Skip to main content

Advertisement

SpringerLink
Log in

Manipulating the tumor microenvironment by adoptive cell transfer of CAR T-cells

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

T-cells expressing synthetic chimeric antigen receptors (CARs) have revolutionized immuno-oncology and highlighted the use of adoptive cell transfer, for the treatment of cancer. The phenomenal clinical success obtained in the treatment of hematological malignancies with CAR T-cells has not been reproduced in the treatment of solid tumors, mainly due to the suppressive and hostile tumor microenvironment (TME). This review will address the immunosuppressive features of the TME, which include the stroma, cytokine and chemokine milieu, suppressive regulatory cells and hypoxic conditions, which can all pose formidable barriers for the effective anti-tumor function of CAR T-cells. Some of the novel next generation CARs that have been developed and tested against the TME, will be discussed, to highlight the status of current research in CAR T-cell therapy for solid tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Adachi K, Kano Y, Nagai T, Okuyama N, Sakoda Y, Tamada K (2018) IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol 36(4):346

    CAS  PubMed  Google Scholar 

  • Ager A, Watson HA, Wehenkel SC, Mohammed RN (2016) Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells. Biochem Soc Trans 44:377–385

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, Liu E, Dakhova O, Ashoori A, Corder A, Gray T, Wu MF, Liu H, Hicks J, Rainusso N, Dotti G, Mei Z, Grilley B, Gee A, Rooney CM, Brenner MK, Heslop HE, Wels WS, Wang LL, Anderson P, Gottschalk S (2015) (HER2)—specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol 33:1688–1696

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, Brudno JN, Stetler-Stevenson M, Feldman SA, Hansen BG, Fellowes VS, Hakim FT, Gress RE, Kochenderfer JN (2016) T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 128:1688–1700

    CAS  PubMed  PubMed Central  Google Scholar 

  • Allard B, Beavis PA, Darcy PK, Stagg J (2016) Immunosuppressive activities of adenosine in cancer. Curr Opin Pharmacol 29:7–16

    CAS  PubMed  Google Scholar 

  • Andersen R, Westergaard MCW, Kjeldsen JW, Muller A, Pedersen NW, Hadrup SR, Met O, Seliger B, Kromann-Andersen B, Hasselager T, Donia M, Svane IM (2018) T-cell responses in the microenvironment of primary renal cell carcinoma-implications for adoptive cell therapy. Cancer Immunol Res 6:222–235

    CAS  PubMed  Google Scholar 

  • Barber A, Zhang T, Demars LR, Conejo-Garcia J, Roby KF, Sentman CL (2007) Chimeric NKG2D receptor-bearing T cells as immunotherapy for ovarian cancer. Cancer Res 67:5003–5008

    CAS  PubMed  Google Scholar 

  • Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G, Chew A, Zhao Y, Levine BL, Albelda SM, Kalos M, June CH (2014) Mesothelin-specific chimeric antigen receptor mrna-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res 2:112–120

    CAS  PubMed  Google Scholar 

  • Beavis PA, Milenkovski N, Henderson MA, John LB, Allard B, Loi S, Kershaw MH, Stagg J, Darcy PK (2015) Adenosine receptor 2A blockade increases the efficacy of Anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol Res 3:506–517

    CAS  PubMed  Google Scholar 

  • Beavis PA, Henderson MA, Giuffrida L, Mills JK, Sek K, Cross RS, Davenport AJ, John LB, Mardiana S, Slaney CY, Johnstone RW, Trapani JA, Stagg J, Loi S, Kats L, Gyorki D, Kershaw MH, Darcy PK (2017) Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J Clin Invest 127:929–941

    PubMed  PubMed Central  Google Scholar 

  • Beecham EJ, Ortiz-Pujols S, Junghans RP (2000) Dynamics of tumor cell killing by human T lymphocytes armed with an anti-carcinoembryonic antigen chimeric immunoglobulin T-cell receptor. J Immunother 23:332–343

    CAS  PubMed  Google Scholar 

  • Beezhold K, Byersdorfer CA (2018) Targeting immuno-metabolism to improve anti-cancer therapies. Cancer Lett 414:127–135

    CAS  PubMed  Google Scholar 

  • Berdeja JB, Lin Y, Raje NS, Siegel DS, Munshi NC, Liedtke M, Jagannath S, Maus MV, Turka A, Lam LP, Hege K, Morgan R, Quigley MT, Kochenderfer J (2017) First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: updated results. In: ASH Annual Meeting and Exposition, Atlanta, 9–12 Dec 2017. Abstract, p 740

    Google Scholar 

  • Bollard CM, Rossig C, Calonge MJ, Huls MH, Wagner HJ, Massague J, Brenner MK, Heslop HE, Rooney CM (2002) Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity. Blood 99:3179–3187

    CAS  PubMed  Google Scholar 

  • Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, Ponzoni M, Rossini S, Mavilio F, Traversari C, Bordignon C (1997) HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276:1719–1724

    CAS  PubMed  Google Scholar 

  • Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang WC, Naranjo A, Starr R, Wagner J, Wright C, Zhai Y, Bading JR, Ressler JA, Portnow J, D’apuzzo M, Forman SJ, Jensen MC (2015) Bioactivity and safety of IL13Ralpha2-redirected chimeric antigen receptor CD8 + T cells in patients with recurrent glioblastoma. Clin Cancer Res 21(18):4062–4072

    Google Scholar 

  • Budde LE, Berger C, Lin Y, Wang J, Lin X, Frayo SE, Brouns SA, Spencer DM, Till BG, Jensen MC, Riddell SR, Press OW (2013) Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. PLoS ONE 8:e82742

    PubMed  PubMed Central  Google Scholar 

  • Burga RA, Thorn M, Point GR, Guha P, Nguyen CT, Licata LA, Dematteo RP, Ayala A, Espat NJ, Junghans RP, Katz SC (2015) Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother 64:817–829

    CAS  PubMed  PubMed Central  Google Scholar 

  • Caruana I, Savoldo B, Hoyos V, Weber G, Liu H, Kim ES, Ittmann MM, Marchetti D, Dotti G (2015) Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med 21:524–529

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chekmasova AA, Rao TD, Nikhamin Y, Park KJ, Levine DA, Spriggs DR, Brentjens RJ (2010) Successful eradication of established peritoneal ovarian tumors in SCID-Beige mice following adoptive transfer of T cells genetically targeted to the MUC16 antigen. Clin Cancer Res 16:3594–3606

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen D, Yang J (2017) Development of novel antigen receptors for CAR T-cell therapy directed toward solid malignancies. Transl Res 187:11–21

    CAS  PubMed  Google Scholar 

  • Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, Sadelain M, Adusumilli PS (2016) Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest 126:3130–3144

    PubMed  PubMed Central  Google Scholar 

  • Chinnasamy D, Yu Z, Kerkar SP, Zhang L, Morgan RA, Restifo NP, Rosenberg SA (2012) Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin Cancer Res 18:1672–1683

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chmielewski M, Abken H (2017) CAR T cells releasing IL-18 convert to T-bet(high) foxo1(low) effectors that exhibit augmented activity against advanced solid tumors. Cell Rep 21:3205–3219

    CAS  PubMed  Google Scholar 

  • Chodon T, Comin-Anduix B, Chmielowski B, Koya RC, Wu Z, Auerbach M, Ng C, Avramis E, Seja E, Villanueva A, Mccannel TA, Ishiyama A, Czernin J, Radu CG, Wang X, Gjertson DW, Cochran AJ, Cornetta K, Wong DJ, Kaplan-Lefko P, Hamid O, Samlowski W, Cohen PA, Daniels GA, Mukherji B, Yang L, Zack JA, Kohn DB, Heath JR, Glaspy JA, Witte ON, Baltimore D, Economou JS, Ribas A (2014) Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin Cancer Res 20:2457–2465

    CAS  PubMed  PubMed Central  Google Scholar 

  • Choi BK, Lee DY, Lee DG, Kim YH, Kim SH, Oh HS, Han C, Kwon BS (2017) 4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8(+) T cell proliferation. Cell Mol Immunol 14:748–757

    CAS  PubMed  Google Scholar 

  • Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266

    CAS  PubMed  Google Scholar 

  • Craddock JA, Lu A, Bear A, Pule M, Brenner MK, Rooney CM, Foster AE (2010) Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother 33:780–788

    CAS  PubMed  PubMed Central  Google Scholar 

  • Deng WW, Li YC, Ma SR, Mao L, Yu GT, Bu LL, Kulkarni AB, Zhang WF, Sun ZJ (2018) Specific blockade CD73 alters the ‘exhausted’ phenotype of T cells in head and neck squamous cell carcinoma. Int J Cancer. https://doi.org/10.1002/ijc.31534

    Article  PubMed  Google Scholar 

  • Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, Heslop HE, Brenner MK, Dotti G, Savoldo B (2009) T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113:6392–6402

    PubMed  PubMed Central  Google Scholar 

  • Dieu-Nosjean MC, Giraldo NA, Kaplon H, Germain C, Fridman WH, Sautes-Fridman C (2016) Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers. Immunol Rev 271:260–275

    CAS  PubMed  Google Scholar 

  • Dudley ME, Rosenberg SA (2003) Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 3:666–675

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dudley ME, Rosenberg SA (2007) Adoptive cell transfer therapy. Semin Oncol 34:524–531

    PubMed  PubMed Central  Google Scholar 

  • Dudley ME, Wunderlich JR, Shelton TE, Even J, Rosenberg SA (2003) Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother 26:332–342

    PubMed  PubMed Central  Google Scholar 

  • Eshhar Z, Waks T, Gross G, Schindler DG (1993) Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA 90:720–724

    CAS  PubMed  PubMed Central  Google Scholar 

  • Eyquem J, Mansilla-Soto J, Giavridis T, Van Der Stegen SJ, Hamieh M, Cunanan KM, Odak A, Gonen M, Sadelain M (2017) Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543:113–117

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fallarino F, Grohmann U, You S, Mcgrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi C, Santamaria P, Fioretti MC, Puccetti P (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176:6752–6761

    CAS  PubMed  Google Scholar 

  • Ferrara N, Alitalo K (1999) Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 5:1359–1364

    CAS  PubMed  Google Scholar 

  • Figueroa JA, Reidy A, Mirandola L, Trotter K, Suvorava N, Figueroa A, Konala V, Aulakh A, Littlefield L, Grizzi F, Rahman RL, Jenkins MR, Musgrove B, Radhi S, D’cunha N, D’cunha, Hermonat LN, Cobos PL, E. & Chiriva-Internati M (2015) Chimeric antigen receptor engineering: a right step in the evolution of adoptive cellular immunotherapy. Int Rev Immunol 34:154–187

    Google Scholar 

  • Foster AE, Dotti G, Lu A, Khalil M, Brenner MK, Heslop HE, Rooney CM, Bollard CM (2008) Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor. J Immunother 31:500–505

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fournier C, Martin F, Zitvogel L, Kroemer G, Galluzzi L, Apetoh L (2017) Trial Watch: Adoptively transferred cells for anticancer immunotherapy. Oncoimmunology 6:e1363139

    PubMed  PubMed Central  Google Scholar 

  • Frank (Xiaohu) F, Zhao W, Liu J, He A, Chen Y, Cao X, Yang N, Wang B, Zhang P, Zhang Y, Wang F, Lei B, Gu L, Wang X, Zhuang Q, Zhang W (2017) Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol 35(18 suppl):LBA3001

    Google Scholar 

  • Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, Wolters P, Martin S, Delbrook C, Yates B, Shalabi H, Fountaine TJ, Shern JF, Majzner RG, Stroncek DF, Sabatino M, Feng Y, Dimitrov DS, Zhang L, Nguyen S, Qin H, Dropulic B, Lee DW, Mackall CL (2018) CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 24:20–28

    CAS  PubMed  Google Scholar 

  • Fu X, Rivera A, Tao L, Zhang X (2013) Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors and increase nanoparticle delivery. Int J Cancer 133:2483–2492

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gabriel SS, Bon N, Chen J, Wekerle T, Bushell A, Fehr T, Cippa PE (2016) Distinctive expression of Bcl-2 factors in regulatory T cells determines a pharmacological target to induce immunological tolerance. Front Immunol 7:73

    PubMed  PubMed Central  Google Scholar 

  • Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, Corder A, Schonfeld K, Koch J, Dotti G, Heslop HE, Gottschalk S, Wels WS, Baker ML, Ahmed N (2013) Tancar: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol Ther Nucleic Acids 2:e105

    PubMed  PubMed Central  Google Scholar 

  • Gross G, Gorochov G, Waks T, Eshhar Z (1989) Generation of effector T cells expressing chimeric T cell receptor with antibody type-specificity. Transplant Proc 21:127–130

    CAS  PubMed  Google Scholar 

  • Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hartmann J, Schussler-Lenz M, Bondanza A, Buchholz CJ (2017) Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med 9:1183–1197

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hay CM, Sult E, Huang Q, Mulgrew K, Fuhrmann SR, McGlinchey KA, Hammond SA, Rothstein R, Rios-Doria J, Poon E, Holoweckyj N, Durham NM, Leow CC, Diedrich G, Damschroder M, Herbst R, Hollingsworth RE, Sachsenmeier KF (2016) Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology 5(8):e1208875. https://doi.org/10.1080/2162402X.2016.1208875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui YC, Cui G, Micevic G, Perales JC, Kleinstein SH, Abel ED, Insogna KL, Feske S, Locasale JW, Bosenberg MW, Rathmell JC, Kaech SM (2015) Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162:1217–1228

    CAS  PubMed  PubMed Central  Google Scholar 

  • Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP (2013) Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med 210:1389–1402

    CAS  PubMed  PubMed Central  Google Scholar 

  • Holzinger A, Barden M, Abken H (2016) The growing world of CAR T cell trials: a systematic review. Cancer Immunol Immunother 65:1433–1450

    CAS  PubMed  Google Scholar 

  • Jiang H, Hegde S, Knolhoff BL, Zhu Y, Herndon JM, Meyer MA, Nywening TM, Hawkins WG, Shapiro IM, Weaver DT, Pachter JA, Wang-Gillam A, Denardo DG (2016) Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 22:851–860

    CAS  PubMed  PubMed Central  Google Scholar 

  • John LB, Devaud C, Duong CP, Yong CS, Beavis PA, Haynes NM, Chow MT, Smyth MJ, Kershaw MH, Darcy PK (2013) Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res 19:5636–5646

    CAS  PubMed  Google Scholar 

  • Johnston B, Butcher EC (2002) Chemokines in rapid leukocyte adhesion triggering and migration. Semin Immunol 14:83–92

    CAS  PubMed  Google Scholar 

  • Joyce JA, Fearon DT (2015) T cell exclusion, immune privilege, and the tumor microenvironment. Science 348:74–80

    CAS  PubMed  Google Scholar 

  • Juillerat A, Marechal A, Filhol JM, Valogne Y, Valton J, Duclert A, Duchateau P, Poirot L (2017) An oxygen sensitive self-decision making engineered CAR T-cell. Sci Rep 7:39833

    CAS  PubMed  PubMed Central  Google Scholar 

  • Junghans RP, Ma Q, Rathore R, Gomes EM, Bais AJ, Lo AS, Abedi M, Davies RA, Cabral HJ, Al-Homsi AS, Cohen SI (2016) Phase I trial of anti-PSMA designer CAR-T cells in prostate cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response. Prostate 76:1257–1270

    CAS  PubMed  Google Scholar 

  • Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    CAS  PubMed  Google Scholar 

  • Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3:95ra73

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kamerkar S, Lebleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, Lee JJ, Kalluri R (2017) Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546:498–503

    CAS  PubMed  PubMed Central  Google Scholar 

  • Karlsson H, Lindqvist AC, Fransson M, Paul-Wetterberg G, Nilsson B, Essand M, Nilsson K, Frisk P, Jernberg-Wiklund H, Loskog A (2013) Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy. Cancer Gene Ther 20:386–393

    CAS  PubMed  Google Scholar 

  • Kawalekar OU, Rs OC, Fraietta JA, Guo L, Mcgettigan SE, Posey AD Jr, Patel PR, Guedan S, Scholler J, Keith B, Snyder NW, Blair IA, Milone MC, June CH (2016) Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44:712

    CAS  PubMed  Google Scholar 

  • Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L, Chen CC, Yang JC, Rosenberg SA, Hwu P (2006) A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 12:6106–6115

    CAS  PubMed  PubMed Central  Google Scholar 

  • Khaled YS, Ammori BJ, Elkord E (2013) Myeloid-derived suppressor cells in cancer: recent progress and prospects. Immunol Cell Biol 91:493–502

    CAS  PubMed  Google Scholar 

  • Kitamura T, Pollard JW (2015) Therapeutic potential of chemokine signal inhibition for metastatic breast cancer. Pharmacol Res 100:266–270

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kloss CLJ, June Ch (2016) Tgfbeta signaling blockade within PSMA targeted CAR human T cells for the eradication of metastatic prostate cancer. Mol Ther 24(Supplement 1):ps252–ps253

    Google Scholar 

  • Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM, Raffeld M, Feldman S, Lu L, Li YF, Ngo LT, Goy A, Feldman T, Spaner DE, Wang ML, Chen CC, Kranick SM, Nath A, Nathan DA, Morton KE, Toomey MA, Rosenberg SA (2015) 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

    CAS  PubMed  Google Scholar 

  • Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I, Onder TT, Wang ZC, Richardson AL, Weinberg RA, Orimo A (2010) Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci USA 107:20009–20014

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koneru M, O’cearbhaill R, Pendharkar S, Spriggs DR, Brentjens RJ (2015a) A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer. J Transl Med 13:102

    PubMed  PubMed Central  Google Scholar 

  • Koneru M, Purdon TJ, Spriggs D, Koneru S, Brentjens RJ (2015b) IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors. Oncoimmunology 4:e994446

    PubMed  PubMed Central  Google Scholar 

  • Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y, Itoh S, Nagase F, Kurosawa Y (1987) Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem Biophys Res Commun 149:960–968

    CAS  PubMed  Google Scholar 

  • Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, Ashton JM, Pei S, Grose V, O’dwyer KM, Liesveld JL, Brookes PS, Becker MW, Jordan CT (2013) BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12:329–341

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lamers CH, Sleijfer S, Vulto AG, Kruit WH, Kliffen M, Debets R, Gratama JW, Stoter G, Oosterwijk E (2006) Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 24:e20–e22

    PubMed  Google Scholar 

  • Lanitis E, Poussin M, Klattenhoff AW, Song D, Sandaltzopoulos R, June CH, Powell DJ, Jr (2013) Chimeric antigen receptor T Cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo. Cancer Immunol Res 1:43–53

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lehner M, Gotz G, Proff J, Schaft N, Dorrie J, Full F, Ensser A, Muller YA, Cerwenka A, Abken H, Parolini O, Ambros PF, Kovar H, Holter W (2012) Redirecting T cells to Ewing’s sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mrna transfection. PLoS ONE 7:e31210

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Liu X, Duan Y, Liu Y, Wang H, Lian S, Zhuang G, Fan Y (2017a) Combined blockade of T cell immunoglobulin and mucin domain 3 and carcinoembryonic antigen-related cell adhesion molecule 1 results in durable therapeutic efficacy in mice with intracranial gliomas. Med Sci Monit 23:3593–3602

    PubMed  PubMed Central  Google Scholar 

  • Li S, Siriwon N, Zhang X, Yang S, Jin T, He F, Kim YJ, Mac J, Lu Z, Wang S, Han X, Wang P (2017b) Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors. Clin Cancer Res 23:6982–6992

    CAS  PubMed  Google Scholar 

  • Ligtenberg MA, Mougiakakos D, Mukhopadhyay M, Witt K, Lladser A, Chmielewski M, Riet T, Abken H, Kiessling R (2016) Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity. J Immunol 196:759–766

    CAS  PubMed  Google Scholar 

  • Liu X, Ranganathan R, Jiang S, Fang C, Sun J, Kim S, Newick K, Lo A, June CH, Zhao Y, Moon EK (2016) A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res 76:1578–1590

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lo A, Wang LS, Scholler J, Monslow J, Avery D, Newick K, O’brien S, Evans RA, Bajor DJ, Clendenin C, Durham AC, Buza EL, Vonderheide RH, June CH, Albelda SM, Pure E (2015) Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res 75:2800–2810

    CAS  PubMed  PubMed Central  Google Scholar 

  • MacLeod DT, Antony J, Martin AJ, Moser RJ, Hekele A, Wetzel KJ, Brown AE, Triggiano MA, Hux JA, Pham CD, Bartsevich VV, Turner CA, Lape J, Kirkland S, Beard CW, Smith J, Hirsch ML, Nicholson MG, Jantz D, Mccreedy B (2017) Integration of a CD19 CAR into the TCR alpha chain locus streamlines production of allogeneic gene-edited CAR T cells. Mol Ther 25:949–961

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martin D, Galisteo R, Gutkind JS (2009) CXCL8/IL8 stimulates vascular endothelial growth factor (VEGF) expression and the autocrine activation of VEGFR2 in endothelial cells by activating nfkappab through the CBM (Carma3/Bcl10/Malt1) complex. J Biol Chem 284:6038–6042

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507–1517

    PubMed  PubMed Central  Google Scholar 

  • Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA (2018) Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 378:439–448

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mittal D, Young A, Stannard K, Yong M, Teng MW, Allard B, Stagg J, Smyth MJ (2014) Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res 74:3652–3658

    CAS  PubMed  Google Scholar 

  • Mohammed S, Sukumaran S, Bajgain P, Watanabe N, Heslop HE, Rooney CM, Brenner MK, Fisher WE, Leen AM, Vera JF (2017) Improving chimeric antigen receptor-modified t cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol Ther 25:249–258

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA (2010) Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18:843–851

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morgan RA, Johnson LA, Davis JL, Zheng Z, Woolard KD, Reap EA, Feldman SA, Chinnasamy N, Kuan CT, Song H, Zhang W, Fine HA, Rosenberg SA (2012) Recognition of glioma stem cells by genetically modified T cells targeting egfrviii and development of adoptive cell therapy for glioma. Hum Gene Ther 23:1043–1053

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM, Thomson M, Lim WA (2016) Engineering customized cell sensing and response behaviors using synthetic notch receptors. Cell 164:780–791

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mueller MM, Fusenig NE (2004) Friends or foes–bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849

    CAS  PubMed  Google Scholar 

  • Munn DH, Mellor AL (2007) Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 117:1147–1154

    CAS  PubMed  PubMed Central  Google Scholar 

  • Najima Y, Tomizawa-Murasawa M, Saito Y, Watanabe T, Ono R, Ochi T, Suzuki N, Fujiwara H, Ohara O, Shultz LD, Yasukawa M, Ishikawa F (2016) Induction of WT1-specific human CD8+ T cells from human hscs in HLA class I Tg NOD/SCID/IL2rgKO mice. Blood 127:722–734

    CAS  PubMed  PubMed Central  Google Scholar 

  • Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, Mcsweeney P, Munoz J, Avivi I, Castro JE, Westin JR, Chavez JC, Ghobadi A, Komanduri KV, Levy R, Jacobsen ED, Witzig TE, Reagan P, Bot A, Rossi J, Navale L, Jiang Y, Aycock J, Elias M, Chang D, Wiezorek J, Go WY (2017) Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531–2544

    PubMed  PubMed Central  Google Scholar 

  • Newick K, O’brien S, Sun J, Kapoor V, Maceyko S, Lo A, Pure E, Moon E, Albelda SM (2016) Augmentation of CAR T-cell trafficking and antitumor efficacy by blocking protein kinase A localization. Cancer Immunol Res 4:541–551

    CAS  PubMed  PubMed Central  Google Scholar 

  • Newick K, O’brien S, Moon E, Albelda SM (2017) CAR T cell therapy for solid tumors. Annu Rev Med 68:139–152

    CAS  PubMed  Google Scholar 

  • Ninomiya S, Narala N, Huye L, Yagyu S, Savoldo B, Dotti G, Heslop HE, Brenner MK, Rooney CM, Ramos CA (2015) Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood 125:3905–3916

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nishio N, Dotti G (2015) Oncolytic virus expressing RANTES and IL-15 enhances function of CAR-modified T cells in solid tumors. Oncoimmunology 4:e988098

    PubMed  PubMed Central  Google Scholar 

  • Orimo A, Weinberg RA (2007) Heterogeneity of stromal fibroblasts in tumors. Cancer Biol Ther 6:618–619

    CAS  PubMed  Google Scholar 

  • Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ (2007) CD4+ CD25+ Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 8:1353–1362

    CAS  PubMed  Google Scholar 

  • Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang WC, Ostberg JR, Jensen MC (2007) Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther 15:825–833

    CAS  PubMed  Google Scholar 

  • Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, Roshal M, Maslak P, Davila M, Brentjens RJ, Sadelain M (2018) Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med 378:449–459

    CAS  PubMed  PubMed Central  Google Scholar 

  • Perna SK, Pagliara D, Mahendravada A, Liu H, Brenner MK, Savoldo B, Dotti G (2014) Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (ctls) without enhancement of regulatory T-cell inhibition. Clin Cancer Res 20:131–139

    CAS  PubMed  Google Scholar 

  • Peske JD, Thompson ED, Gemta L, Baylis RA, Fu YX, Engelhard VH (2015) Effector lymphocyte-induced lymph node-like vasculature enables naive T-cell entry into tumours and enhanced anti-tumour immunity. Nat Commun 6:7114

    CAS  PubMed  Google Scholar 

  • Pikor LA, Bell JC, Diallo JS (2015) Oncolytic viruses: exploiting cancer’s deal with the devil. Trends Cancer 1:266–277

    PubMed  Google Scholar 

  • Pituch KC, Miska J, Krenciute G, Panek WK, Li G, Rodriguez-Cruz T, Wu M, Han Y, Lesniak MS, Gottschalk S, Balyasnikova IV (2018) Adoptive transfer of IL13Ralpha2-specific chimeric antigen receptor T cells creates a pro-inflammatory environment in glioblastoma. Mol Ther 26(4):986–995

    Google Scholar 

  • Porter DL, Kalos M, Zheng Z, Levine B, June C (2011) Chimeric antigen receptor therapy for B-cell malignancies. J Cancer 2:331–332

    PubMed  PubMed Central  Google Scholar 

  • Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, White JG, Keely PJ (2008) Collagen density promotes mammary tumor initiation and progression. BMC Med 6:11

    PubMed  PubMed Central  Google Scholar 

  • Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z, Yvon E, Weiss HL, Liu H, Rooney CM, Heslop HE, Brenner MK (2008) Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 14:1264–1270

    CAS  PubMed  PubMed Central  Google Scholar 

  • Raskovalova T, Lokshin A, Huang X, Su Y, Mandic M, Zarour HM, Jackson EK, Gorelik E (2007) Inhibition of cytokine production and cytotoxic activity of human antimelanoma specific CD8+ and CD4+ T lymphocytes by adenosine-protein kinase A type I signaling. Cancer Res 67:5949–5956

    CAS  PubMed  Google Scholar 

  • Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y (2017) Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res 23:2255–2266

    CAS  PubMed  Google Scholar 

  • Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29:917–924

    PubMed  PubMed Central  Google Scholar 

  • Robbins PF, Kassim SH, Tran TL, Crystal JS, Morgan RA, Feldman SA, Yang JC, Dudley ME, Wunderlich JR, Sherry RM, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Li YF, El-Gamil M, Rosenberg SA (2015) A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin Cancer Res 21:1019–1027

    CAS  PubMed  Google Scholar 

  • Rodgers DT, Mazagova M, Hampton EN, Cao Y, Ramadoss NS, Wang IR, Schulman A, Du J, Wang F, Singer O, Ma J, Nunez V, Shen J, Woods AK, Wright TM, Schultz PG, Kim CH, Young TS (2016) Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. Proc Natl Acad Sci USA 113:E459–E468

    CAS  PubMed  PubMed Central  Google Scholar 

  • Romeo C, Seed B (1991) Cellular immunity to HIV activated by CD4 fused to T cell or Fc receptor polypeptides. Cell 64:1037–1046

    CAS  PubMed  Google Scholar 

  • Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA et al (1988) Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 319:1676–1680

    CAS  PubMed  Google Scholar 

  • Roybal KT, Rupp LJ, Morsut L, Walker WJ, Mcnally KA, Park JS, Lim WA (2016a) Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164:770–779

    CAS  PubMed  PubMed Central  Google Scholar 

  • Roybal KT, Williams JZ, Morsut L, Rupp LJ, Kolinko I, Choe JH, Walker WJ, Mcnally KA, Lim WA (2016b) Engineering T cells with customized therapeutic response programs using synthetic notch receptors. Cell 167:419–432 e16

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rupp LJ, Schumann K, Roybal KT, Gate RE, Ye CJ, Lim WA, Marson A (2017) CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep 7:737

    PubMed  PubMed Central  Google Scholar 

  • Sadelain M, Brentjens R, Riviere I (2013) The basic principles of chimeric antigen receptor design. Cancer Discov 3:388–398

    CAS  PubMed  PubMed Central  Google Scholar 

  • Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean MC, Validire P, Trautmann A, Mami-Chouaib F, Donnadieu E (2012) Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest 122:899–910

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE, Watkins SC, Ferris RL, Delgoffe GM (2016) The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45:701–703

    CAS  PubMed  Google Scholar 

  • Schuberth PC, Hagedorn C, Jensen SM, Gulati P, Van Den Broek M, Mischo A, Soltermann A, Jungel A, Belaunzaran M, Stahel O, Renner RC, Petrausch U (2013) Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells. J Transl Med 11:187

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D, Wasik M, Levine BL, Lacey SF, Melenhorst JJ, Porter DL, June CH (2017) Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med 377:2545–2554

    PubMed  PubMed Central  Google Scholar 

  • Shaffer DR, Savoldo B, Yi Z, Chow KK, Kakarla S, Spencer DM, Dotti G, Wu MF, Liu H, Kenney S, Gottschalk S (2011) T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood 117:4304–4314

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA (2010) Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 70:6171–6180

    CAS  PubMed  PubMed Central  Google Scholar 

  • Siriwon N, Kim YJ, Siegler E, Chen X, Rohrs JA, Liu Y, Wang P (2018) CAR-T cells surface-engineered with drug-encapsulated nanoparticles can ameliorate intratumoral T-cell hypofunction. Cancer Immunol Res. https://doi.org/10.1158/2326-6066.CIR-17-0502

    Article  PubMed  Google Scholar 

  • Siska PJ, Beckermann KE, Mason FM, Andrejeva G, Greenplate AR, Sendor AB, Chiang YJ, Corona AL, Gemta LF, Vincent BG, Wang RC, Kim B, Hong J, Chen CL, Bullock TN, Irish JM, Rathmell WK, Rathmell JC (2017) Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight 2:e93411

    PubMed Central  Google Scholar 

  • Smith TT, Moffett HF, Stephan SB, Opel CF, Dumigan AG, Jiang X, Pillarisetty VG, Pillai SPS, Wittrup KD, Stephan MT (2017a) Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J Clin Invest 127:2176–2191

    PubMed  PubMed Central  Google Scholar 

  • Smith TT, Stephan SB, Moffett HF, Mcknight LE, Ji W, Reiman D, Bonagofski E, Wohlfahrt ME, Pillai SPS, Stephan MT (2017b) In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers. Nat Nanotechnol 12:813–820

    CAS  PubMed  PubMed Central  Google Scholar 

  • Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S, Zammataro L, Pasqualini F, Nebuloni M, Chiabrando C, Mantovani A, Allavena P (2010) Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility. J Immunol 185:642–652

    CAS  PubMed  Google Scholar 

  • Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF (2014) 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. J Immunother Cancer 2:3

    PubMed  PubMed Central  Google Scholar 

  • Stephan MT, Ponomarev V, Brentjens RJ, Chang AH, Dobrenkov KV, Heller G, Sadelain M (2007) T cell-encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med 13:1440–1449

    CAS  PubMed  Google Scholar 

  • Suarez ER, De C, Sun K, Sui J, Freeman J, Signoretti GJ, Zhu S, Q. & Marasco WA (2016) Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 7:34341–34355

    PubMed  PubMed Central  Google Scholar 

  • Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z, Roychoudhuri R, Palmer DC, Muranski P, Karoly ED, Mohney RP, Klebanoff CA, Lal A, Finkel T, Restifo NP, Gattinoni L (2013) Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest 123:4479–4488

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sukumar M, Liu J, Mehta GU, Patel SJ, Roychoudhuri R, Crompton JG, Klebanoff CA, Ji Y, Li P, Yu Z, Whitehill GD, Clever D, Eil RL, Palmer DC, Mitra S, Rao M, Keyvanfar K, Schrump DS, Wang E, Marincola FM, Gattinoni L, Leonard WJ, Muranski P, Finkel T, Restifo NP (2016) Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell Metab 23:63–76

    CAS  PubMed  Google Scholar 

  • Sun Z, Fourcade J, Pagliano O, Chauvin JM, Sander C, Kirkwood JM, Zarour HM (2015) IL10 and PD-1 cooperate to limit the activity of tumor-specific CD8+ T Cells. Cancer Res 75:1635–1644

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tang XJ, Sun XY, Huang KM, Zhang L, Yang ZS, Zou DD, Wang B, Warnock GL, Dai LJ, Luo J (2015) Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy. Oncotarget 6:44179–44190

    PubMed  PubMed Central  Google Scholar 

  • Theocharis AD, Skandalis SS, Gialeli C, Karamanos NK (2016) Extracellular matrix structure. Adv Drug Deliv Rev 97:4–27

    CAS  PubMed  Google Scholar 

  • Toyokuni S, Okamoto K, Yodoi J, Hiai H (1995) Persistent oxidative stress in cancer. FEBS Lett 358:1–3

    CAS  PubMed  Google Scholar 

  • Turcotte M, Allard D, Mittal D, Bareche Y, Buisseret L, Jose V, Pommey S, Delisle V, Loi S, Joensuu H, Kellokumpu-Lehtinen PL, Sotiriou C, Smyth MJ, Stagg J (2017) CD73 promotes resistance to HER2/ErbB2 antibody therapy. Cancer Res 77(20):5652–5663. https://doi.org/10.1158/0008-5472.CAN-17-0707

    Article  CAS  PubMed  Google Scholar 

  • Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, Hawkins R, Chaney C, Cherian S, Chen X, Soma L, Wood B, Li D, Heimfeld S, Riddell SR, Maloney DG (2016) Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med 8(355):355ra116

    PubMed  PubMed Central  Google Scholar 

  • Vijayan D, Barkauskas DS, Stannard K, Sult E, Buonpane R, Takeda K, Teng MWL, Sachsenmeier K, Hay C, Smyth MJ (2017) Selective activation of anti-CD73 mechanisms in control of primary tumors and metastases. Oncoimmunology 6(5):e1312044. https://doi.org/10.1080/2162402X.2017.1312044

    Article  PubMed  PubMed Central  Google Scholar 

  • Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vignali D, Kallikourdis M (2017) Improving homing in T cell therapy. Cytokine Growth Factor Rev 36:107–116

    CAS  PubMed  Google Scholar 

  • Wang QJ, Yu Z, Hanada KI, Patel K, Kleiner D, Restifo NP, Yang JC (2017) Preclinical Evaluation of Chimeric Antigen Receptors Targeting CD70-Expressing Cancers. Clin Cancer Res 23:2267–2276

    CAS  PubMed  Google Scholar 

  • Wei X, Lai Y, Li J, Qin L, Xu Y, Zhao R, Li B, Lin S, Wang S, Wu Q, Liang Q, Peng M, Yu F, Li Y, Zhang X, Wu Y, Liu P, Pei D, Yao Y, Li P (2017) PSCA and MUC1 in non-small-cell lung cancer as targets of chimeric antigen receptor T cells. Oncoimmunology 6:e1284722

    PubMed  PubMed Central  Google Scholar 

  • Westwood JA, Smyth MJ, Teng MW, Moeller M, Trapani JA, Scott AM, Smyth FE, Cartwright GA, Power BE, Honemann D, Prince HM, Darcy PK, Kershaw MH (2005) Adoptive transfer of T cells modified with a humanized chimeric receptor gene inhibits growth of Lewis-Y-expressing tumors in mice. Proc Natl Acad Sci USA 102:19051–19056

    CAS  PubMed  PubMed Central  Google Scholar 

  • Whilding LM, Parente-Pereira AC, Zabinski T, Davies DM, Petrovic RMG, Kao YV, Saxena SA, Romain A, Costa-Guerra JA, Violette S, Itamochi H, Ghaem-Maghami S, Vallath S, Marshall JF, Maher J (2017) Targeting of aberrant alphavbeta6 integrin expression in solid tumors using chimeric antigen receptor-engineered T cells. Mol Ther 25:2427

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wilkie S, Picco G, Foster J, Davies DM, Julien S, Cooper L, Arif S, Mather SJ, Taylor-Papadimitriou J, Burchell JM, Maher J (2008) Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol 180:4901–4909

    CAS  PubMed  Google Scholar 

  • Wilkie S, Van Schalkwyk MC, Hobbs S, Davies DM, Van Der Stegen SJ, Pereira AC, Burbridge SE, Box C, Eccles SA, Maher J (2012) Dual targeting of erbb2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling. J Clin Immunol 32:1059–1070

    CAS  PubMed  Google Scholar 

  • Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA (2015) Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350:aab4077

    PubMed  PubMed Central  Google Scholar 

  • Yeku OO, Purdon TJ, Koneru M, Spriggs D, Brentjens RJ (2017) Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Sci Rep 7:10541

    PubMed  PubMed Central  Google Scholar 

  • Yong CSM, Dardalhon V, Devaud C, Taylor N, Darcy PK, Kershaw MH (2017) CAR T-cell therapy of solid tumors. Immunol Cell Biol 95:356–363

    CAS  PubMed  Google Scholar 

  • Yoon DH, Osborn MJ, Tolar J, Kim CJ (2018) Incorporation of immune checkpoint blockade into chimeric antigen receptor T cells (CAR-Ts): combination or built-in CAR-T. Int J Mol Sci 19:340

    PubMed Central  Google Scholar 

  • You F, Jiang L, Zhang B, Lu Q, Zhou Q, Liao X, Wu H, Du K, Zhu Y, Meng H, Gong Z, Zong Y, Huang L, Lu M, Tang J, Li Y, Zhai X, Wang X, Ye S, Chen D, Yuan L, Qi L, Yang L (2016) Phase 1 clinical trial demonstrated that MUC1 positive metastatic seminal vesicle cancer can be effectively eradicated by modified Anti-MUC1 chimeric antigen receptor transduced T cells. Sci China Life Sci 59:386–397

    CAS  PubMed  Google Scholar 

  • Zacharakis N, Chinnasamy H, Black M, Xu H, Lu YC, Zheng Z, Pasetto A, Langhan M, Shelton T, Prickett T, Gartner J, Jia L, Trebska-Mcgowan K, Somerville RP, Robbins PF, Rosenberg SA, Goff SL, Feldman SA (2018) Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat Med 24:724–730

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Kerkar SP, Yu Z, Zheng Z, Yang S, Restifo NP, Rosenberg SA, Morgan RA (2011) Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. Mol Ther 19:751–759

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang E, Gu J, Xu H (2018) Prospects for chimeric antigen receptor-modified T cell therapy for solid tumors. Mol Cancer 17:7

    PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Wang QJ, Yang S, Kochenderfer JN, Zheng Z, Zhong X, Sadelain M, Eshhar Z, Rosenberg SA, Morgan RA (2009) A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity. J Immunol 183:5563–5574

    CAS  PubMed  Google Scholar 

  • Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, Sharpe AH, Vallera DA, Azuma M, Levine BL, June CH, Murphy WJ, Munn DH, Blazar BR (2010) Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood 116:2484–2493

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zuccolotto G, Fracasso G, Merlo A, Montagner IM, Rondina M, Bobisse S, Figini M, Cingarlini S, Colombatti M, Zanovello P, Rosato A (2014) PSMA-specific CAR-engineered T cells eradicate disseminated prostate cancer in preclinical models. PLoS ONE 9:e109427

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia

    Kavitha Gowrishankar, Lucy Birtwistle & Kenneth Micklethwaite

  2. Sydney Cellular Therapies Laboratory; Blood and Bone Marrow Transplant Unit; Department of Haematology; Sydney Medical School, Westmead Hospital, Sydney, NSW, Australia

    Kenneth Micklethwaite

Authors
  1. Kavitha Gowrishankar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucy Birtwistle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenneth Micklethwaite
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kavitha Gowrishankar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gowrishankar, K., Birtwistle, L. & Micklethwaite, K. Manipulating the tumor microenvironment by adoptive cell transfer of CAR T-cells. Mamm Genome 29, 739–756 (2018). https://doi.org/10.1007/s00335-018-9756-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-018-9756-5

Keywords

Search

Navigation