Abstract
The immune system is a potent inhibitor of tumor growth with curative potential, constituting in many eyes the future of antineoplastic therapy. Adoptive cell therapy (ACT) is a form of immunotherapy in which autologous cancer-cognate lymphocytes are expanded and modified ex vivo and re-infused to combat the tumor. This review follows the evolvement of ACT and treatment protocols, focusing on unresolved dilemmas regarding this treatment while providing evidence for its effectiveness in refractory patients. Future directions of ACT are discussed, in particular with regard to genetic engineering of autologous cells, and the role of ACT in the era of checkpoint inhibitors is addressed.
References
- 1 . Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29(8), 1093–1102 (2009).
- 2 . Passive transfer of transplantation immunity. Nature 171(4345), 267–268 (1953).
- 3 . Adoptive chemoimmunotherapy of cancer in animals: a review of results, principles, and problems*. Ann. NY Acad. Sci. 277(1), 492–504 (1976).
- 4 . Purification and partial sequence analysis of human T-cell growth factor. Proc. Natl Acad. Sci. USA 80(19), 5990–5994 (1983).
- 5 . The Transformed Cell: Unlocking the Mysteries of Cancer. Putnam Adult, NY, USA (1992).
- 6 Aldesleukin Product Approval Information – Licensing Action. www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080733.htm.
- 7 . A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233(4770), 1318–1321 (1986).
- 8 . Originally published as Volume 2, Issue 7719 New approach to immunotherapy of melanoma. Lancet 298(7719), 293–295 (1971).
- 9 . Intralymphatic therapy with immune lymphocytes. Cancer 28(5), 1126–1128 (1971).
- 10 High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17(7), 2105 (1999).
- 11 . High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J. Sci. Am. 6(Suppl. 1), S11–S14 (2000).
- 12 Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study. J. Clin. Oncol. 6(5), 839–853 (1988).
- 13 Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N. Engl. J. Med. 319(25), 1676–1680 (1988).
- 14 Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J. Natl Cancer Inst. 86(15), 1159–1166 (1994).
- 15 Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91(3), 756–763 (1998).
- 16 A Phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J. Immunother. 25(3), 243–251 (2002).
- 17 Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298(5594), 850–854 (2002).
- 18 Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J. Clin. Oncol. 23(10), 2346–2357 (2005).
- 19 Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med.
doi:10.1056/NEJMoa1604958 (2016) (Epub ahead of print). - 20 Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J. Clin. Oncol. 26(32), 5233–5239 (2008).
- 21 Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202(7), 907–912 (2005).
- 22 Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J. Clin. Oncol. 34(20), 2389–2397 (2016).
- 23 CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J. Immunol. 174(5), 2591–2601 (2005).
- 24 Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J. Clin. Invest. 117(8), 2197–2204 (2007).
- 25 Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350(6264), 1084–1089 (2015).
- 26 Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350(6264), 1079–1084 (2015).
- 27 . Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J. Sci. Am. 6(Suppl. 1), S55–57 (2000).
- 28 . Regulatory T cells in cancer immunotherapy. Curr. Opin. Immunol. 27, 1–7 (2014).
- 29 Low-dose IL-2 selectively activates subsets of CD4+ Tregs and NK cells. JCI Insight 1(18), e89278 (2016).
- 30 Adoptive immunotherapy with tumor-infiltrating lymphocytes and interleukin-2 in patients with metastatic malignant melanoma and renal cell carcinoma: a pilot study. J. Clin. Oncol. 13(8), 1939–1949 (1995).
- 31 Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. J. Transl. Med. 10, 169 (2012).
- 32 Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc. Natl Acad. Sci. USA 99(25), 16168–16173 (2002).
- 33 Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin. Cancer Res. 19(17), 4792–4800 (2013).
- 34 Impact of clinical and pathologic features on tumor-infiltrating lymphocyte expansion from surgically excised melanoma metastases for adoptive T-cell therapy. Clin. Cancer Res. 17(14), 4882–4891 (2011).
- 35 Metastatic lung lesions as a preferred resection site for immunotherapy with tumor infiltrating lymphocytes. J. Immunother. 39(5), 218–222 (2016).
- 36 Tumor infiltrating lymphocyte therapy for metastatic melanoma: analysis of tumors resected for TIL. J. Immunother. 33(8), (2010).
- 37 . Continuous 4–1BB co-stimulatory signals for the optimal expansion of tumor-infiltrating lymphocytes for adoptive T-cell therapy. Oncoimmunology 2(9), e25581 (2013).
- 38 Costimulation through the CD137/4–1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function. J. Immunother. 34(3), 236–250 (2011).
- 39 TGF-beta1 induces preferential rapid expansion and persistence of tumor antigen-specific CD8+ T cells for adoptive immunotherapy. J. Immunother. 33(4), 371–381 (2010).
- 40 Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J. Immunol. 173(12), 7125–7130 (2004).
- 41 Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma. J. Clin. Oncol. 7(2), 250–261 (1989).
- 42 Histopathological analysis of metastatic melanoma deposits in patients receiving adoptive immunotherapy with tumor-infiltrating lymphocytes. Cancer Immunol. Immunother. 38(5), 299–303 (1994).
- 43 Localization of 111indium-labeled tumor infiltrating lymphocytes to tumor in patients receiving adoptive immunotherapy. Augmentation with cyclophosphamide and correlation with response. Cancer 73(6), 1731–1737 (1994).
- 44 Persistence of tumor infiltrating lymphocytes in adoptive immunotherapy correlates with telomere length. J. Immunother. 30(1), 123–129 (2007).
- 45 Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin. Cancer Res. 18(24), 6758–6770 (2012).
- 46 Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2. Hum. Gene Ther. 19(5), 496–510 (2008).
- 47 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(5), 1019–1027 (2014).
- 48 CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin. Cancer Res. 16(24), 6122–6131 (2010).
- 49 . Characterization and comparison of ‘standard’ and ‘young’ tumour-infiltrating lymphocytes for adoptive cell therapy at a Danish translational research institution. Scand. J. Immunol. 75(2), 157–167 (2012).
- 50 Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J. Clin. Oncol. 31(17), 2152–2159 (2013).
- 51 Tumor-specific CD4+ melanoma tumor-infiltrating lymphocytes. J. Immunother. 35(5), 400–408 (2012).
- 52 Treatment of metastatic melanoma with autologous CD4+ T Cells against NY-ESO-1. N. Engl. J. Med. 358(25), 2698–2703 (2008).
- 53 . Tumor-specific effector CD8+ T cells that can establish immunological memory in humans after adoptive transfer are marked by expression of IL7 receptor and c-myc. Cancer Res. 75(16), 3216–3226 (2015).
- 54 . Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 4(12), 1191–1198 (2003).
- 55 . Landscape of tumor antigens in t cell immunotherapy. J. Immunol. 195(11), 5117–5122 (2015).
- 56 Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314(5796), 126 (2006).
- 57 Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114(3), 535 (2009).
- 58 Cancer regression and neurologic toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. (Hagerstown, Md: 1997) 36(2), 133–151 (2013).
- 59 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(5), 1019–1027 (2015).
- 60 T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19(3), 620–626 (2011).
- 61 Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122(6), 863–871 (2013).
- 62 Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19(6), 747–752 (2013).
- 63 Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344(6184), 641 (2014).
- 64 . TCR mispairing in genetically modified T cells was detected by fluorescence resonance energy transfer. Mol. Biol. Rep. 37(8), 3951–3956 (2010).
- 65 TCR-engineered T cells: a model of inducible TCR expression to dissect the interrelationship between two TCRs. Eur. J. Immunol. 44(1), 265–274 (2014).
- 66 RNAi-mediated TCR knockdown prevents autoimmunity in mice caused by mixed TCR dimers following TCR gene transfer. Mol. Ther. 22(11), 1983–1991 (2014).
- 67 TCRs genetically linked to CD28 and CD3Îμ do not mispair with endogenous TCR chains and mediate enhanced T cell persistence and anti-melanoma activity. J. Immunol. 193(10), 5315–5326 (2014).
- 68 Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses. Clin. Cancer Res. 16(22), 5458–5468 (2010).
- 69 CXCR1 as a novel target for directing reactive T cells toward melanoma: implications for adoptive cell transfer immunotherapy. Cancer Immunol. Immunother. 61(10), 1833–1847 (2012).
- 70 Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin. Cancer Res. 21(10), 2278–2288 (2015).
- 71 Messenger RNA encoding constitutively active Toll-like receptor 4 enhances effector functions of human T cells. Clin. Exp. Immunol. 182(2), 220–229 (2015).
- 72 Adoptive immunotherapy combined with intratumoral TLR agonist delivery eradicates established melanoma in mice. Cancer Immunol. Immunother. 60(5), 671–683 (2011).
- 73 . Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl Acad. Sci. USA 86(24), 10024–10028 (1989).
- 74 . Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors. J. Immunol. 151(11), 6577–6582 (1993).
- 75 T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a Phase 1 dose-escalation trial. Lancet 385(9967), 517–528 (2015).
- 76 Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371(16), 1507–1517 (2014).
- 77 CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5(177), 177ra138 (2013).
- 78 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(6), 540–549 (2015).
- 79 Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J. Clin. Oncol. 34(10), 1112–1121 (2016).
- 80 Immunotherapy of metastatic melanoma using genetically engineered GD2-specific T cells. Clin. Cancer Res. 15(18), 5852–5860 (2009).
- 81 A novel anti-GD2/4–1BB chimeric antigen receptor triggers neuroblastoma cell killing. Oncotarget 6(28), 24884–24894 (2015).
- 82 . Anti-GD3 chimeric sFv-CD28/T-cell receptor zeta designer T cells for treatment of metastatic melanoma and other neuroectodermal tumors. Clin. Cancer Res. 16(10), 2769–2780 (2010).
- 83 Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 118(23), 6050–6056 (2011).
- 84 . Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 6(2), 133–146 (2016).
- 85 Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol. Res. 2(2), 112–120 (2014).
- 86 Anti-mesothelin chimeric antigen receptor T cells in patients with epithelial ovarian cancer. Presented at: 2016 ASCO Annual Meeting. J. Clin. Oncol. 34(Suppl. Abstract 5511), (2016).
- 87 Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365(18), 1673–1683 (2011).
- 88 Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci. Transl. Med. 6(261), 261ra151 (2014).
- 89 Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA+ liver metastases. Clin. Cancer Res. 21(14), 3149–3159 (2015).
- 90 Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery. Cancer Gene Ther. 23(5), 142–148 (2016).
- 91 . Advanced generation anti-prostate specific membrane antigen designer T cells for prostate cancer immunotherapy. Prostate 74(3), 286–296 (2014).
- 92 PSMA-specific CAR-engineered T cells eradicate disseminated prostate cancer in preclinical models. PLoS ONE 9(10), e109427 (2014).
- 93 . Engineered T cell receptor-mimic antibody, (TCRm) chimeric antigen receptor (CAR) T cells against the intracellular protein Wilms tumor-1 (WT1) for treatment of hematologic and solid cancers. Blood 124(21), 2155–2155 (2014).
- 94 Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30(2), 492–500 (2016).
- 95 CD19 CAR-T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J. Clin. Invest. 126(6), 2123–2138 (2016).
- 96 Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood 128(4), 519–528 (2016).
- 97 CD28 costimulation improves expansion and persistence of chimeric antigen receptor modified T cells in lymphoma patients. J. Clin. Invest. 121(5), 1822–1826 (2011).
- 98 Chimeric receptors with 4–1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18(4), 676–684 (2004).
- 99 Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Invest. 126(8), 3130–3144 (2016).
- 100 . Blockade of TGF-beta signaling greatly enhances the efficacy of TCR gene therapy of cancer. J. Immunol. 191(6), 3232–3239 (2013).
- 101 Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17(13), 4550–4557 (2011).