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Adoptive Cell Transfer As Personalized Immunotherapy for Human Cancer Steven A CANCER IMMUNOLOGY AND IMMUNOTHERAPY REVIEWS mice (6), and studies in 1982 demonstrated that the intravenous injection of immune lymphocytes expanded in IL-2 could effectively treat bulky Adoptive cell transfer as personalized subcutaneous FBL3 lymphomas (7). In addition, administration of IL-2 after cell transfer could enhance the therapeutic potential of these adop- immunotherapy for human cancer tively transferred lymphocytes (8). The demonstra- tion in 1985 that IL-2 administration could result Steven A. Rosenberg* and Nicholas P. Restifo* in complete durable tumor regressions in some patients with metastatic melanoma (9)provided Adoptive cell therapy (ACT) is a highly personalized cancer therapy that involves a stimulus to identify the specific T cells and their administration to the cancer-bearing host of immune cells with direct anticancer activity. cognate antigens involved in this cancer immuno- ACT using naturally occurring tumor-reactive lymphocytes has mediated durable, complete therapy. Lymphocytes infiltrating into the stroma regressions in patients with melanoma, probably by targeting somatic mutations of growing, transplantable tumors were shown to exclusive to each cancer. These results have expanded the reach of ACT to the treatment represent a concentrated source of lymphocytes ca- of common epithelial cancers. In addition, the ability to genetically engineer lymphocytes pable of recognizing tumor in vitro, and studies in to express conventional T cell receptors or chimeric antigen receptors has further murine tumor models demonstrated that the adop- extended the successful application of ACT for cancer treatment. tive transfer of these syngeneic tumor-infiltrating lymphocytes (TILs) expanded in IL-2 could mediate doptive cell therapy (ACT) has multiple manipulate T cells in culture. Thus, ACT used regression of established lung and liver tumors advantages compared with other forms of transfer of syngeneic lymphocytes from rodents (10). In vitro studies in 1986 showed that human cancer immunotherapy that rely on the heavily immunized against the tumor, and modest TILs obtained from resected melanomas contained active in vivo development of sufficient growth inhibition of small established tumors cells capable of specific recognition of autologous A 1 2 11 numbers of antitumor T cells with the func- was observed ( , ). In early preclinical studies, tumors ( ), and these studies led in 1988 to the tions necessary to mediate cancer regression. For theimportanceofhostinhibitoryfactorswassug- first demonstration that ACT using autologous use in ACT, large numbers of antitumor lympho- gested by findings that lymphodepletion using TILs could mediate objective regression of can- cytes (up to 1011) can be readily grown in vitro either chemotherapy or radiation before cell trans- cer in patients with metastatic melanoma (12). on April 28, 2015 and selected for high-avidity recognition of the fer enhanced the ability of transferred lymphocytes Populations of TILs that grow from tumors tumor, as well as for the effector functions required to treat established tumors (3, 4). are generally mixtures of CD8+ and CD4+ T cells to mediate cancer regression. In vitro activation The ability to use ACT was facilitated by the with few if any major contaminating cells in allows such cells to be released from the inhibito- description of T cell growth factor [interleukin-2 mature cultures. The ability of pure populations ry factors that exist in vivo. Perhaps most impor- (IL-2)] in 1976, which provided a means to grow of T lymphocytes to mediate cancer regression tantly, ACT enables the manipulation of the host T lymphocytes ex vivo, often without loss of ef- in patients provided the first direct evidence that before cell transfer to provide a favorable micro- fector functions (5). The direct administration of T cells played a vital role in human cancer immu- environment that better supports antitumor im- high doses of IL-2 could inhibit tumor growth in notherapy. However, responses were often of short munity. ACT is a “living” treatment because the www.sciencemag.org administered cells can proliferate in vivo and maintain their antitumor effector functions. Reinfuse post- Excise lymphodepletion tumor A major factor limiting the successful use of ACT in humans is the identification of cells that can target antigens selectively expressed on the cancer and not on essential normal tissues. ACT has used either natural host cells that exhibit antitumor reactivity or host cells that have been Downloaded from genetically engineered with antitumor T cell re- Select and ceptors (TCRs) or chimeric antigen receptors (CARs). expand to With the use of these approaches, ACT has me- 1010 cells Plate diated dramatic regressions in a variety of cancer fragments histologies, including melanoma, cervical cancer, lymphoma, leukemia, bile duct cancer, and neuro- blastoma. This Review will discuss the current state --+ of ACT for the treatment of human cancer, as well as the principles of effective treatment that point toward improvements in this approach. - + - A brief history of ACT Assay for VerylittlewasknownaboutthefunctionofT specific tumor lymphocytes until the 1960s, when it was shown recognition that lymphocytes were the mediators of allo- Culture with graft rejection in experimental animals. Attempts 6000 IU/mL IL-2 to use T cells to treat transplanted murine tu- mors were limited by the inability to expand and Fig. 1. General schema for using the adoptive cell transfer of naturally occurring autologous TILs. The resected melanoma specimen is digested into a single-cell suspension or divided into multiple tumor fragments Surgery Branch, National Cancer Institute, Center for Cancer that are individually grown in IL-2. Lymphocytes overgrow, destroy tumors within 2 to 3 weeks, and generate Research, National Institutes of Health, 9000 Rockville Pike, pure cultures of lymphocytes that can be tested for reactivity in coculture assays. Individual cultures are then CRC Building, Room 3W-3940, Bethesda, MD 20892, USA. *Corresponding author. E-mail: [email protected] (S.A.R.); restifo@ rapidly expanded in the presence of excess irradiated feeder lymphocytes, OKT3, and IL-2. By approximately nih.gov (N.P.R.) 5 to 6 weeks after resecting the tumor, up to 1011 lymphocytes can be obtained for infusion into patients. 62 3APRIL2015• VOL 348 ISSUE 6230 sciencemag.org SCIENCE duration, and the transferred cells could rarely tered for 5 days followed by cells and IL-2 given at 34 complete responders thus far seen in the two be found in the circulation just days after admin- 720,000 IU/kg to tolerance (Fig. 2). In a pilot study trials at the NCI, only one has recurred, and only istration. A critical improvement in the applica- in the Surgery Branch, National Cancer Institute one patient with complete regression received more tion of ACT to the treatment of human cancer was (NCI), objective cancer regressions by RECIST crite- than one treatment. The brain is not a sanctuary reported in 2002, when it was shown that lympho- ria (Response Evaluation Criteria in Solid Tumors) site, and regression of brain metastases has been depletion using a nonmyeloablative chemotherapy were seen in 21 of 43 patients (49%), including 5 observed (21). Prior treatment with targeted ther- regimen administered immediately before TIL patients (12%) who underwent complete cancer apy using the Braf inhibitor vemurafenib (Zelboraf) transfer could lead to increased cancer regression, regression (13).When200or1200centigray(cGy; does not appear to affect the likelihood of having as well as the persistent oligoclonal repopulation 1 Gy = 100 rads) total-body irradiation (TBI) was an OR to ACT treatment in patients with mela- of the host with the transferred antitumor lympho- added to the preparative regimen in pilot trials noma. ACT can also be effective after other immu- cytes (13). In some patients, the administered anti- of 25 patients each, objective response (OR) rates notherapies have failed. Of the 194 patients treated tumor cells represented up to 80% of the CD8+ T cells in the circulation months after the infusion. Lymphocyte cultures can be grown from many tumor histologies; however, melanoma appeared Lymphodepletion prior to T cell transfer is followed tobetheonlycancerthatreproduciblygaverise to TIL cultures capable of specific antitumor rec- by immune reconstitution ognition. The stimulus to more widely apply ACT Peripheral blood cell count to treat multiple human cancers led to studies 6000 cells per mm3 of the genetic engineering of lymphocytes to White blood express antitumor receptors. Following mouse 5000 cell count 14 models ( ), it was shown for the first time in Cyclophosphamide humans in 2006 that administration of normal Absolute 4000 circulating lymphocytes transduced with a retro- Fludarabine neutrophil virus encoding a TCR that recognized the MART-1 count 3000 melanoma-melanocyte antigen could mediate T cell tumor regression (15). Administration of lympho- 2000 transfer cytes genetically engineered to express a chimeric antigen receptor (CAR) against the B cell anti- genCD19wasshownin2010tomediateregres- 1000 IL-2 Absolute 16 lymphocyte sion of an advanced B cell lymphoma ( ). These count findings of the use of either naturally occurring 0 -10 -5 0 5 10 15 20 25 or genetically engineered antitumor T cells set Days from cell infusion the stage for the extended development of ACT for the treatment of human cancer. Fig. 2. A substantial increase in cell persistence and
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