar
• Park, J. H. et al. Impact of the conditioning chemotherapy on outcomes in adoptive T cell therapy: results from a phase I clinical trial of autologous CD19-targeted T cells for patients with relapsed CLL. Blood 120, 1797 (2012).
  Google Scholar
• Ramos, C. et al. Clinical responses in patients infused with T lymphocytes redirected to target κ-light immunoglobulin chain. Blood 122, 506 (2013).
  Google Scholar
• Hahn, T. et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review. Biol. Blood Marrow Transplant. 12, 1–30 (2006).
  CAS PubMed Google Scholar
• Eapen, M. et al. Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood 107, 4961–4967 (2006).
  CAS PubMed PubMed Central Google Scholar
• Porter, D. L. et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).
  CAS PubMed PubMed Central Google Scholar
• Porter, D. L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7, 303ra139 (2015).
  PubMed PubMed Central Google Scholar
• Christopoulos, P. et al. Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL. Blood 117, 3836–3846 (2011).
  CAS PubMed Google Scholar
• Riches, J. C. et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 121, 1612–1621 (2013).
  CAS PubMed PubMed Central Google Scholar
• McClanahan, F. et al. Mechanisms of PD-L1/PD-1 mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eμ-TCL1 CLL mouse model. Blood 126, 212–221 (2015).
  CAS PubMed PubMed Central Google Scholar
• D'Arena, G. et al. Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease. Leuk. Res. 35, 363–368 (2011).
  PubMed Google Scholar
• Jitschin, R. et al. CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs . Blood 124, 750–760 (2014).
  CAS PubMed Google Scholar
• Boissard, F. et al. Nurse like cells: chronic lymphocytic leukemia associated macrophages. Leuk. Lymphoma 56, 1570–1572 (2015).
  CAS PubMed Google Scholar
• Burger, J. A. et al. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood 96, 2655–2663 (2000).
  CAS PubMed Google Scholar
• Saulep-Easton, D. et al. The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells. Leukemia 30, 163–172 (2015).
  PubMed PubMed Central Google Scholar
• Kochenderfer, J. N. et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 33, 540–549 (2014).
  PubMed PubMed Central Google Scholar
• Schuster, S. J. et al. Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. J. Clin. Oncol. 33, 8516 (2015).
  Google Scholar
• Sauter, C. S. et al. Phase I trial of 19-28z chimeric antigen receptor modified T cells (19-28z CAR-T) post-high dose therapy and autologous stem cell transplant (HDT-ASCT) for relapsed and refractory (rel/ref) aggressive B-cell non-Hodgkin lymphoma (B-NHL). J. Clin. Oncol. 33, 8515 (2015).
  Google Scholar
• Savoldo, B. et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Invest. 121, 1822–1826 (2011).
  CAS PubMed PubMed Central Google Scholar
• Maude, S. L., Barrett, D., Teachey, D. T. & Grupp, S. A. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 20, 119–122 (2014).
  CAS PubMed PubMed Central Google Scholar
• Frey, N. V. et al. Refractory cytokine release syndrome in recipients of chimeric antigen receptor (CAR) T cells. Blood 124, 2296 (2014).
  Google Scholar
• Haso, W. et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 121, 1165–1174 (2013).
  CAS PubMed PubMed Central Google Scholar
• Berger, C. et al. Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells. Cancer Immunol. Res. 3, 206–216 (2015).
  CAS PubMed Google Scholar
• Hudecek, M. et al. The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood 116, 4532–4541 (2010).
  CAS PubMed PubMed Central Google Scholar
• Ying, Z.-T. et al. First-in-patient proof of safety and efficacy of a 4th generation chimeric antigen receptor-modified T cells for the treatment of relapsed or refractory CD30 positive lymphomas [poster]. Presented at the 13th International Conference on Malignant Lymphoma (2015).
• Carpenter, R. O. et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin. Cancer Res. 19, 2048–2060 (2013).
  CAS PubMed PubMed Central Google Scholar
• Chu, J. et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia 28, 917–927 (2014).
  CAS PubMed Google Scholar
• Mihara, K. et al. T-cell immunotherapy with a chimeric receptor against CD38 is effective in eliminating myeloma cells. Leukemia 26, 365–367 (2012).
  CAS PubMed Google Scholar
• Drent, E. et al. CD38 chimeric antigen receptor engineered T cells as therapeutic tools for multiple myeloma. Blood 124, 4759 (2014).
  Google Scholar
• Guo, B. et al. CD138-directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma. J. Cell. Immunother. http://dx.doi.org/10.1016/j.jocit.2014.11.001, (2015).
• Kenderian, S. S. et al. CD33 specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia 29, 1637–1647 (2015).
  CAS PubMed PubMed Central Google Scholar
• Gill, S. et al. Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Blood 123, 2343–2354 (2014).
  CAS PubMed PubMed Central Google Scholar
• Tettamanti, S. et al. Targeting of acute myeloid leukaemia by cytokine-induced killer cells redirected with a novel CD123-specific chimeric antigen receptor. Br. J. Haematol. 161, 389–401 (2013).
  CAS PubMed Google Scholar
• Mardiros, A. et al. T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood 122, 3138–3148 (2013).
  CAS PubMed PubMed Central Google Scholar
• Jackson, H. J., Rafiq, S. & Brentjens, R. J. Driving CAR T cells forward. Nat. Rev. Clin. Oncol. http://dx.doi.org/10.1038/nrclinonc.2016.36, (2016).
• Marusyk, A. & Polyak, K. Tumor heterogeneity: causes and consequences. Biochim. Biophys. Acta 1805, 105–117 (2010).
  CAS PubMed Google Scholar
• Fidler, I. J. & Hart, I. R. Biological diversity in metastatic neoplasms: origins and implications. Science 217, 998–1003 (1982).
  CAS PubMed Google Scholar
• Adusumilli, P. S. et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci. Transl. Med. 6, 261ra151 (2014).
  PubMed PubMed Central Google Scholar
• Beatty, G. L. et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol. Res. 2, 112–120 (2014).
  CAS PubMed Google Scholar
• Tanyi, J. et al. Safety and feasibility of chimeric antigen receptor modified T cells directed against mesothelin (CART-meso) in patients with mesothelin expressing cancers [abstract]. Cancer Res. 75 (Suppl.), CT105 (2015).
  Google Scholar
• Louis, C. U. et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 118, 6050–6056 (2011).
  CAS PubMed PubMed Central Google Scholar
• Singh, N. et al. Nature of tumor control by permanently and transiently modified GD2 chimeric antigen receptor T cells in xenograft models of neuroblastoma. Cancer Immunol. Res. 2, 1059–1070 (2014).
  CAS PubMed PubMed Central Google Scholar
• Johnson, L. A. et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci. Transl. Med. 7, 275ra22 (2015).
  CAS PubMed PubMed Central Google Scholar
• Koneru, M. et al. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology 4, e994446 (2015).
  PubMed PubMed Central Google Scholar
• Koneru, M. et al. A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16ecto directed chimeric antigen receptors for recurrent ovarian cancer. J. Transl. Med. 13, 102 (2015).
  PubMed PubMed Central Google Scholar
• Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).
  CAS PubMed PubMed Central Google Scholar
• Moon, E. K. et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin. Cancer Res. 20, 4262–4273 (2014).
  CAS PubMed PubMed Central Google Scholar
• Ankri, C. et al. Human T cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity. J. Immunol. 191, 4121–4129 (2013).
  CAS PubMed Google Scholar
• Kobold, S. et al. Impact of a new fusion receptor on PD-1-mediated immunosuppression in adoptive T cell therapy. J. Natl. Cancer Inst. 107, djv146 (2015).
  PubMed PubMed Central Google Scholar
• Heemskerk, B. et al. Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum. Gene Ther. 19, 496–510 (2008).
  CAS PubMed Google Scholar
• Hoyos, V. et al. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 24, 1160–1170 (2010).
  CAS PubMed PubMed Central Google Scholar
• Leonard, J. P. et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-γ production. Blood 90, 2541–2548 (1997).
  CAS PubMed Google Scholar
• Chinnasamy, D. et al. Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin. Cancer Res. 18, 1672–1683 (2012).
  CAS PubMed PubMed Central Google Scholar
• Kerkar, S. P. et al. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J. Clin. Invest. 121, 4746–4757 (2011).
  CAS PubMed PubMed Central Google Scholar
• Kerkar, S. P. et al. Collapse of the tumor stroma is triggered by IL-12 induction of Fas. Mol. Ther. 21, 1369–1377 (2013).
  CAS PubMed PubMed Central Google Scholar
• Pegram, H. J. et al. IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia 29, 415–422 (2015).
  CAS PubMed Google Scholar
• Dunn, G. P. et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).
  CAS PubMed Google Scholar
• Koebel, C. M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–907 (2007).
  CAS PubMed Google Scholar
• Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
  CAS PubMed Google Scholar
• Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).
  CAS PubMed Google Scholar
• Vesely, M. D., Kershaw, M. H., Schreiber, R. D. & Smyth, M. J. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 29, 235–271 (2011).
  CAS PubMed Google Scholar
• Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).
  CAS PubMed PubMed Central Google Scholar
• Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
  CAS PubMed PubMed Central Google Scholar
• John, L. B. et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin. Cancer Res. 19, 5636–5646 (2013).
  CAS PubMed Google Scholar
• Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
  PubMed Google Scholar
• Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of _KRAS_-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015).
  CAS PubMed PubMed Central Google Scholar
• US National Library of Science. ClinicalTrials.gov[online], (2015).
• Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747–752 (2013).
  CAS PubMed PubMed Central Google Scholar
• Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).
  CAS PubMed PubMed Central Google Scholar
• Dudley, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).
  CAS PubMed PubMed Central Google Scholar
• Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).
  CAS PubMed PubMed Central Google Scholar
• Stafford, J. H. et al. Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization. Neuro Oncol. http://dx.doi.org/10.1093/neuonc/nov272, (2015).
• Lipson, E. J. et al. Safety and immunologic correlates of melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting. J. Transl. Med. 13, 214 (2015).
  PubMed PubMed Central Google Scholar
• DiLillo, D. J. & Ravetch, J. V. Differential Fc-receptor engagement drives an anti-tumor vaccinal effect. Cell 161, 1035–1045 (2015).
  CAS PubMed PubMed Central Google Scholar
• Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-α. Science 330, 827–830 (2010).
  CAS PubMed Google Scholar