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Personalized Cell Transfer Immunotherapy for B-Cell Malignancies and Solid Cancers

2011; Elsevier BV; Volume: 19; Issue: 11 Linguagem: Inglês

10.1038/mt.2011.223

1525-0024

Steven A. Rosenberg, James N. Kochenderfer,

Virus-based gene therapy research

Two independent groups have now corroborated and extended our earlier report1Kochenderfer JN Wilson WH Janik JE Dudley ME Stetler-Stevenson M Feldman SA et al.Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19.Blood. 2010; 116: 4099-4102Crossref PubMed Scopus (990) Google Scholar that the administration of autologous cells transduced with a chimeric antigen receptor (CAR) targeting the CD19 molecule could eradicate CD19+ B-lineage cells in humans and was associated with the regression of advanced follicular lymphoma.2Porter DL Levine BL Kalos M Bagg A June CH Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.N Engl J Med. 2011; 365: 725-733Crossref PubMed Scopus (2636) Google Scholar,3Kalos M Levine BL Porter DL Katz S Grupp SA Bagg A et al.T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.Sci Transl Med. 2011; 3: 95ra73Crossref PubMed Scopus (1805) Google Scholar,4Brentjens RJ Rivière I Park JH Davila ML Wang X Stefanski J et al.Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias.Blood. 2011; (e-pub ahead of print 17 August 2011)PubMed Google Scholar These studies have opened opportunities to tailor the genetic modification of autologous lymphocytes with receptors suitable for antigens presented on a patient's unique cancer and thus personalize cancer immunotherapy. The clearest demonstration of the ability of adoptive cell transfer (ACT) therapy to mediate the regression of metastatic cancer comes from clinical trials in patients with refractory metastatic melanoma.5Dudley ME Wunderlich JR Robbins PF Yang JC Hwu P Schwartzentruber DJ et al.Cancer regression and autoimmunity in patients after clonal repopulation with anti-tumor lymphocytes.Science. 2002; 298: 850-854Crossref PubMed Scopus (2396) Google Scholar,6Dudley ME Yang JC Sherry R Hughes MS Royal R Kammula U et al.Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens.J Clin Oncol. 2008; 26: 5233-5239Crossref PubMed Scopus (1088) Google Scholar,7Rosenberg SA Yang JC Sherry RM Kammula US Hughes MS Phan GQ et al.Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.Clin Cancer Res. 2011; 17: 4550-4557Crossref PubMed Scopus (1538) Google Scholar The adoptive transfer of autologous tumor-infiltrating lymphocytes following a lymphodepleting regimen mediated durable complete regressions in up to 40% of patients.7Rosenberg SA Yang JC Sherry RM Kammula US Hughes MS Phan GQ et al.Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.Clin Cancer Res. 2011; 17: 4550-4557Crossref PubMed Scopus (1538) Google Scholar Melanoma, however, is the only cancer that naturally gives rise to autologous cells with antitumor activity. The success of ACT in melanoma thus stimulated attempts to genetically engineer normal circulating T cells to express antitumor receptors reactive with a wide variety of antigens.8Rosenberg SA Restifo NP Yang JC Morgan RA Dudley ME Adoptive cell transfer: a clinical path to effective cancer immunotherapy.Nat Rev Cancer. 2008; 8: 299-308Crossref PubMed Scopus (1223) Google Scholar,9Rosenberg SA Cell transfer immunotherapy for metastatic solid cancer—what clinicians need to know.Nat Rev Clin Oncol. 2011; (e-pub ahead of print 2 August 2011)PubMed Google Scholar The first successful cancer regressions induced by the adoptive transfer of autologous cells genetically engineered to express a conventional T-cell receptor (TCR) were reported by Morgan et al.,10Morgan RA Dudley ME Wunderlich JR Hughes MS Yang JC Sherry RM et al.Cancer regression in patients after transfer of genetically engineered lymphocytes.Science. 2006; 314: 126-129Crossref PubMed Scopus (2116) Google Scholar who showed that cells transduced with a TCR reactive with the MART-1 melanoma/melanocyte antigen could mediate regression of melanoma metastases and, using improved receptors in a later study, observed regressions in up to 30% of patients.11Johnson LA Morgan RA Dudley ME Cassard L Yang JC Hughes MS et al.Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen.Blood. 2009; 114: 535-546Crossref PubMed Scopus (1090) Google Scholar In contrast to conventional TCRs that recognize antigens in a major histocompatibility complex (MHC)–restricted fashion, the recognition of cell surface antigens by CARs is not restricted by the MHC because these receptors comprise a single chain of the heavy- and light-chain variable regions of an antibody fused to T-cell intracellular signaling chains such as CD3ζ, CD28, and 4/1BB.12Morgan RA Dudley ME Rosenberg SA Adoptive cell therapy: genetic modification to redirect effector cell specificity.Cancer J. 2010; 16: 336-341Crossref PubMed Scopus (77) Google Scholar,13Gross G Waks T Eshhar Z Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity.Proc Natl Acad Sci USA. 1989; 86: 10024-10028Crossref PubMed Scopus (998) Google Scholar Early attempts to use CARs to treat patients targeted an α-folate receptor overexpressed on ovarian cancers14Hwu P Yang JC Cowherd R Treisman J Shafer GE Rosenberg SA In vivo antitumor activity of T-cells redirected with chimeric antibody/T-cell receptor genes.Cancer Res. 1995; 55: 3369-3373PubMed Google Scholar,15Kershaw MH Westwood JA Parker LL Wang G Eshhar Z Mavroukakis SA et al.A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer.Clin Cancer Res. 2006; 12: 6106-6115Crossref PubMed Scopus (922) Google Scholar or carbonic anhydrase IX overexpressed on kidney cancer.16Lamers CHJ Sleiffer S Vulto AG Kruit WH Kliffen M Debets R et al.Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience.J Clin Oncol. 2006; 24: e20-e22Crossref PubMed Scopus (699) Google Scholar In neither of these two trials was any antitumor effect seen. The first successful CAR gene therapy targeted the glycoprotein GD2 in patients with relapsed neuroblastoma; three of 11 patients experienced complete regressions that were sustained in 2 of them, and evidence of tumor necrosis was seen in additional patients (personal communication from the ref. 17Pule MA Savoldo B Myers GD Rossig C Russell HV Dotti G et al.Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma.Nat Med. 2008; 14: 1264-1270Crossref PubMed Scopus (927) Google Scholar group). In applying ACT therapy to a wide variety of cancers, the choice of antigen is critical. These target antigens fall into three main categories. The first includes antigens uniquely expressed on cancers. Targeting antigens encoded by shared mutations that are essential for maintenance of the malignant phenotype would be ideal, but this has not yet been successfully realized. Cancer/testis (CT) antigens can be ideal targets because they are expressed during fetal development but not expressed on any normal adult tissue (except the testes, which are immunologically protected) and are re-expressed on about 25% of common solid cancers.18Simpson AJ Caballero OL Jungbluth A Chen YT Old LJ Cancer/testis antigens, gametogenesis and cancer.Nat Rev Cancer. 2005; 5: 615-625Crossref PubMed Scopus (1260) Google Scholar Because there are more than 100 CT antigens, testing tumors for specific antigen expression represents an attractive approach to personalized immunotherapy. ACT therapy with T cells specific for the CT antigen NY-ESO-1 mediated good antitumor responses in patients with melanoma and synovial cell sarcomas without toxicity to any normal tissues.19Robbins PF Morgan RA Feldman SA Yang JC Sherry RM Dudley ME et al.Tumor regression in patients with metastatic synovial sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1.J Clin Oncol. 2011; 29: 917-924Crossref PubMed Scopus (1234) Google Scholar Ongoing studies are targeting the MAGE-A3 CT antigen, which is highly expressed on a variety of solid cancers such as cancers of the lung, esophagus, and head and neck.20Chinnasamy N Wargo JA Yu Z Rao M Frankel TL Riley JP et al.A TCR targeting the HLA-A*01-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer.J Immunol. 2011; 186: 685-696Crossref PubMed Scopus (130) Google Scholar A second category of targets includes proteins that are overexpressed on tumors relative to normal tissues. Because this has resulted in severe on-target toxicity to normal tissue in studies targeting carbonic anhydrase IX (biliary tract toxicity),16Lamers CHJ Sleiffer S Vulto AG Kruit WH Kliffen M Debets R et al.Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience.J Clin Oncol. 2006; 24: e20-e22Crossref PubMed Scopus (699) Google Scholar carcinoembryonic antigen (colitis),21Parkhurst MR Yang JC Langan RC Dudley ME Nathan DA Feldman SA et al.T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis.Mol Ther. 2011; 19: 620-626Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar melanoma/melanocyte antigens (uveitis),11Johnson LA Morgan RA Dudley ME Cassard L Yang JC Hughes MS et al.Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen.Blood. 2009; 114: 535-546Crossref PubMed Scopus (1090) Google Scholar and HER-2 (lung toxicity),22Morgan RA Yang JC Kitano M Dudley ME Laurencot CM Rosenberg SA Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.Mol Ther. 2010; 18: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1762) Google Scholar this class of antigens should be targeted with caution. A third class of targets includes antigens that are expressed on cancer as well as in nonessential normal tissues, so the cancer can be impacted without severe sequelae to the host. An example of this approach is the targeting of the CD19 protein, expressed on normal B cells and on the great majority of B-cell lymphomas and B-cell leukemias.23Brentjens RJ Latouche JB Santos E Marti F Gong MC Lyddane C et al.Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15.Nat Med. 2003; 9: 279-286Crossref PubMed Scopus (511) Google Scholar,24Cooper LJ Topp MS Serrano LM Gonzalez S Chang WC Naranjo A et al.T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B lineage leukemia effect.Blood. 2003; 101: 1637-1644Crossref PubMed Scopus (222) Google Scholar,25Brentjens RJ Santos E Nikhamin Y Yeh R Matsushita M La Perle K et al.Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts.Clin Cancer Res. 2007; 13: 5426-5435Crossref PubMed Scopus (344) Google Scholar,26Cheadle EJ Hawkins RE Batha H O’Neill AL Dovedi SJ Gilham DE Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells.J Immunother. 2010; 184: 1885-1896Google Scholar,27Imai C Mihara K Andreansky M Nicholson IC Pui CH Geiger TL et al.Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia.Leukemia. 2004; 18: 678-684Google Scholar,28Kowolik CM Topps MS Gonzalez S Pfeiffer T Olivares S Gonzalez N et al.CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells.Cancer Res. 2006; 66: 10995-11004Crossref PubMed Scopus (382) Google Scholar,29Milone MC Fish JD Carpenito C Carroll RG Binder GK Teachey D et al.Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo.Mol Ther. 2009; 17: 1453-1464Abstract Full Text Full Text PDF PubMed Scopus (823) Google Scholar,30Rossig C Bär A Pscherer S Altvater B Pule M Rooney CM et al.Target antigen expression on a professional antigen-presenting cell induces superior proliferative antitumor T-cell responses via chimeric T-cell receptors.J Immunother. 2006; 29: 21-31Crossref PubMed Scopus (23) Google Scholar,31Jensen MC Popplewell L Cooper LJ DiGiusto D Kalos M Ostberg JR et al.Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans.Biol Blood Marrow Transplant. 2010; 16: 1245-1256Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar,32Kochenderfer JN Feldman SA Zhao Y Xu H Black MA Morgan RA et al.Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor.J Immunother. 2009; 32: 689-702Crossref PubMed Scopus (284) Google Scholar,33Kochenderfer JN Yu Z Frasheri D Restifo NP Rosenberg SA Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells.Blood. 2010; 116: 3875-3886Crossref PubMed Scopus (252) Google Scholar Although critical for the induction of humoral immune responses, transient elimination of CD19-expressing cells is well tolerated. The first effective treatment using a CAR against CD19 was reported by Kochenderfer et al. in a patient with advanced follicular lymphoma treated with chemotherapy followed by the adoptive transfer of T cells transduced with a gammaretrovirus encoding an anti-CD19 CAR and administration of interleukin-2 (IL-2).1Kochenderfer JN Wilson WH Janik JE Dudley ME Stetler-Stevenson M Feldman SA et al.Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19.Blood. 2010; 116: 4099-4102Crossref PubMed Scopus (990) Google Scholar The patient experienced a dramatic regression of his lymphoma, and, interestingly, his B-lineage cells were completely eradicated from the blood and bone marrow for 36 weeks after infusion of CAR-transduced T cells. Consistent with an eradication of B-lineage cells, the patient also developed severe hypogammaglobulinemia.1Kochenderfer JN Wilson WH Janik JE Dudley ME Stetler-Stevenson M Feldman SA et al.Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19.Blood. 2010; 116: 4099-4102Crossref PubMed Scopus (990) Google Scholar Seven months after his initial CAR-transduced T-cell infusion, the patient's lymphoma started to progress. He was treated a second time with the same regimen, and he remained in a partial remission as of 17 months after his second cell infusion (unpublished data; Figure 1). We subsequently treated an additional seven patients using this regimen (three with B-cell lymphomas and four with chronic lymphocytic leukemia, CLL) (unpublished observations). One patient with lymphoma died of a documented H1N1 pneumonia shortly after treatment. Five of the remaining six patients experienced an objective remission, including one complete remission (Kochenderfer et al., unpublished data). Two recently published pilot trials using anti-CD19 CAR-expressing T cells2Porter DL Levine BL Kalos M Bagg A June CH Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.N Engl J Med. 2011; 365: 725-733Crossref PubMed Scopus (2636) Google Scholar,3Kalos M Levine BL Porter DL Katz S Grupp SA Bagg A et al.T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.Sci Transl Med. 2011; 3: 95ra73Crossref PubMed Scopus (1805) Google Scholar,4Brentjens RJ Rivière I Park JH Davila ML Wang X Stefanski J et al.Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias.Blood. 2011; (e-pub ahead of print 17 August 2011)PubMed Google Scholar confirm many of the findings we reported. Kalos et al. reported three patients with CLL who received chemotherapy followed by infusions of T cells transduced with a lentiviral vector encoding an anti-CD19 CAR.3Kalos M Levine BL Porter DL Katz S Grupp SA Bagg A et al.T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.Sci Transl Med. 2011; 3: 95ra73Crossref PubMed Scopus (1805) Google Scholar Two patients obtained complete remissions of CLL, and the third obtained a partial remission. Eradication of normal B cells and hypogammaglobulinemia were again observed. Brentjens et al. recently reported results in eight patients with progressive CLL treated with an anti-CD19 CAR (as well as one patient with acute lymphocytic leukemia treated in remission).4Brentjens RJ Rivière I Park JH Davila ML Wang X Stefanski J et al.Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias.Blood. 2011; (e-pub ahead of print 17 August 2011)PubMed Google Scholar Three CLL patients were treated without cyclophosphamide conditioning, and no objective responses were seen. A fourth patient died soon after T-cell infusion and was not evaluable for clinical response.34Brentjens R Yeh R Bernal Y Riviere I Sadelain M Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase 1 clinical trial.Mol Ther. 2010; 18: 666-668Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar Four patients with CLL received cyclophosphamide preconditioning chemotherapy prior to CAR-transduced cell infusion; one of the four exhibited an objective reduction of peripheral lymphadenopathy lasting 6 months. Thus, all the reported responding patients received preconditioning chemotherapy with cyclophosphamide. The impact of this chemotherapy must be considered in evaluating the effectiveness of these treatments, although the prolonged depletion of normal B cells seen by us and by Kalos et al. is highly suggestive evidence for an in vivo effect of the CAR-transduced cells. The CAR used in our clinical trial1Kochenderfer JN Wilson WH Janik JE Dudley ME Stetler-Stevenson M Feldman SA et al.Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19.Blood. 2010; 116: 4099-4102Crossref PubMed Scopus (990) Google Scholar and that of Brentjens et al.4Brentjens RJ Rivière I Park JH Davila ML Wang X Stefanski J et al.Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias.Blood. 2011; (e-pub ahead of print 17 August 2011)PubMed Google Scholar contained a CD28-costimulatory domain plus the cytoplasmic portion of the CD3ζ molecule, whereas the CAR used by Kalos et al. used a CAR containing a 4-1BB domain but not CD28 (ref. 3Kalos M Levine BL Porter DL Katz S Grupp SA Bagg A et al.T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.Sci Transl Med. 2011; 3: 95ra73Crossref PubMed Scopus (1805) Google Scholar). Human T cells transduced with CARs containing a CD28 moiety have recently been shown to exhibit modestly enhanced proliferation and persistence compared with T cells transduced with CARs that lack CD28 (ref. 35Savoldo B Ramos CA Liu E Mims MP Keating MJ Carrum G et al.CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients.J Clin Invest. 2011; 121: 1822-1826Crossref PubMed Scopus (765) Google Scholar). Kalos et al. reported more extensive proliferation of the transferred cells in two of three patients and long persistence of CAR-transduced T cells.3Kalos M Levine BL Porter DL Katz S Grupp SA Bagg A et al.T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.Sci Transl Med. 2011; 3: 95ra73Crossref PubMed Scopus (1805) Google Scholar These results suggest that 4-1BB moieties may provide enhanced proliferation and persistence of CAR-transduced T cells compared with the CD28 costimulatory domain, but a larger cohort of patients is needed before any firm conclusions can be drawn about the role of these intracellular costimulatory signals. The toxicities seen in the three trials were similar and resulted primarily from the sequelae of neutropenia, cytokine release, and tumor lysis syndrome. Fever, hypotension, capillary leak, and severe malaise were common. There was no clear evidence that the different signaling chains used in the CAR constructs impacted toxicity. It is not known whether IL-2 administration after cells contributes to the antitumor effects of the CAR administration, although in several animal models IL-2 significantly improved the effectiveness of ACT therapy.36Klebanoff CA Gattinoni L Palmer DC Muranski P Ji Y Hinrichs CS et al.Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice.Clin Cancer Res. 2011; 17: 5343-5352Crossref PubMed Scopus (211) Google Scholar,37Gattinoni L Powell DJ Rosenberg SA Restifo NP Adoptive immunotherapy for cancer: building on success.Nat Rev Immunol. 2006; 6: 383-393Crossref PubMed Scopus (727) Google Scholar The introduction of genes encoding herpes simplex thymidine kinase (ref. 38Bonini C Brenner MK Heslop HE Morgan RA Genetic modification of T cells.Biol Blood Marrow Transplant. 2011; 17: S15-S20Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar) or an inducible caspase 9 (ref. 39Tey S Dotti G Rooney CM Heslop HE Brenner MK Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation.Biol Blood Marrow Transplant. 2007; 13: 913-924Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar) provide an opportunity to eliminate transduced cells in vivo by providing prodrugs to activate cell death pathways. This approach has been of value in averting graft-vs.-host disease following allogeneic stem cell transplants38Bonini C Brenner MK Heslop HE Morgan RA Genetic modification of T cells.Biol Blood Marrow Transplant. 2011; 17: S15-S20Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar and may be of value in situations in which the transduced cells may be expected to have long-term deleterious effects. Despite the above successes, significant questions remain concerning the optimization of ACT therapy for cancer treatment—particularly for solid tumors, which may have an intensely immunosuppressive tumor environment. Experiments in animal models have shown that preconditioning lymphodepletion was essential for the effectiveness of cell transfer studies based on several factors, including the depletion of host regulatory T cells and myeloid suppressor cells (ref. 37Gattinoni L Powell DJ Rosenberg SA Restifo NP Adoptive immunotherapy for cancer: building on success.Nat Rev Immunol. 2006; 6: 383-393Crossref PubMed Scopus (727) Google Scholar), whereas elimination of endogenous lymphocytes also increases circulating levels of homeostatic cytokines such as IL-7 and IL-15 (ref. 6Dudley ME Yang JC Sherry R Hughes MS Royal R Kammula U et al.Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens.J Clin Oncol. 2008; 26: 5233-5239Crossref PubMed Scopus (1088) Google Scholar), which are thus able to supply the transferred cells with an endogenous source of growth-promoting cytokines without competing with endogenous lymphocytes. There is no apparent significant difference between the use of gammaretroviruses or lentiviruses, although the intracellular signaling chains used may have an impact on results. The use, individually or in combination, of CD3ζ, CD28, and 4-1BB is being explored and may impact the persistence and clinical effectiveness of the transduced cells. In addition, preclinical studies have shown that transducing genes encoding other molecules, such as IL-2 (ref. 40Liu K Rosenberg SA Transduction of an interleukin-2 gene into human melanoma-reactive lymphocytes results in their continued growth in the absence of exogenous IL-2 and maintenance of specific antitumor activity.J Immunol. 2001; 167: 6356-6365Crossref PubMed Scopus (96) Google Scholar), IL-12 (ref. 41Kerkar SP Muranski P Kaiser A Boni A Sanchez-Perez L Yu Z et al.Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts.Cancer Res. 2010; 70: 6725-6734Crossref PubMed Scopus (198) Google Scholar), and CD80 (ref. 42Stephan MT Ponomarev V Brentjens RJ Chang AH Dobrenkov KV Heller G et al.T cell–encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection.Nat Med. 2007; 13: 1440-1449Crossref PubMed Scopus (224) Google Scholar), in conjunction with antitumor receptors may increase the antitumor effects of ACT. Perhaps most importantly, these pilot trials utilizing CD19 CAR-transduced cells to treat patients with B-cell lymphomas and CLL provide further evidence of the potential usefulness of ACT therapy as a new form of immunotherapy for the treatment of cancer. The ability to genetically engineer T cells to express antitumor receptors has opened the door to an era of personalized immunotherapy in which tumors will be tested for the expression of antigens and the receptor for therapy will be selected that is appropriate for each individual patient.