Review
. 2014 Oct; 6(7):833-52.
doi: 10.2217/imt.14.51.

Targeting CD8+ T-cell tolerance for cancer immunotherapy

Stephanie R Jackson 1 Jinyun Yuan  Ryan M Teague  
Affiliations
  • PMID: 25290416
  •     144 References
  •     24 citations

Abstract

In the final issue of Science in 2013, the American Association of Science recognized progress in the field of cancer immunotherapy as the 'Breakthrough of the Year.' The achievements were actually twofold, owing to the early success of genetically engineered chimeric antigen receptors (CAR) and to the mounting clinical triumphs achieved with checkpoint blockade antibodies. While fundamentally very different, the common thread of these independent strategies is the ability to prevent or overcome mechanisms of CD8(+) T-cell tolerance for improved tumor immunity. Here we discuss how circumventing T-cell tolerance has provided experimental insights that have guided the field of clinical cancer immunotherapy to a place where real breakthroughs can finally be claimed.

Keywords: CD8+ T-cell checkpoint blockade; adoptive cell transfer; cancer immunotherapy; cancer vaccine; chimeric antigen receptor; lymphodepletion; tolerance.

Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.
F Stephen Hodi, Marcus Butler, +17 authors, Glenn Dranoff.
Proc Natl Acad Sci U S A, 2008 Feb 22; 105(8). PMID: 18287062    Free PMC article.
Highly Cited.
Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4.
L Chen, S Ashe, +5 authors, P S Linsley.
Cell, 1992 Dec 24; 71(7). PMID: 1335364
Highly Cited.
Restoring function in exhausted CD8 T cells during chronic viral infection.
Daniel L Barber, E John Wherry, +5 authors, Rafi Ahmed.
Nature, 2005 Dec 31; 439(7077). PMID: 16382236
Highly Cited.
Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}.
Mark P Rubinstein, Marek Kovar, +4 authors, Jonathan Sprent.
Proc Natl Acad Sci U S A, 2006 Jun 08; 103(24). PMID: 16757567    Free PMC article.
Highly Cited.
In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB).
De-Gang Song, Qunrui Ye, +7 authors, Daniel J Powell.
Cancer Res, 2011 May 07; 71(13). PMID: 21546571    Free PMC article.
Highly Cited.
IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes.
Ilaria Peluso, Massimo Claudio Fantini, +5 authors, Giovanni Monteleone.
J Immunol, 2007 Jan 05; 178(2). PMID: 17202333
Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells.
Luca Gattinoni, Steven E Finkelstein, +10 authors, Nicholas P Restifo.
J Exp Med, 2005 Oct 06; 202(7). PMID: 16203864    Free PMC article.
Highly Cited.
Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells.
R J North.
J Exp Med, 1982 Apr 01; 155(4). PMID: 6460831    Free PMC article.
Highly Cited.
Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma.
Antoni Ribas, Begoña Comin-Anduix, +15 authors, Jesus Gomez-Navarro.
Clin Cancer Res, 2009 Oct 01; 15(19). PMID: 19789309    Free PMC article.
Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.
Ganesh Suntharalingam, Meghan R Perry, +4 authors, Nicki Panoskaltsis.
N Engl J Med, 2006 Aug 16; 355(10). PMID: 16908486
Highly Cited.
Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes.
Mark E Dudley, John R Wunderlich, +16 authors, Steven A Rosenberg.
Science, 2002 Sep 21; 298(5594). PMID: 12242449    Free PMC article.
Highly Cited.
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma.
Mark E Dudley, John R Wunderlich, +18 authors, Steven A Rosenberg.
J Clin Oncol, 2005 Apr 01; 23(10). PMID: 15800326    Free PMC article.
Highly Cited.
A phase I study of dacetuzumab (SGN-40, a humanized anti-CD40 monoclonal antibody) in patients with chronic lymphocytic leukemia.
Richard R Furman, Andres Forero-Torres, Andrei Shustov, Jonathan G Drachman.
Leuk Lymphoma, 2009 Dec 30; 51(2). PMID: 20038235
Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance.
Catherine A Sabatos, Sumone Chakravarti, +7 authors, Vijay K Kuchroo.
Nat Immunol, 2003 Oct 14; 4(11). PMID: 14556006
Highly Cited.
Clinical perspectives on targeting of myeloid derived suppressor cells in the treatment of cancer.
Yana G Najjar, James H Finke.
Front Oncol, 2013 Mar 20; 3. PMID: 23508517    Free PMC article.
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.
Lihua E Budde, Carolina Berger, +9 authors, Oliver W Press.
PLoS One, 2013 Dec 21; 8(12). PMID: 24358223    Free PMC article.
Highly Cited.
Oligodendrocytes enforce immune tolerance of the uninfected brain by purging the peripheral repertoire of autoreactive CD8+ T cells.
Shin-Young Na, Andreas Hermann, +3 authors, Thomas Hünig.
Immunity, 2012 Jun 12; 37(1). PMID: 22683122
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
Julie R Brahmer, Scott S Tykodi, +23 authors, Jon M Wigginton.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658128    Free PMC article.
Highly Cited.
Dendritic cells and the control of immunity.
J Banchereau, R M Steinman.
Nature, 1998 Apr 01; 392(6673). PMID: 9521319
Highly Cited. Review.
Cancer immunotherapy via dendritic cells.
Karolina Palucka, Jacques Banchereau.
Nat Rev Cancer, 2012 Mar 23; 12(4). PMID: 22437871    Free PMC article.
Highly Cited. Review.
Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1.
Paul F Robbins, Richard A Morgan, +18 authors, Steven A Rosenberg.
J Clin Oncol, 2011 Feb 02; 29(7). PMID: 21282551    Free PMC article.
Highly Cited.
Improved survival with ipilimumab in patients with metastatic melanoma.
F Stephen Hodi, Steven J O'Day, +26 authors, Walter J Urba.
N Engl J Med, 2010 Jun 08; 363(8). PMID: 20525992    Free PMC article.
Highly Cited.
CAR T cells: driving the road from the laboratory to the clinic.
Eleanor J Cheadle, Hannah Gornall, +3 authors, David E Gilham.
Immunol Rev, 2013 Dec 18; 257(1). PMID: 24329792
Review.
CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy.
L Diehl, A T den Boer, +5 authors, R E Toes.
Nat Med, 1999 Jul 08; 5(7). PMID: 10395322
Highly Cited.
Interleukin-2 receptor signaling: at the interface between tolerance and immunity.
Thomas R Malek, Iris Castro.
Immunity, 2010 Aug 25; 33(2). PMID: 20732639    Free PMC article.
Highly Cited. Review.
CD40 ligation reverses T cell tolerance in acute myeloid leukemia.
Long Zhang, Xiufen Chen, +4 authors, Justin Kline.
J Clin Invest, 2013 Apr 27; 123(5). PMID: 23619361    Free PMC article.
A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma.
Mohamad Hussein, James R Berenson, +6 authors, Nancy Whiting.
Haematologica, 2010 Feb 06; 95(5). PMID: 20133895    Free PMC article.
First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American society of clinical oncology meeting.
Andrea Molckovsky, Lillian L Siu.
J Hematol Oncol, 2008 Oct 31; 1. PMID: 18959794    Free PMC article.
The promise and potential pitfalls of chimeric antigen receptors.
Michel Sadelain, Renier Brentjens, Isabelle Rivière.
Curr Opin Immunol, 2009 Mar 31; 21(2). PMID: 19327974    Free PMC article.
Highly Cited. Review.
Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin 2.
T J Eberlein, M Rosenstein, S A Rosenberg.
J Exp Med, 1982 Aug 01; 156(2). PMID: 6980254    Free PMC article.
Highly Cited.
OX40 costimulation turns off Foxp3+ Tregs.
Minh Diem Vu, Xiang Xiao, +6 authors, Xian Chang Li.
Blood, 2007 Jun 19; 110(7). PMID: 17575071    Free PMC article.
Highly Cited.
Peripheral tolerance of CD8 T lymphocytes.
William L Redmond, Linda A Sherman.
Immunity, 2005 Mar 23; 22(3). PMID: 15780985
Review.
Adoptive immunotherapy for cancer: harnessing the T cell response.
Nicholas P Restifo, Mark E Dudley, Steven A Rosenberg.
Nat Rev Immunol, 2012 Mar 23; 12(4). PMID: 22437939    Free PMC article.
Highly Cited. Review.
Characterization of the MRC OX40 antigen of activated CD4 positive T lymphocytes--a molecule related to nerve growth factor receptor.
S Mallett, S Fossum, A N Barclay.
EMBO J, 1990 Apr 01; 9(4). PMID: 2157591    Free PMC article.
Highly Cited.
Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis.
David Saadoun, Michelle Rosenzwajg, +6 authors, David Klatzmann.
N Engl J Med, 2011 Dec 02; 365(22). PMID: 22129253
Highly Cited.
II. Contribution to the Knowledge of Sarcoma.
W B Coley.
Ann Surg, 1891 Sep 01; 14(3). PMID: 17859590    Free PMC article.
Highly Cited.
Role of LAG-3 in regulatory T cells.
Ching-Tai Huang, Creg J Workman, +11 authors, Dario A A Vignali.
Immunity, 2004 Oct 16; 21(4). PMID: 15485628
Highly Cited.
Release from regulatory T cell-mediated suppression during the onset of tissue-specific autoimmunity is associated with elevated IL-21.
Louise E Clough, Chun Jing Wang, +4 authors, Lucy S K Walker.
J Immunol, 2008 Apr 09; 180(8). PMID: 18390721
Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients.
Joannes F M Jacobs, Cornelis J A Punt, +8 authors, Gosse J Adema.
Clin Cancer Res, 2010 Aug 26; 16(20). PMID: 20736326
Adoptive cell transfer: a clinical path to effective cancer immunotherapy.
Steven A Rosenberg, Nicholas P Restifo, +2 authors, Mark E Dudley.
Nat Rev Cancer, 2008 Mar 21; 8(4). PMID: 18354418    Free PMC article.
Highly Cited. Review.
Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation.
Nikolaos Patsoukis, Julia Brown, +3 authors, Vassiliki A Boussiotis.
Sci Signal, 2012 Jun 29; 5(230). PMID: 22740686    Free PMC article.
Highly Cited.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L Topalian, F Stephen Hodi, +27 authors, Mario Sznol.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658127    Free PMC article.
Highly Cited.
PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.
Michael A Curran, Welby Montalvo, Hideo Yagita, James P Allison.
Proc Natl Acad Sci U S A, 2010 Feb 18; 107(9). PMID: 20160101    Free PMC article.
Highly Cited.
Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells.
Jens Dannull, Zhen Su, +8 authors, Johannes Vieweg.
J Clin Invest, 2005 Nov 26; 115(12). PMID: 16308572    Free PMC article.
Highly Cited.
Phase I trial of ALT-801, an interleukin-2/T-cell receptor fusion protein targeting p53 (aa264-272)/HLA-A*0201 complex, in patients with advanced malignancies.
Mayer N Fishman, John A Thompson, +8 authors, Hing C Wong.
Clin Cancer Res, 2011 Oct 14; 17(24). PMID: 21994418    Free PMC article.
A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma.
William Bensinger, Richard T Maziarz, +8 authors, Edward A Stadtmauer.
Br J Haematol, 2012 Aug 07; 159(1). PMID: 22861192
IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes.
Yongqing Li, Cassian Yee.
Blood, 2007 Oct 09; 111(1). PMID: 17921346    Free PMC article.
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.
Jason D Fontenot, Marc A Gavin, Alexander Y Rudensky.
Nat Immunol, 2003 Mar 04; 4(4). PMID: 12612578
Highly Cited.
Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.
Richard A Morgan, James C Yang, +3 authors, Steven A Rosenberg.
Mol Ther, 2010 Feb 25; 18(4). PMID: 20179677    Free PMC article.
Highly Cited.
Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state.
Andrea Schietinger, Jeffrey J Delrow, +2 authors, Philip D Greenberg.
Science, 2012 Jan 24; 335(6069). PMID: 22267581    Free PMC article.
Highly Cited.
Systemic administration of interleukin-2 in humans.
M T Lotze, R J Robb, +2 authors, S A Rosenberg.
J Biol Response Mod, 1984 Oct 01; 3(5). PMID: 6334135
The differential production of cytokines by human Langerhans cells and dermal CD14(+) DCs controls CTL priming.
Jacques Banchereau, LuAnn Thompson-Snipes, +6 authors, Eynav Klechevsky.
Blood, 2012 Apr 27; 119(24). PMID: 22535664    Free PMC article.
The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design.
Thomas A Waldmann.
Nat Rev Immunol, 2006 Jul 27; 6(8). PMID: 16868550
Highly Cited. Review.
Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells.
B K Cho, V P Rao, +2 authors, J Chen.
J Exp Med, 2000 Aug 22; 192(4). PMID: 10952724    Free PMC article.
Highly Cited.
Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells.
Andrew J Rech, Robert H Vonderheide.
Ann N Y Acad Sci, 2009 Sep 23; 1174. PMID: 19769742
Highly Cited. Review.
Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.
P Waterhouse, J M Penninger, +6 authors, T W Mak.
Science, 1995 Nov 10; 270(5238). PMID: 7481803
Highly Cited.
Mechanism of T cell tolerance induced by myeloid-derived suppressor cells.
Srinivas Nagaraj, Adam G Schrum, +2 authors, Dmitry I Gabrilovich.
J Immunol, 2010 Feb 10; 184(6). PMID: 20142361    Free PMC article.
Highly Cited.
In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination.
Laura C Bonifaz, David P Bonnyay, +7 authors, Ralph M Steinman.
J Exp Med, 2004 Mar 17; 199(6). PMID: 15024047    Free PMC article.
Highly Cited.
Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor.
W R Godfrey, F F Fagnoni, +2 authors, E G Engleman.
J Exp Med, 1994 Aug 01; 180(2). PMID: 7913952    Free PMC article.
Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses.
I Gramaglia, A D Weinberg, M Lemon, M Croft.
J Immunol, 1998 Dec 23; 161(12). PMID: 9862675
Highly Cited.
Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy.
C Marcela Diaz-Montero, Mohamed Labib Salem, +3 authors, Alberto J Montero.
Cancer Immunol Immunother, 2008 May 01; 58(1). PMID: 18446337    Free PMC article.
Highly Cited.
Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation.
L A Schubert, E Jeffery, +2 authors, S F Ziegler.
J Biol Chem, 2001 Aug 03; 276(40). PMID: 11483607
Highly Cited.
Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation.
S Read, V Malmström, F Powrie.
J Exp Med, 2000 Jul 19; 192(2). PMID: 10899916    Free PMC article.
Highly Cited.
Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory pathways of CD8+ T-cell tolerance.
Melissa M Berrien-Elliott, Stephanie R Jackson, +6 authors, Ryan M Teague.
Cancer Res, 2012 Nov 29; 73(2). PMID: 23188506    Free PMC article.
Potential uses of interleukin 2 in cancer therapy.
M A Cheever, J A Thompson, D J Peace, P D Greenberg.
Immunobiology, 1986 Sep 01; 172(3-5). PMID: 3492434
PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model.
Long Zhang, Thomas F Gajewski, Justin Kline.
Blood, 2009 May 07; 114(8). PMID: 19417208    Free PMC article.
Highly Cited.
Costimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function.
Jessica Ann Hernandez-Chacon, Yufeng Li, +5 authors, Laszlo G Radvanyi.
J Immunother, 2011 Mar 11; 34(3). PMID: 21389874    Free PMC article.
Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors.
Ryan M Teague, Blythe D Sather, +8 authors, Philip D Greenberg.
Nat Med, 2006 Feb 14; 12(3). PMID: 16474399
Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'.
Aron M Levin, Darren L Bates, +11 authors, K Christopher Garcia.
Nature, 2012 Mar 27; 484(7395). PMID: 22446627    Free PMC article.
Highly Cited.
Development of a Listeria monocytogenes based vaccine against prostate cancer.
Vafa Shahabi, Mariela Reyes-Reyes, +3 authors, Paulo Maciag.
Cancer Immunol Immunother, 2008 Feb 15; 57(9). PMID: 18273616
Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning.
Hollie J Pegram, James C Lee, +4 authors, Renier J Brentjens.
Blood, 2012 Feb 23; 119(18). PMID: 22354001    Free PMC article.
Highly Cited.
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
Tyler J Curiel, George Coukos, +18 authors, Weiping Zou.
Nat Med, 2004 Aug 24; 10(9). PMID: 15322536
Highly Cited.
High-dose recombinant interleukin 2 in the treatment of patients with disseminated cancer. Responses, treatment-related morbidity, and histologic findings.
M T Lotze, A E Chang, +3 authors, S A Rosenberg.
JAMA, 1986 Dec 12; 256(22). PMID: 3491225
Highly Cited.
Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients.
P P Lee, C Yee, +9 authors, M M Davis.
Nat Med, 1999 Jun 17; 5(6). PMID: 10371507
Highly Cited.
Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody.
Robert H Vonderheide, Keith T Flaherty, +12 authors, Scott J Antonia.
J Clin Oncol, 2007 Mar 01; 25(7). PMID: 17327609
Highly Cited.
Cytosolic entry controls CD8+-T-cell potency during bacterial infection.
Keith S Bahjat, Weiqun Liu, +4 authors, Dirk G Brockstedt.
Infect Immun, 2006 Sep 07; 74(11). PMID: 16954391    Free PMC article.
CAR T cells transform to trucks: chimeric antigen receptor-redirected T cells engineered to deliver inducible IL-12 modulate the tumour stroma to combat cancer.
Markus Chmielewski, Hinrich Abken.
Cancer Immunol Immunother, 2012 Jan 26; 61(8). PMID: 22274776
Review.
Listeria-based vaccines can overcome tolerance by expanding low avidity CD8+ T cells capable of eradicating a solid tumor in a transgenic mouse model of cancer.
Nicholas C Souders, Duane A Sewell, +4 authors, Yvonne Paterson.
Cancer Immun, 2007 Feb 07; 7. PMID: 17279610    Free PMC article.
A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction.
Dung T Le, Dirk G Brockstedt, +19 authors, Daniel A Laheru.
Clin Cancer Res, 2011 Dec 08; 18(3). PMID: 22147941    Free PMC article.
Highly Cited.
Basic principles of tumor-associated regulatory T cell biology.
Peter A Savage, Sven Malchow, Daniel S Leventhal.
Trends Immunol, 2012 Sep 25; 34(1). PMID: 22999714    Free PMC article.
Review.
New insights into the regulation of T cells by gamma(c) family cytokines.
Yrina Rochman, Rosanne Spolski, Warren J Leonard.
Nat Rev Immunol, 2009 Jun 23; 9(7). PMID: 19543225    Free PMC article.
Highly Cited. Review.
Selective stimulation of T cell subsets with antibody-cytokine immune complexes.
Onur Boyman, Marek Kovar, +2 authors, Jonathan Sprent.
Science, 2006 Feb 18; 311(5769). PMID: 16484453
Highly Cited.
Presence of the T-cell activation marker OX-40 on tumor infiltrating lymphocytes and draining lymph node cells from patients with melanoma and head and neck cancers.
J T Vetto, S Lum, +4 authors, A Weinberg.
Am J Surg, 1997 Oct 27; 174(3). PMID: 9324133
Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia.
John C Byrd, Thomas J Kipps, +8 authors, Susan O'Brien.
Leuk Lymphoma, 2012 Apr 06; 53(11). PMID: 22475052    Free PMC article.
Raising the bar: the curative potential of human cancer immunotherapy.
Steven A Rosenberg.
Sci Transl Med, 2012 Mar 31; 4(127). PMID: 22461638    Free PMC article.
Highly Cited. Review.
T cell receptor gene therapy for cancer.
Thomas M Schmitt, Gunnar B Ragnarsson, Philip D Greenberg.
Hum Gene Ther, 2009 Aug 26; 20(11). PMID: 19702439    Free PMC article.
Review.
CTLA-4: new insights into its biological function and use in tumor immunotherapy.
Jackson G Egen, Michael S Kuhns, James P Allison.
Nat Immunol, 2002 Jun 28; 3(7). PMID: 12087419
Highly Cited. Review.
Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.
Haidong Dong, Scott E Strome, +10 authors, Lieping Chen.
Nat Med, 2002 Jul 02; 8(8). PMID: 12091876
Highly Cited.
IL-15:IL-15 receptor alpha superagonist complex: high-level co-expression in recombinant mammalian cells, purification and characterization.
Kai-ping Han, Xiaoyun Zhu, +9 authors, Hing C Wong.
Cytokine, 2011 Oct 25; 56(3). PMID: 22019703    Free PMC article.
Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation.
A W Goldrath, L Y Bogatzki, M J Bevan.
J Exp Med, 2000 Aug 22; 192(4). PMID: 10952725    Free PMC article.
Highly Cited.
Phenotypic and functional analysis of CD8(+) T cells undergoing peripheral deletion in response to cross-presentation of self-antigen.
J Hernandez, S Aung, W L Redmond, L A Sherman.
J Exp Med, 2001 Sep 19; 194(6). PMID: 11560988    Free PMC article.
The first clinical use of a live-attenuated Listeria monocytogenes vaccine: a Phase I safety study of Lm-LLO-E7 in patients with advanced carcinoma of the cervix.
Paulo Cesar Maciag, Sinisa Radulovic, John Rothman.
Vaccine, 2009 Apr 25; 27(30). PMID: 19389451
Highly Cited.
Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40.
E M Sotomayor, I Borrello, +6 authors, H I Levitsky.
Nat Med, 1999 Jul 08; 5(7). PMID: 10395323
Highly Cited.
Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.
Steven A Rosenberg, James C Yang, +12 authors, Mark E Dudley.
Clin Cancer Res, 2011 Apr 19; 17(13). PMID: 21498393    Free PMC article.
Highly Cited.
Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial.
Renier Brentjens, Raymond Yeh, +2 authors, Michel Sadelain.
Mol Ther, 2010 Apr 02; 18(4). PMID: 20357779    Free PMC article.
Highly Cited.
OX40 is a potent immune-stimulating target in late-stage cancer patients.
Brendan D Curti, Magdalena Kovacsovics-Bankowski, +20 authors, Andrew D Weinberg.
Cancer Res, 2013 Nov 02; 73(24). PMID: 24177180    Free PMC article.
Highly Cited.
In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2.
M T Lotze, Y L Matory, +5 authors, S A Rosenberg.
J Immunol, 1985 Oct 01; 135(4). PMID: 2993418
Highly Cited.
4-1BB costimulatory signals preferentially induce CD8+ T cell proliferation and lead to the amplification in vivo of cytotoxic T cell responses.
W W Shuford, K Klussman, +11 authors, R S Mittler.
J Exp Med, 1997 Jul 07; 186(1). PMID: 9206996    Free PMC article.
Highly Cited.
Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors.
I Melero, W W Shuford, +5 authors, L Chen.
Nat Med, 1997 Jun 01; 3(6). PMID: 9176498
Highly Cited.
Nivolumab plus ipilimumab in advanced melanoma.
Jedd D Wolchok, Harriet Kluger, +21 authors, Mario Sznol.
N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724867    Free PMC article.
Highly Cited.
Enhanced-affinity murine T-cell receptors for tumor/self-antigens can be safe in gene therapy despite surpassing the threshold for thymic selection.
Thomas M Schmitt, David H Aggen, +4 authors, Philip D Greenberg.
Blood, 2013 May 16; 122(3). PMID: 23673862    Free PMC article.
Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor αSu/Fc fusion complex in syngeneic murine models of multiple myeloma.
Wenxin Xu, Monica Jones, +10 authors, Hing C Wong.
Cancer Res, 2013 May 07; 73(10). PMID: 23644531    Free PMC article.
Highly Cited.
Two Listeria monocytogenes vaccine vectors that express different molecular forms of human papilloma virus-16 (HPV-16) E7 induce qualitatively different T cell immunity that correlates with their ability to induce regression of established tumors immortalized by HPV-16.
G R Gunn, A Zubair, +3 authors, Y Paterson.
J Immunol, 2001 Nov 21; 167(11). PMID: 11714814
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
Harnessing human dendritic cell subsets for medicine.
Hideki Ueno, Nathalie Schmitt, +8 authors, Karolina Palucka.
Immunol Rev, 2010 Mar 03; 234(1). PMID: 20193020    Free PMC article.
Review.
Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells.
Joseph F Grosso, Monica V Goldberg, +7 authors, Charles G Drake.
J Immunol, 2009 May 21; 182(11). PMID: 19454660    Free PMC article.
The blockade of immune checkpoints in cancer immunotherapy.
Drew M Pardoll.
Nat Rev Cancer, 2012 Mar 23; 12(4). PMID: 22437870    Free PMC article.
Highly Cited. Review.
Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer.
B Almand, J I Clark, +5 authors, D I Gabrilovich.
J Immunol, 2000 Dec 21; 166(1). PMID: 11123353
Highly Cited.
Management of immune-related adverse events and kinetics of response with ipilimumab.
Jeffrey S Weber, Katharina C Kähler, Axel Hauschild.
J Clin Oncol, 2012 May 23; 30(21). PMID: 22614989
Highly Cited. Review.
Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma.
Markus Chmielewski, Andreas A Hombach, Hinrich Abken.
Immunol Rev, 2013 Dec 18; 257(1). PMID: 24329791
Review.
Sipuleucel-T immunotherapy for castration-resistant prostate cancer.
Philip W Kantoff, Celestia S Higano, +11 authors, IMPACT Study Investigators.
N Engl J Med, 2010 Sep 08; 363(5). PMID: 20818862
Highly Cited.
Immune evasion in acute myeloid leukemia: current concepts and future directions.
Ryan M Teague, Justin Kline.
J Immunother Cancer, 2013 Dec 20; 1(13). PMID: 24353898    Free PMC article.
Cancer regression in patients after transfer of genetically engineered lymphocytes.
Richard A Morgan, Mark E Dudley, +13 authors, Steven A Rosenberg.
Science, 2006 Sep 02; 314(5796). PMID: 16946036    Free PMC article.
Highly Cited.
Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy.
Richard A Morgan, Nachimuthu Chinnasamy, +28 authors, Steven A Rosenberg.
J Immunother, 2013 Feb 05; 36(2). PMID: 23377668    Free PMC article.
Highly Cited.
Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors.
Ryan A Wilcox, Dallas B Flies, +6 authors, Lieping Chen.
J Clin Invest, 2002 Mar 06; 109(5). PMID: 11877473    Free PMC article.
The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection.
Arlene H Sharpe, E John Wherry, Rafi Ahmed, Gordon J Freeman.
Nat Immunol, 2007 Feb 17; 8(3). PMID: 17304234
Highly Cited. Review.
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.
Markus Chmielewski, Caroline Kopecky, Andreas A Hombach, Hinrich Abken.
Cancer Res, 2011 Jul 12; 71(17). PMID: 21742772
Highly Cited.
IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy.
Christian S Hinrichs, Rosanne Spolski, +7 authors, Nicholas P Restifo.
Blood, 2008 Feb 16; 111(11). PMID: 18276844    Free PMC article.
Highly Cited.
Selective in vitro growth of T lymphocytes from normal human bone marrows.
D A Morgan, F W Ruscetti, R Gallo.
Science, 1976 Sep 10; 193(4257). PMID: 181845
Highly Cited.
Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma.
Gerald P Linette, Edward A Stadtmauer, +20 authors, Carl H June.
Blood, 2013 Jun 19; 122(6). PMID: 23770775    Free PMC article.
Highly Cited.
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity.
Kaori Sakuishi, Lionel Apetoh, +3 authors, Ana C Anderson.
J Exp Med, 2010 Sep 08; 207(10). PMID: 20819927    Free PMC article.
Highly Cited.
CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help.
R R French, H T Chan, A L Tutt, M J Glennie.
Nat Med, 1999 May 06; 5(5). PMID: 10229232
Highly Cited.
Re-adapting T cells for cancer therapy: from mouse models to clinical trials.
Ingunn M Stromnes, Thomas M Schmitt, +2 authors, Philip D Greenberg.
Immunol Rev, 2013 Dec 18; 257(1). PMID: 24329795    Free PMC article.
Review.
Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function.
Rong Zeng, Rosanne Spolski, +9 authors, Warren J Leonard.
J Exp Med, 2005 Jan 05; 201(1). PMID: 15630141    Free PMC article.
Highly Cited.
Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo.
D Hawiger, K Inaba, +6 authors, M C Nussenzweig.
J Exp Med, 2001 Sep 19; 194(6). PMID: 11560993    Free PMC article.
Highly Cited.
Interleukin-21: basic biology and implications for cancer and autoimmunity.
Rosanne Spolski, Warren J Leonard.
Annu Rev Immunol, 2007 Oct 24; 26. PMID: 17953510
Highly Cited. Review.
Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4.
Omar S Qureshi, Yong Zheng, +12 authors, David M Sansom.
Science, 2011 Apr 09; 332(6029). PMID: 21474713    Free PMC article.
Highly Cited.
Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4.
T Takahashi, T Tagami, +5 authors, S Sakaguchi.
J Exp Med, 2000 Jul 19; 192(2). PMID: 10899917    Free PMC article.
Highly Cited.
Studies on the immunological response to foreign tumor transplants in the mouse. I. The role of lymph node cells in conferring immunity by adoptive transfer.
N A MITCHISON.
J Exp Med, 1955 Aug 01; 102(2). PMID: 13242741    Free PMC article.
Highly Cited.
OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor.
Michael J Gough, Carl E Ruby, +3 authors, Andrew D Weinberg.
Cancer Res, 2008 Jul 03; 68(13). PMID: 18593921
Mitigating the toxic effects of anticancer immunotherapy.
Tara C Gangadhar, Robert H Vonderheide.
Nat Rev Clin Oncol, 2014 Jan 22; 11(2). PMID: 24445516
Highly Cited. Review.
Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy.
Wei Liao, Jian-Xin Lin, Warren J Leonard.
Immunity, 2013 Jan 29; 38(1). PMID: 23352221    Free PMC article.
Highly Cited. Review.
Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
Stephan A Grupp, Michael Kalos, +10 authors, Carl H June.
N Engl J Med, 2013 Mar 27; 368(16). PMID: 23527958    Free PMC article.
Highly Cited.
Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity.
Suzanne Ostrand-Rosenberg.
Cancer Immunol Immunother, 2010 Apr 24; 59(10). PMID: 20414655    Free PMC article.
Highly Cited. Review.
Molecular basis of T cell inactivation by CTLA-4.
K M Lee, E Chuang, +7 authors, J A Bluestone.
Science, 1998 Dec 18; 282(5397). PMID: 9856951
Highly Cited.
OX40 promotes Bcl-xL and Bcl-2 expression and is essential for long-term survival of CD4 T cells.
P R Rogers, J Song, +2 authors, M Croft.
Immunity, 2001 Sep 25; 15(3). PMID: 11567634
Highly Cited.
Combination checkpoint blockade--taking melanoma immunotherapy to the next level.
James L Riley.
N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724866
Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance.
Alberto Sánchez-Fueyo, Jane Tian, +10 authors, Terry B Strom.
Nat Immunol, 2003 Oct 14; 4(11). PMID: 14556005
Highly Cited.
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.
Omid Hamid, Caroline Robert, +23 authors, Antoni Ribas.
N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724846    Free PMC article.
Highly Cited.
TNF/TNFR family members in costimulation of T cell responses.
Tania H Watts.
Annu Rev Immunol, 2005 Mar 18; 23. PMID: 15771565
Highly Cited. Review.
Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma.
S A Rosenberg, J C Yang, +13 authors, D E White.
Nat Med, 1998 Mar 21; 4(3). PMID: 9500606    Free PMC article.
Highly Cited.
The IL-2 receptor beta chain (p70): role in mediating signals for LAK, NK, and proliferative activities.
J P Siegel, M Sharon, P L Smith, W J Leonard.
Science, 1987 Oct 02; 238(4823). PMID: 3116668
Highly Cited.
Induction of cytotoxicity in resting human T lymphocytes bound to tumor cells by antibody heteroconjugates.
G Jung, J A Ledbetter, H J Müller-Eberhard.
Proc Natl Acad Sci U S A, 1987 Jul 01; 84(13). PMID: 3110771    Free PMC article.
CTLA-4 suppresses proximal TCR signaling in resting human CD4(+) T cells by inhibiting ZAP-70 Tyr(319) phosphorylation: a potential role for tyrosine phosphatases.
Christine Guntermann, Denis R Alexander.
J Immunol, 2002 Apr 24; 168(9). PMID: 11970985
Neuropilin-1 expression is induced on tolerant self-reactive CD8+ T cells but is dispensable for the tolerant phenotype.
Stephanie R Jackson, Melissa Berrien-Elliott, +2 authors, Ryan M Teague.
PLoS One, 2014 Oct 25; 9(10). PMID: 25343644    Free PMC article.
Checkpoint blockade immunotherapy relies on T-bet but not Eomes to induce effector function in tumor-infiltrating CD8+ T cells.
Melissa M Berrien-Elliott, Jinyun Yuan, +4 authors, Ryan M Teague.
Cancer Immunol Res, 2014 Dec 18; 3(2). PMID: 25516478    Free PMC article.
Immune based therapy for melanoma.
Robert Ancuceanu, Monica Neagu.
Indian J Med Res, 2016 Apr 29; 143(2). PMID: 27121512    Free PMC article.
Review.
Rescue of Tolerant CD8+ T Cells during Cancer Immunotherapy with IL2:Antibody Complexes.
Lauryn E Klevorn, Melissa M Berrien-Elliott, +4 authors, Ryan M Teague.
Cancer Immunol Res, 2016 Nov 03; 4(12). PMID: 27803062    Free PMC article.
Platelet Metabolism and Other Targeted Drugs; Potential Impact on Immunotherapy.
Preeti Kanikarla-Marie, Michael Lam, +3 authors, David G Menter.
Front Oncol, 2018 May 08; 8. PMID: 29732316    Free PMC article.
Review.
A Syngeneic Mouse B-Cell Lymphoma Model for Pre-Clinical Evaluation of CD19 CAR T Cells.
Gray Kueberuwa, Weiming Zheng, +2 authors, Robert E Hawkins.
J Vis Exp, 2018 Nov 06; (140). PMID: 30394400    Free PMC article.
Utility of CD8 score by automated quantitative image analysis in head and neck squamous cell carcinoma.
Douglas J Hartman, Fahad Ahmad, +2 authors, Liron Pantanowitz.
Oral Oncol, 2018 Nov 10; 86. PMID: 30409313    Free PMC article.
Immunotherapy in Ovarian Cancer.
Weimin Wang, Janice Rebecca Liu, Weiping Zou.
Surg Oncol Clin N Am, 2019 May 14; 28(3). PMID: 31079799    Free PMC article.
Review.
TCR Retrogenic Mice as a Model To Map Self-Tolerance Mechanisms to the Cancer Mucosa Antigen GUCY2C.
Tara S Abraham, John C Flickinger, Scott A Waldman, Adam E Snook.
J Immunol, 2019 Jan 16; 202(4). PMID: 30642983    Free PMC article.
Immune precision medicine for cancer: a novel insight based on the efficiency of immune effector cells.
Jean-François Rossi, Patrice Céballos, Zhao-Yang Lu.
Cancer Commun (Lond), 2019 Jun 16; 39(1). PMID: 31200766    Free PMC article.
Review.
Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy.
Carina Hage, Sabine Hoves, +8 authors, Thomas Pöschinger.
PLoS One, 2019 Jul 11; 14(7). PMID: 31291357    Free PMC article.
What is the potential use of platelet-rich-plasma (PRP) in cancer treatment? A mini review.
Angela C M Luzo, Wagner J Fávaro, Amedea B Seabra, Nelson Durán.
Heliyon, 2020 Apr 08; 6(3). PMID: 32258495    Free PMC article.
Review.
Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy.
Rama Soundararajan, Jared J Fradette, +18 authors, Sendurai A Mani.
Cancers (Basel), 2019 May 30; 11(5). PMID: 31137625    Free PMC article.
Review.
Engineering bionic T cells: signal 1, signal 2, signal 3, reprogramming and the removal of inhibitory mechanisms.
Iñaki Etxeberria, Irene Olivera, +4 authors, Ignacio Melero.
Cell Mol Immunol, 2020 May 21; 17(6). PMID: 32433539    Free PMC article.
Review.
Stimuli-Responsive Biomaterials for Vaccines and Immunotherapeutic Applications.
Noah Pacifici, Amir Bolandparvaz, Jamal S Lewis.
Adv Ther (Weinh), 2020 Aug 25;. PMID: 32838028    Free PMC article.
Recombinant AAV-CEA Tumor Vaccine in Combination with an Immune Adjuvant Breaks Tolerance and Provides Protective Immunity.
Jonathan A Hensel, Vinayak Khattar, Reading Ashton, Selvarangan Ponnazhagan.
Mol Ther Oncolytics, 2019 Jan 23; 12. PMID: 30666318    Free PMC article.
Boosting the Immune Response with the Combination of Electrochemotherapy and Immunotherapy: A New Weapon for Squamous Cell Carcinoma of the Head and Neck?
Francesco Longo, Francesco Perri, +8 authors, Raffaele Solla.
Cancers (Basel), 2020 Oct 02; 12(10). PMID: 32998297    Free PMC article.
The suppressive effect of co-inhibiting PD-1 and CTLA-4 expression on H22 hepatomas in mice.
Leilei Liang, Keli Ge, Fengying Zhang, Yinlin Ge.
Cell Mol Biol Lett, 2018 Dec 20; 23. PMID: 30564277    Free PMC article.
Defining muscle-invasive bladder cancer immunotypes by introducing tumor mutation burden, CD8+ T cells, and molecular subtypes.
Zihao Chen, Guojun Liu, +5 authors, Zhifeng Wang.
Hereditas, 2021 Jan 04; 158(1). PMID: 33388091    Free PMC article.
Robust antigen-specific CD8 T cell tolerance to a model prostate cancer neoantigen.
Zoila A Lopez-Bujanda, Matthew G Chaimowitz, +3 authors, Charles G Drake.
Oncoimmunology, 2021 Jan 19; 9(1). PMID: 33457094    Free PMC article.
A Palette of Cytokines to Measure Anti-Tumor Efficacy of T Cell-Based Therapeutics.
Prathyaya Ramesh, Rohan Shivde, +2 authors, I Caroline Le Poole.
Cancers (Basel), 2021 Mar 07; 13(4). PMID: 33669271    Free PMC article.
Review.
The interplay between cancer associated fibroblasts and immune cells in the context of radiation therapy.
Miles Piper, Adam C Mueller, Sana D Karam.
Mol Carcinog, 2020 May 05; 59(7). PMID: 32363633    Free PMC article.
Review.
Robust Prediction of Immune Checkpoint Inhibition Therapy for Non-Small Cell Lung Cancer.
Jiehan Jiang, Zheng Jin, +9 authors, Kui Xiao.
Front Immunol, 2021 May 01; 12. PMID: 33927719    Free PMC article.
Cisplatin remodels the tumor immune microenvironment via the transcription factor EB in ovarian cancer.
Wei Liu, Yanqiu Wang, +4 authors, Yonghui Zou.
Cell Death Discov, 2021 Jun 07; 7(1). PMID: 34091590    Free PMC article.