Cancer Immunology at the Crossroads: Experimental Immunotherapies Cancer Immunology Research T-cell–based Immunotherapy: Adoptive Cell Transfer and Checkpoint Inhibition Roch Houot1,2, Liora Michal Schultz3, Aurelien Marabelle4, and Holbrook Kohrt5 Abstract Tumor immunotherapy has had demonstrable efficacy in and immune checkpoint inhibitor antibodies. In this review, we patients with cancer. The most promising results have been with describe the different T-cell–based strategies currently in clinical T-cell–based therapies. These include adoptive cell transfer of trials and put their applications, present and future, into perspec- tumor-infiltrating lymphocytes, genetically engineered T cells, tive. Cancer Immunol Res; 3(10); 1115–22. Ó2015 AACR. Introduction on the type of tumor. Here we also compare and contrast the potential benefit and toxicities of monotherapy versus combina- T cells are believed to play a major role in immunosurveillance torial approaches (adoptive T cells and checkpoint inhibitor and tumor eradication. On the basis of this paradigm, over the antibodies; Table 2). past quarter century, therapies have been developed to generate, educate, and/or enhance T cells against tumors (Fig. 1). Although the initial demonstration that T cells had the potential to treat Adoptive T-cell Transfer cancer comes from allogeneic stem cell transplantation, here we Adoptive T-cell Transfer offers several advantages. Antitumor focus on autologous T cells, which can be manipulated in two T cells with high-avidity recognition of tumor antigens can be ways to treat cancer: either ex vivo using adoptive cell transfer expanded in vitro in large numbers, genetically engineered, and/or (ACT) or in vivo using T-cell targeting antibodies. activated ex vivo to acquire antitumor functions. In addition, the The first adoptive transfer approach consists of the infusion of host can be manipulated before cell transfer to eliminate suppres- autologous lymphocytes with antitumor properties. These lym- sor cells (such as T-regulatory lymphocytes and myeloid-derived phocytes can be derived from unmodified (i.e., naturally occur- suppressor cells) and promote in vivo expansion of transferred ring) T cells isolated from resected tumors (tumor-infiltrating lymphocytes (through "homeostatic expansion") by eliminating lymphocytes, TIL) or genetically engineered T cells recognizing endogenous lymphocytes that can behave like a cytokine sink tumor antigens [T-cell receptors (TCR) or chimeric antigen recep- that competes for the same survival and stimulatory factors (not- tors (CAR)]. The second approach consists of direct in vivo stim- ably cytokines such as IL7 and IL15). The lymphocytes infused ulation of lymphocytes in patients using antibodies, including during ACT function as "living drugs" that can induce long-term checkpoint inhibitors and bispecifics (Fig. 2). Each of these protection. strategies has its own characteristics (Table 1): the identification of a tumor antigen (Ag), whether it is needed or not, the type of Tumor-infiltrating lymphocytes tumor Ag that is targeted (surface vs. intracellular), the nature Tumor-infiltrating lymphocytes are a heterogeneous cell pop- of the T-cell response that is generated against the tumor (mono- ulation found within neoplastic lesions and are mainly composed clonal vs. polyclonal), the durability of immune protection of T cells. A fraction of TILs express TCRs directed against unique (short term/passive vs. long lasting/active), and the methods of or shared tumor-associated antigens and exert cytotoxic effects production of the "drug" (off-the-shelf vs. customized, person- against malignant cells. These TILs can be isolated from resected alized vs. "universal"). On the basis of these characteristics, some tumors, selected and expanded ex vivo. T-cell therapies may be more applicable than others, depending The initial studies, published in 1988, consisted of the admin- istration of TILs to patients with metastatic melanomas (1). However, these cells were unable to persist in vivo, despite con- 1CHU Rennes, Service Hematologie Clinique, Rennes, France. 2INSERM 3 comitant administration of IL2, a T-cell growth factor. This U917, Rennes, France. Department of Pediatrics, Division of Stem Cell fi Transplantation and Regenerative Medicine, Lucile Packard Children's approach was signi cantly improved by the administration of a Hospital and Stanford University, Stanford, California. 4Gustave lymphodepleting preparative regimen consisting of chemother- Roussy Cancer Center, Drug Development Department, INSERM apy (usually cyclophosphamide and fludarabine) with or without U1015,Villejuif, France. 5Department of Medicine, Division of Oncology, Stanford University, Stanford, California. total-body irradiation (TBI). In recent protocols, overall response rates and complete response rates for metastatic melanoma were Note: All the authors contributed equally to this article. around 50% and 20%, respectively (2, 3). Responses were seen Corresponding Author: Holbrook Kohrt, Stanford University Medical Center, in all visceral sites including brain. Most importantly, these Division of Oncology, 269 Campus Drive, CCSR 1105, Stanford, CA 94305. Phone: responses appeared durable. Among patients who achieve a 650-736-1083; Fax: 650-736-1454; E-mail: [email protected] complete tumor regression (22% of the patients, n ¼ 20), 95% doi: 10.1158/2326-6066.CIR-15-0190 of them have ongoing complete regressions beyond 5 years and Ó2015 American Association for Cancer Research. may be cured (3). www.aacrjournals.org 1115 Downloaded from cancerimmunolres.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. Houot et al. Figure 1. History of T-cell therapy in cancer. This timeline presents a historical perspective on important developments in the field. See refs. 12, 15, 34, 40, and 41. Although this strategy allows expansion and persistence of a ade. Unmodified T cells can also be used to treat virally large number of polyclonal antitumor T cells, there are several associated cancers [e.g., Epstein-Barr virus (EBV)– or human limitations to this approach. The first limitation relates to papillomavirus (HPV)–associated tumors] that express viral feasibility. The tumor needs to be resected for isolation and foreign antigens. EBV-associated tumors include Burkitt lym- expansion of TILs. The patient needs to be "suitable" to tolerate phoma, nasopharyngeal carcinoma, lymphoproliferative dis- lymphodepletion and IL2-based treatments and remain suit- orders, some Hodgkin and non–Hodgkin lymphoma, and able during the several-week period required to expand the cells gastric carcinoma. EBV expresses latency genes in transformed in vitro. The laboratories producing TILs need to be specialized cells, and the viral proteins can be targeted by T cells. EBV- and have highly trained personnel. The procedure is expensive. specific T cells can be isolated and expanded from peripheral Most significantly, this approach may not be applicable in blood. Donor and third-party (i.e., allogeneic) EBV-specific tumors other than melanoma. Indeed, the efficacy of naturally T cells have been successfully used to treat posttransplant occurring TILs seems to be primarily restricted to melanoma, lymphoproliferative disorders (6). Autologous EBV–specific for reasons that are not fully understood. Melanoma is unusual T cells also demonstrated promising efficacy in EBV-associated among cancers in that it naturally gives rise to high numbers of tumors such as nasopharyngeal carcinoma (7, 8) and Hodgkin antitumor T cells infiltrating into tumors. Although TILs can be disease (9, 10). isolated from many cancers, to date, only those from melano- mas consistently possess specific cytolysis against the tumors Genetically modified T cells (TCRs, CARs) from which they were generated (4). This may be due to the As mentioned previously, a major limitation in the more strong immunogenicity of melanoma resulting from the high widespread application of TIL therapy is the difficulty in iden- frequency of mutational events (5). Nevertheless, some tumors tifying antigen-specific T cells in other cancer types. Although might be responsive to TIL therapy, especially those expressing naturally occurring TILs have demonstrated efficacy in mela- potentially immunogenic mutational epitopes (high frequency noma, all tumor types with identifiable tumor-associated anti- of somatic mutations) and those sensitive to checkpoint block- gens can be lysed by T cells engineered to recognize tumor 1116 Cancer Immunol Res; 3(10) October 2015 Cancer Immunology Research Downloaded from cancerimmunolres.aacrjournals.org on September 30, 2021. © 2015 American Association for Cancer Research. T-cell–based Therapies Adoptive cell transfer Unmodified T cells Genetically modified T cells ABTILs TCRs Tumor Ag (e.g., CD19) MHC/Ag TCR Figure 2. Strategies for use of T-cell therapies for cancer. Anticancer T-cell–based Chimeric antigen receptor therapy can be performed (A, D) by Tumor ex vivo manipulation of T cells through ACT of unmodified (TILs) C CARs CD3 or genetically modified T cells (TCRs, CARs) and (B, D) by in vivo Bispecific Ab manipulation of T cells using antibodies (bispecific and checkpoint inhibitors). These approaches may Inhibitory receptor induce monoclonal (TCRs, CARs, (e.g., PD-1) bispecific antibodies) or polyclonal Ligand of inhibitory (TILs, checkpoint inhibitors) receptor (e.g., PD-1 antitumor T cells. Ag, antigen. ligands, PD-L1, PD-L2) Blocking mAb for the receptor (e.g., anti–PD-1)