Adoptive T cell therapy for cancer in the clinic

Abstract

Over the past 50 years, two fundamentally different strategies to stimulate antitumor immunity have been tested in humans: therapeutic vaccination and passive immunization. Passive immunization, herein referred to as adoptive T cell therapy, is the transfusion of autologous or allogeneic T cells into tumor-bearing hosts, i.e., patients. Evidence that T cells can help to control tumor growth has been provided by the analysis of tumor prevalence in immunodeficient mice and humans (1, 2). In the 1970s, Chester Southam and colleagues demonstrated that subcutaneous growth of human tumor autografts to patients bearing advanced cancers was inhibited by cotransfer of autologous leukocytes in about half of the patients (3). This suggested that leukocytes with a specific inhibitory effect on the implantation and growth of cancer cells were present in many patients with advanced cancer and could be used as potential candidates for adoptive immunotherapy. Furthermore, recent evidence indicates that tumor infiltration by human T cells is a powerful predictive biomarker of survival for ovarian and colorectal cancers (4, 5).Therapeutic cancer vaccines are entering the realm of clinical medicine, but despite more than 60 years of research into this therapeutic approach (6), there are currently no FDA-approved adoptive T cell therapies for cancer. However, the recent explosion of knowledge in the fields of T cell and cancer biology has enabled new approaches that might bring adoptive T cell transfer to the routine practice of clinical medicine, with an impact similar to that of the advent of transfusion medicine, which was enabled by blood bank transfusion technology in the first half of the last century. The application of recent lessons from adoptive transfer in lymphodepleted hosts (7), the ability to overcome barriers presented by Tregs (8,9), and the use of improved culture systems (10) have not yet been tested in randomized clinical trials. The intent of this review on the use adoptive T cell therapy for cancer in the clinic is to focus on issues facing the field, with an emphasis on therapy with CTLs, tumor-infiltrating lymphocytes (TILs), engineered T cells, and the use of adoptive T cell transfers to facilitate therapeutic cancer vaccines. CTL therapyAt present, there is a plethora of suitable CTL targets for many tumors (11). Improved CTL cell culture technology (12) has permitted the first clinical tests of adoptive transfer of CTLs, and the approach seems to result in substantial activity in patients with melanoma; CTLs derived from PBLs were used to treat patients with refractory, metastatic melanoma, and 8 of the 20 patients had minor, mixed, or stable antitumor immune responses (13). Furthermore, the infusion of autologous melanoma-associated antigen recognized by T cells 1-specific (MART-1-specific) CD8 + T cells into a patient with metastatic melanoma resulted in T cell infiltration into both the skin and tumor tissue (14). The in vivo efficacy of the infused T cell population was indicated by the destruction of...

IL-15 enhances the antitumor effect of human antigen-specific CD8+T cells by cellular senescence delay

“…In a variety of clinical trials, with both solid and hematologic cancers, adoptive T-cell transfer has emerged as one of the most effective immunotherapies. 2 Early clinical studies have demonstrated a 50-70% clinical response in patients. [3][4][5] However, the optimal protocols for expansion of T cells, especially antigenspecific CD8 C T cells, remain to be determined.…”

Microenvironnement immunitaire et cancer

“…Ainsi, se dessine une nouvelle prise en charge des patients prenant en compte l'extension tumorale et la qualité de la réaction immunitaire in situ, pour une optimisation du suivi et de la thérapie des patients à risque de récidive. De récents succès spectaculaires de l'immunothérapie antitumorale ont été obtenus en thérapie adoptive par transfert de lymphocytes T [10,11], par des vaccins antitumoraux, tels que le premier vaccin cellulaire Sipuleucel-T approuvé par la Food and drug administration (FDA) [12], et par des biothérapies utilisant des anticorps monoclonaux bloquant des molécules inhibitrices de la réponse lymphocytaire T, tels que les anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) (ipilimumab) [13,38], ou les anti-PD-1 (programmed cell death 1)/PD-L1 (programmed cell death ligand 1) [14][15][16]. Ces données cliniques récentes fournissent des éléments de preuve 1 [1], constitue le fondement de l'immunocancérologie.…”

Extending the lifespan and efficacies of immune cells used in adoptive transfer for cancer immunotherapies–A review

“…Prior chemotherapy to induce lymphodepletion is important for efficacy of these transferred cells as seen in object clinical responses, and also their longevity. 57 After cell infusion, patients are typically given IL-2 (either high or low dose) to maintain the activity of the TILs. (2) Autologous whole T cells or CD8 C T cells taken from the periphery and selected for their tumor antigen specificity or stimulated with tumor antigens presented by APCs -This approach involves the expansion of tumor antigen specific CD4 C or CD8 C T cells by using APCs loaded with one or more tumor antigens.…”