Abstract
Adoptive T cell therapy (ACT) is a rapidly evolving therapeutic approach designed to harness T cell specificity and function to fight diseases. Based on the evidence that T lymphocytes can mediate a potent anti-tumor response, initially ACT solely relied on the isolation, in vitro expansion, and infusion of tumor-infiltrating or circulating tumor-specific T cells. Although effective in a subset of cases, in the first ACT clinical trials several patients experienced disease progression, in some cases after temporary disease control. This evidence prompted researchers to improve ACT products by taking advantage of the continuously evolving gene engineering field and by improving manufacturing protocols, to enable the generation of effective and long-term persisting tumor-specific T cell products. Despite recent advances, several challenges, including prioritization of antigen targets, identification, and optimization of tumor-specific T cell receptors, in the development of tools enabling T cells to counteract the immunosuppressive tumor microenvironment, still need to be faced. This review aims at summarizing the major achievements, hurdles and possible solutions designed to improve the ACT efficacy and safety profile in the context of liquid and solid tumors.
Highlights
Adoptive T cell therapy for cancer (ACT) is a branch of cancer immunotherapy that relies on the ability to redirect T cell specificity to selectively target tumor antigens
ACT stemmed from two remarkable clinical observations: (i) The magnitude of T cells infiltrating tumor masses often correlates with response to treatment [1] and (ii) Allogeneic donor T cells infused in the context of hematopoietic stem cell transplantation promote clinical response in hematological malignancies [2]
The first ACT strategies tested with autologous T lymphocytes were based on the isolation of T cells infiltrating primary lesions resected from patients with melanoma, followed by their in vitro expansion with high-doses of interleukin-2 (IL-2) [17]
Summary
Adoptive T cell therapy for cancer (ACT) is a branch of cancer immunotherapy that relies on the ability to redirect T cell specificity to selectively target tumor antigens. ACT solely relied on tumor-specific T cells isolated from the tumor masses and expanded in vitro [3]. This approach was limited to resectable tumors from which enough T cells could be harvested and expanded. TCR-Based ACT: Achievements, Hurdles, Goals antigens (Figure 1) This new opportunity shifted the research focus and raised some novel questions: the main issue was no more how to harvest a sufficient number of tumor-specific T cells from each single patient, but how to isolate and harness highavidity tumor-specific TCRs, and how to proficiently generate and expand the most fit engineered T cells.
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