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Realism and pragmatism in developing an effective chimeric antigen receptor T-cell product for solid cancers

  • Ahmed Z. Gad
    Correspondence
    Correspondence: Ahmed Z. Gad, BPharm, MSc, or Nabil Ahmed, MD, MPH, Center for Cell and Gene Therapy, Baylor College of Medicine, 1102 Bates Street, Suite 1770, MC3-3320, Houston, TX 77030.
    Affiliations
    Basic Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

    Biotechnology Program, School of Sciences and Engineering, The American University in Cairo, New Cairo, Egypt
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  • Shahenda El-Naggar
    Affiliations
    Basic Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt
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  • Nabil Ahmed
    Correspondence
    Correspondence: Ahmed Z. Gad, BPharm, MSc, or Nabil Ahmed, MD, MPH, Center for Cell and Gene Therapy, Baylor College of Medicine, 1102 Bates Street, Suite 1770, MC3-3320, Houston, TX 77030.
    Affiliations
    Basic Research Department, Children's Cancer Hospital Egypt 57357, Cairo, Egypt

    Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, Houston, Texas, USA

    Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA
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Published:September 02, 2016DOI:https://doi.org/10.1016/j.jcyt.2016.07.004

      Abstract

      Over the last two decades, harnessing the power of the immune system has shown substantial promise. Specifically, the successes that chimeric antigen receptor (CAR) T cells achieved in the treatment of hematologic malignancies provided a concrete platform for further development in solid tumors. Considering that the latter contribute more than three quarters of cancer-related deaths in humans makes it clear that solid tumors represent the larger medical challenge, but also the larger developmental promise in the market. In solid tumors though, the more is achieved the more challenges are unveiled. The mere fact that engineered T cells are personalized therapies rather than a mass product has been a main constraint for clinical outspread. Further, the complexity of the hostile solid tumor microenvironment, antigenic diversity and dynamicity and the presence of a tenacious stem cell population rendered the effective development to the clinic questionable. In this article we shed light on the importance of a realistic understanding of challenges faced in solid tumors and some very innovative efforts to overcome these challenges in a manner that paves a pragmatic yet realistic road toward effective development at the discovery level and beyond.

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      References

        • Vanneman M.
        • Dranoff G.
        Combining immunotherapy and targeted therapies in cancer treatment.
        Nat Rev Cancer. 2012; 12: 237-251
        • Mellman I.
        • Coukos G.
        • Dranoff G.
        Cancer immunotherapy comes of age.
        Nature. 2011; 480: 480-489
        • Huang X.
        • Park H.
        • Greene J.
        • Pao J.
        • Mulvey E.
        • Zhou S.X.
        • et al.
        IGF1R-and ROR1-specific CAR T cells as a potential therapy for high risk sarcomas.
        PLoS ONE. 2015; 10: e0133152
        • Kantoff P.W.
        Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
        N Engl J Med. 2010; 363: 411-422
        • Ames E.
        • Murphy W.J.
        Advantages and clinical applications of natural killer cells in cancer immunotherapy.
        Cancer Immunol Immunother. 2014; 63: 21-28https://doi.org/10.1007/s00262-013-1469-8
        • Atkins M.B.
        • Lotze M.T.
        • Dutcher J.P.
        • Fisher R.I.
        • Weiss G.
        • Margolin K.
        • et al.
        High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993.
        J Clin Oncol. 1999; 17: 2105
        • June C.H.C.
        Adoptive T cell therapy for cancer in the clinic.
        J Clin Invest. 2007; 117: 1466-1476https://doi.org/10.1172/JCI32446.1466
        • Porter D.L.
        • Levine B.L.
        • Kalos M.
        • Bagg A.
        • June C.H.
        Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.
        N Engl J Med. 2011; 365: 725-733
        • Christiansen J.
        • Rajasekaran A.K.
        Biological impediments to monoclonal antibody–based cancer immunotherapy.
        Mol Cancer Ther. 2004; 3: 1493-1501
        • Fousek K.
        • Ahmed N.
        The evolution of T-cell therapies for solid malignancies.
        Clin Cancer Res. 2015; 21: 3384-3392
        • Mihara K.
        • Yanagihara K.
        • Takigahira M.
        • Kitanaka A.
        • Imai C.
        • Bhattacharyya J.
        • et al.
        Synergistic and persistent effect of T-cell immunotherapy with anti-CD19 or anti-CD38 chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin lymphoma.
        Br J Haematol. 2010; 151: 37-46https://doi.org/10.1111/j.1365-2141.2010.08297.x
        • Poschke I.
        • Lövgren T.
        • Adamson L.
        • Nyström M.
        • Andersson E.
        • Hansson J.
        • et al.
        A phase I clinical trial combining dendritic cell vaccination with adoptive T cell transfer in patients with stage IV melanoma.
        Cancer Immunol Immunother. 2014; 63: 1061-1071
        • Hensley S.E.
        • Das S.R.
        • Bailey A.L.
        • Schmidt L.M.
        • Hickman H.D.
        • Jayaraman A.
        • et al.
        Hemagglutinin receptor binding avidity drives influenza a virus antigenic drift.
        Science. 2009; 326: 734-736
        • Engels B.
        • Engelhard V.H.
        • Sidney J.
        • Sette A.
        • Binder D.C.
        • Liu R.B.
        • et al.
        Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity.
        Cancer Cell. 2013; 23: 516-526https://doi.org/10.1016/j.ccr.2013.03.018
        • Bollard C.M.
        • Heslop H.E.
        • Brenner M.K.
        Gene-marking studies of hematopoietic cells.
        Int J Hematol. 2001; 73: 14-22
        • Tey S.-K.
        • Brenner M.K.
        The continuing contribution of gene marking to cell and gene therapy.
        Mol Ther. 2007; 15: 666-676
        • Kershaw M.H.
        • Wang G.
        • Westwood J.A.
        • Pachynski R.K.
        • Tiffany H.L.
        • Marincola F.M.
        • et al.
        Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2.
        Hum Gene Ther. 2002; 13: 1971-1980
        • Peng W.
        • Ye Y.
        • Rabinovich B.A.
        • Liu C.
        • Lou Y.
        • Zhang M.
        • et al.
        Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses.
        Clin Cancer Res. 2010; 16: 5458-5468https://doi.org/10.1158/1078-0432.CCR-10-0712
        • Rosenberg S.A.
        • Packard B.S.
        • Aebersold P.M.
        • Solomon D.
        • Topalian S.L.
        • Toy S.T.
        • et al.
        Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma.
        N Engl J Med. 1988; 319: 1676-1680https://doi.org/10.1056/NEJM198812223192527
        • Aranda F.
        • Vacchelli E.
        • Obrist F.
        • Eggermont A.
        • Galon J.
        Adoptive cell transfer for anticancer immunotherapy.
        Oncoimmunology. 2014; 3: 1-13
        • Morgan R.A.
        Cancer regression in patients after transfer of genetically engineered lymphocytes.
        Science. 2006; 314: 126-129
        • Rapoport A.P.
        • Stadtmauer E.A.
        • Binder-Scholl G.K.
        • Goloubeva O.
        • Vogl D.T.
        • Lacey S.F.
        • et al.
        NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma.
        Nat Med. 2015; 21: 914-921
        • Robbins P.F.
        Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1.
        J Clin Oncol. 2011; 29: 917-924
        • van der Veken L.T.
        • Hagedoorn R.S.
        • van Loenen M.M.
        • Willemze R.
        • Falkenburg J.H.F.
        • Heemskerk M.H.M.
        αβ T-cell receptor engineered γδ T cells mediate effective antileukemic reactivity.
        Cancer Res. 2006; 66: 3331-3337
        • Kuball J.
        • Dossett M.L.
        • Wolfl M.
        • Ho W.Y.
        • Voss R.-H.
        • Fowler C.
        • et al.
        Facilitating matched pairing and expression of TCR chains introduced into human T cells.
        Blood. 2006; 109: 2331-2338
        • Eshhar Z.
        • Waks T.
        • Grosst G.
        • Schindler D.G.
        Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the y or C subunits of the immunoglobulin and T-cell receptors.
        Immunology. 1993; 90: 720-724https://doi.org/10.1073/pnas.90.2.720
        • Maher J.
        • Brentjens R.J.
        • Gunset G.
        • Riviere I.
        • Sadelain M.
        Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR[zeta]/CD28 receptor.
        Nat Biotechnol. 2002; 20: 70-75
        • Milone M.C.
        • Fish J.D.
        • Carpenito C.
        • Carroll R.G.
        • Binder G.K.
        • Teachey D.
        • et al.
        Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo.
        Mol Ther. 2009; 17: 1453-1464
        • Finney H.M.
        • Akbar A.N.
        • Lawson A.D.G.
        Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCRζ chain.
        J Immunol. 2004; 172: 104-113https://doi.org/10.4049/jimmunol.172.1.104
        • Kalos M.
        • Levine B.L.
        • Porter D.L.
        • Katz S.
        • Grupp S.A.
        • Bagg A.
        • et al.
        T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.
        Sci Transl Med. 2011; 3: 95ra73https://doi.org/10.1126/scitranslmed.3002842
        • Grupp S.A.
        • Kalos M.
        • Barrett D.
        • Aplenc R.
        • Porter D.L.
        • Rheingold S.R.
        • et al.
        Chimeric antigen receptor–modified T cells for acute lymphoid leukemia.
        N Engl J Med. 2013; 368: 1509-1518
        • Brentjens R.J.
        • Davila M.L.
        • Riviere I.
        • Park J.
        • Wang X.
        • Cowell L.G.
        • et al.
        CD19-Targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.
        Sci Transl Med. 2013; 5: 177ra38
        • Ahmed N.
        • Ratnayake M.
        • Savoldo B.
        • Perlaky L.
        • Dotti G.
        • Wels W.S.
        • et al.
        Regression of experimental medulloblastoma following transfer of HER2-specific T cells.
        Cancer Res. 2007; 67: 5957-5964https://doi.org/10.1158/0008-5472.CAN-06-4309
        • Ahmed N.
        • Salsman V.S.
        • Yvon E.
        • Louis C.U.
        • Perlaky L.
        • Wels W.S.
        • et al.
        Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression.
        Mol Ther. 2009; 17: 1779-1787https://doi.org/10.1038/mt.2009.133
        • Ahmed N.
        • Salsman V.S.
        • Kew Y.
        • Shaffer D.
        • Powell S.
        • Zhang Y.J.
        • et al.
        HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors.
        Clin Cancer Res. 2010; 16: 474-485https://doi.org/10.1158/1078-0432.CCR-09-1322
        • Haso W.
        • Lee D.W.
        • Shah N.N.
        • Stetler-Stevenson M.
        • Yuan C.M.
        • Pastan I.H.
        • et al.
        Anti-CD22-chimeric antigen receptors targeting B cell precursor acute lymphoblastic leukemia.
        Blood. 2012; 121: 1165-1174https://doi.org/10.1182/blood-2012-06-438002
        • Gardner R.
        • Wu D.
        • Cherian S.
        • Fang M.
        • Hanafi L.-A.
        • Finney O.
        • et al.
        Acquisition of a CD19 negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T cell therapy.
        Blood. 2016; 127: 2406-2410
        • Heemskerk M.H.M.
        • Hagedoorn R.S.
        • van der Hoorn M.A.W.G.
        • van der Veken L.T.
        • Hoogeboom M.
        • Kester M.G.D.
        • et al.
        Efficiency of T-cell receptor expression in dual-specific T cells is controlled by the intrinsic qualities of the TCR chains within the TCR-CD3 complex.
        Blood. 2006; 109: 235-243
        • Hegde M.
        • Corder A.
        • Chow K.K.H.
        • Mukherjee M.
        • Ashoori A.
        • Kew Y.
        • et al.
        Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma.
        Mol Ther. 2013; 21: 2087-2101https://doi.org/10.1038/mt.2013.185
        • Grada Z.
        • Hegde M.
        • Byrd T.
        • Shaffer D.R.
        • Ghazi A.
        • Brawley V.S.
        • et al.
        TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy.
        Mol Ther Nucleic Acids. 2013; 2: e105https://doi.org/10.1038/mtna.2013.32
        • Patel S.D.
        • Moskalenko M.
        • Tian T.
        • Smith D.
        • McGuinness R.
        • Chen L.
        • et al.
        T-cell killing of heterogenous tumor or viral targets with bispecific chimeric immune receptors.
        Cancer Gene Ther. 2000; 7: 1127-1134https://doi.org/10.1038/sj.cgt.7700213
        • Stone J.D.
        • Aggen D.H.
        • Schietinger A.
        • Schreiber H.
        • Kranz D.M.
        A sensitivity scale for targeting T cells with chimeric antigen receptors (CARs) and bispecific T-cell Engagers (BiTEs).
        Oncoimmunology. 2012; 1: 863-873https://doi.org/10.4161/onci.20592
        • Iwahori K.
        • Kakarla S.
        • Velasquez M.P.
        • Yu F.
        • Yi Z.
        • Gerken C.
        • et al.
        Engager T cells: a new class of antigen-specific T cells that redirect bystander T cells.
        Mol Ther. 2015; 23: 171-178
        • Savoldo B.
        • Ramos C.A.
        • Liu E.
        • Mims M.P.
        • Keating M.J.
        • Carrum G.
        • et al.
        CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients.
        J Clin Invest. 2011; 121: 1822-1826https://doi.org/10.1172/JCI46110
        • Ghazi A.
        • Ashoori A.
        • Hanley P.J.
        • Brawley V.S.
        • Shaffer D.R.
        • Kew Y.
        • et al.
        Generation of polyclonal CMV-specific T cells for the adoptive immunotherapy of glioblastoma.
        J Immunother. 2012; 35: 159-168https://doi.org/10.1097/CJI.0b013e318247642f
        • Wakefield A.
        • Pignata A.
        • Ghazi A.
        • Ashoori A.
        • Hegde M.
        • Landi D.
        • et al.
        Is CMV a target in pediatric glioblastoma? Expression of CMV proteins, pp65 and IE1-72 and CMV nucleic acids in a cohort of pediatric glioblastoma patients.
        J Neurooncol. 2015; 125: 307-315https://doi.org/10.1007/s11060-015-1905-z
        • Pule M.A.
        • Savoldo B.
        • Myers G.D.
        • Rossig C.
        • Russell V, H.
        • Dotti G.
        • et al.
        Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma.
        Nat Med. 2008; 14: 1264-1270https://doi.org/10.1038/nm.1882
        • Ahmed N.
        CMV-specific cytotoxic T lymphocytes expressing CAR targeting HER2 in patients with GBM (HERT-GBM).
        ClinicalTrials.gov. 2014: 2010-2013 ([Internet])
        • Wrzesinski C.
        • Paulos C.M.
        • Kaiser A.
        • Muranski P.
        • Palmer D.C.
        • Gattinoni L.
        • et al.
        Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells.
        J Immunother. 2010; 33
        • Dudley M.E.
        • Wunderlich J.R.
        • Yang J.C.
        • Sherry R.M.
        • Topalian S.L.
        • Restifo N.P.
        • et al.
        Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma.
        J Clin Oncol. 2005; 23: 2346-2357https://doi.org/10.1200/JCO.2005.00.240
        • Slaney C.Y.
        • Kershaw M.H.
        • Darcy P.K.
        Trafficking of T cells into tumors.
        Cancer Res. 2014; 74: 7168-7174https://doi.org/10.1158/0008-5472.CAN-14-2458
        • Devaud C.
        • John L.B.
        • Westwood J.A.
        • Darcy P.K.
        • Kershaw M.H.
        Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy.
        Oncoimmunology. 2013; 2: e25961https://doi.org/10.4161/onci.25961
        • Harlin H.
        • Meng Y.
        • Peterson A.C.
        • Zha Y.
        • Tretiakova M.
        • Slingluff C.
        • et al.
        Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment.
        Cancer Res. 2009; 69: 3077-3085
        • Spear P.
        • Barber A.
        • Sentman C.L.
        Collaboration of chimeric antigen receptor (CAR)-expressing T cells and host T cells for optimal elimination of established ovarian tumors.
        Oncoimmunology. 2013; 2: e23564https://doi.org/10.4161/onci.23564
        • Chinnasamy D.
        • Yu Z.
        • Kerkar S.P.
        • Zhang L.
        • Morgan R.A.
        • Restifo N.P.
        • et al.
        Local delivery of lnterleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice.
        Clin Cancer Res. 2012; 18: 1672-1683https://doi.org/10.1158/1078-0432.CCR-11-3050
        • Wang L.C.
        • Lo A.
        • Scholler J.
        • Sun J.
        • Majumdar R.S.
        • Kapoor V.
        • et al.
        Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity.
        Cancer Immunol Res. 2014; 2: 154-166https://doi.org/10.1158/2326-6066.CIR-13-0027
        • Kakarla S.
        • Chow K.K.H.
        • Mata M.
        • Shaffer D.R.
        • Song X.-T.
        • Wu M.-F.
        • et al.
        Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma.
        Mol Ther. 2013; 21: 1611-1620https://doi.org/10.1038/mt.2013.110
        • Sharma P.
        • Allison J.P.
        The future of immune checkpoint therapy.
        Science. 2015; 348: 56-61
        • Robert C.
        • Schachter J.
        • Long V, G.
        • Arance A.
        • Grob J.J.
        • Mortier L.
        • et al.
        Pembrolizumab versus ipilimumab in advanced melanoma.
        N Engl J Med. 2015; 372: 2521-2532https://doi.org/10.1056/NEJMoa1503093
        • Powles T.
        • Eder J.P.
        • Fine G.D.
        • Braiteh F.S.
        • Loriot Y.
        • Cruz C.
        • et al.
        MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.
        Nature. 2014; 515: 558-562
        • Curran M.A.
        • Montalvo W.
        • Yagita H.
        • Allison J.P.
        PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.
        Proc Natl Acad Sci USA. 2010; 107: 4275-4280https://doi.org/10.1073/pnas.0915174107
        • Yu P.
        • Steel J.C.
        • Zhang M.
        • Morris J.C.
        • Waldmann T.A.
        Simultaneous blockade of multiple immune system inhibitory checkpoints enhances antitumor activity mediated by interleukin-15 in a murine metastatic colon carcinoma model.
        Clin Cancer Res. 2010; 16: 6019-6028https://doi.org/10.1158/1078-0432.CCR-10-1966
        • Peng W.
        • Liu C.
        • Xu C.
        • Lou Y.
        • Chen J.
        • Yang Y.
        • et al.
        PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines.
        Cancer Res. 2012; 72: 5209-5218https://doi.org/10.1158/0008-5472.CAN-12-1187
        • Morales J.K.
        • Kmieciak M.
        • Graham L.
        • Feldmesser M.
        • Bear H.D.
        • Manjili M.H.
        Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells.
        Cancer Immunol Immunother. 2009; 58: 941-953https://doi.org/10.1007/s00262-008-0609-z
        • Chmielewski M.
        • Kopecky C.
        • Hombach A.A.
        • Abken H.
        IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression.
        Cancer Res. 2011; 71: 5697-5706https://doi.org/10.1158/0008-5472.CAN-11-0103
        • Kerkar S.P.
        • Goldszmid R.S.
        • Muranski P.
        • Chinnasamy D.
        • Yu Z.
        • Reger R.N.
        • et al.
        IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors.
        J Clin Invest. 2011; 121: 4746-4757https://doi.org/10.1172/JCI58814
        • Gorelik L.
        • Flavell R.A.
        Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells.
        Nat Med. 2001; 7: 1118-1122https://doi.org/10.1100/tsw.2002.873
        • Zhang L.
        • Yu Z.
        • Muranski P.
        • Palmer D.C.
        • Restifo N.P.
        • Rosenberg S.A.
        • et al.
        Inhibition of TGF-β signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy.
        Gene Ther. 2012; : 575-580https://doi.org/10.1038/gt.2012.75
        • Foster A.E.
        • Dotti G.
        • Lu A.
        • Khalil M.
        • Brenner M.K.
        • Heslop H.E.
        • et al.
        Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-β receptor.
        J Immunother. 2008; 31: 500-505https://doi.org/10.1097/CJI.0b013e318177092b.Antitumor
        • Gammaitoni L.
        • Leuci V.
        • Mesiano G.
        • Giraudo L.
        • Todorovic M.
        • Carnevale-Schianca F.
        • et al.
        Immunotherapy of cancer stem cells in solid tumors: initial findings and future prospective.
        Expert Opin Biol Ther. 2014; 14: 1259-1270
        • Greenberg N.M.
        • DeMayo F.
        • Finegold M.J.
        • Medina D.
        • Tilley W.D.
        • Aspinall J.O.
        • et al.
        Prostate cancer in a transgenic mouse.
        Proc Natl Acad Sci USA. 1995; 92: 3439-3443
        • Jachetti E.
        • Mazzoleni S.
        • Grioni M.
        • Ricupito A.
        • Brambillasca C.
        • Generoso L.
        • et al.
        Prostate cancer stem cells are targets of both innate and adaptive immunity and elicit tumor-specific immune responses.
        Oncoimmunology. 2013; 2: e24520https://doi.org/10.4161/onci.24520
        • Brown C.E.
        • Starr R.
        • Martinez C.
        • Aguilar B.
        • D'Apuzzo M.
        • Todorov I.
        • et al.
        Recognition and killing of brain tumor stem-like initiating cells by CD8+ Cytolytic T cells.
        Cancer Res. 2009; 69: 8886-8893https://doi.org/10.1158/0008-5472.CAN-09-2687
        • Morgan R.A.
        • Johnson L.A.
        • Davis J.L.
        • Zheng Z.
        • Woolard K.D.
        • Reap E.A.
        • et al.
        Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma.
        Hum Gene Ther. 2012; 23: 1043-1053
        • Brown C.E.
        • Starr R.
        • Aguilar B.
        • Shami A.F.
        • Apuzzo M.D.
        • Barish M.E.
        • et al.
        Stem-like tumor initiating cells isolated from IL13Rα2-expressing gliomas are targeted and killed by IL13-zetakine redirected T cells.
        Clin Cancer Res. 2012; 18: 2199-2209https://doi.org/10.1158/1078-0432.CCR-11-1669
        • Cioffi M.
        • Dorado J.
        • Baeuerle P.A.
        • Heeschen C.
        EpCAM/CD3-bispecific T-cell engaging antibody MT110 eliminates primary human pancreatic cancer stem cells.
        Clin Cancer Res. 2012; 18: 465-474https://doi.org/10.1158/1078-0432.CCR-11-1270
        • Kalos M.
        • June C.H.
        Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology.
        Immunity. 2013; 39: 49-60https://doi.org/10.1016/j.immuni.2013.07.002
        • Morgan R.A.
        • Chinnasamy N.
        • Abate-Daga D.D.
        • Gros A.
        • Robbins F.
        • Zheng Z.
        • et al.
        Cancer regression and neurologic toxicity following anti-MAGE- A3 TCR gene therapy.
        J Immunother. 2014; 36: 133-151https://doi.org/10.1097/CJI.0b013e3182829903.Cancer
        • Wilkie S.
        • Van Schalkwyk M.C.I.
        • Hobbs S.
        • Davies D.M.
        • Van Der Stegen S.J.C.
        • Pereira A.C.P.
        • et al.
        Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling.
        J Clin Immunol. 2012; 32: 1059-1070https://doi.org/10.1007/s10875-012-9689-9
        • Fedorov V.D.
        • Themeli M.
        • Sadelain M.
        PD-1– and CTLA-4–based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses.
        Sci Transl Med. 2013; 5: 215ra172
        • Petrovic R.M.
        • Wilkie S.
        • Maher J.
        Abstract A082: developing a PD-1 based inhibitory chimeric antigen receptor (ICAR) for co-expression, to overcome off-tumor toxicity when targeting ErbB2 using engineered T cells.
        Cancer Immunol Res. 2016; 4: A082https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR15-A082
        • Ma J.S.Y.
        • Kim J.
        • Kazane S.A.
        • Choi S.
        • Yun H.
        • Kim M.
        • et al.
        Versatile strategy for controlling the specificity and activity of engineered T cells.
        Proc Natl Acad Sci USA. 2016; 113: E450-8https://doi.org/10.1073/pnas.1524193113
        • Roybal K.T.
        • Rupp L.J.
        • Morsut L.
        • Walker W.J.
        • McNally K.A.
        • Park J.S.
        • et al.
        Precision tumor recognition by T cells with combinatorial antigen-sensing circuits.
        Cell. 2016; 164: 770-779https://doi.org/10.1016/j.cell.2016.01.011
        • Morsut L.
        • Roybal K.T.
        • Xiong X.
        • Gordley R.M.
        • Coyle S.M.
        • Thomson M.
        • et al.
        Engineering customized cell sensing and response behaviors using synthetic notch receptors.
        Cell. 2016; 164: 780-791https://doi.org/10.1016/j.cell.2016.01.012
        • Di Stasi A.
        • Tey S.-K.
        • Dotti G.
        • Fujita Y.
        • Kennedy-Nasser A.
        • Martinez C.
        • et al.
        Inducible apoptosis as a safety switch for adoptive cell therapy.
        N Engl J Med. 2011; 365: 1673-1683https://doi.org/10.1056/NEJMoa1106152
        • Straathof K.C.
        • Pulè M.A.
        • Yotnda P.
        • Dotti G.
        • Vanin E.F.
        • Brenner M.K.
        • et al.
        An inducible caspase 9 safety switch for T-cell therapy.
        Blood. 2005; 105: 4247-4254https://doi.org/10.1182/blood-2004-11-4564
        • Friedland A.E.
        • Lu T.K.
        • Wang X.
        • Shi D.
        • Church G.
        • Collins J.J.
        Synthetic gene networks that count.
        Science. 2009; 324: 1199-1202
        • Vera J.F.
        • Brenner L.J.
        • Gerdemann U.
        • Ngo M.C.
        • Sili U.
        • Liu H.
        • et al.
        Accelerated production of antigen-specific T cells for preclinical and clinical applications using gas-permeable rapid expansion cultureware (G-Rex).
        J Immunother. 2010; 33: 305-315https://doi.org/10.1097/CJI.0b013e3181c0c3cb
        • Liu L.
        • Sommermeyer D.
        • Cabanov A.
        • Kosasih P.
        • Hill T.
        • Riddell S.R.
        Inclusion of Strep-tag II in design of antigen receptors for T-cell immunotherapy.
        Nat Biotechnol. 2016; https://doi.org/10.1038/nbt.3461
        • Arasaratnam R.J.
        • Leen A.M.
        Adoptive T cell therapy for the treatment of viral infections.
        Ann Transl Med. 2015; 3: 278https://doi.org/10.3978/j.issn.2305-5839.2015.10.12
        • Barrett D.M.
        • Grupp S.A.
        • June C.H.
        Chimeric antigen receptor– and TCR-modified T cells enter main street and wall street.
        J Immunol. 2015; 195: 755-761https://doi.org/10.4049/jimmunol.1500751
        • Hammerstrom A.E.
        • Cauley D.H.
        • Atkinson B.J.
        • Sharma P.
        Cancer immunotherapy: sipuleucel-T and beyond.
        Pharmacotherapy. 2011; 31: 813-828https://doi.org/10.1592/phco.31.8.813
        • Higano C.S.
        • Schellhammer P.F.
        • Small E.J.
        • Burch P.A.
        • Nemunaitis J.
        • Yuh L.
        • et al.
        Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer.
        Cancer. 2009; 115: 3670-3679https://doi.org/10.1002/cncr.24429
        • Serafino P.
        • Church S.
        Dendreon files for bankruptcy as cancer drug disappoints.
        Bloomberg, 2014
        • Joe V.P.
        Biden's cancer “moonshot” price tag up to $1 billion.
        Chicago Trib, 2016
      1. A windfall for US biomedical science.
        Nat Med. 2016; 22: 115