Principles of adoptive T cell cancer therapy

Abstract

The transfusion of T cells, also called adoptive T cell therapy, is an effective treatment for viral infections and has induced regression of cancer in early-stage clinical trials. However, recent advances in cellular immunology and tumor biology are guiding new approaches to adoptive T cell therapy. For example, use of engineered T cells is being tested as a strategy to improve the functions of effector and memory T cells, and manipulation of the host to overcome immunotoxic effects in the tumor microenvironment has led to promising results in early-stage clinical trials. Challenges that face the field and must be addressed before adoptive T cell therapy can be translated into routine clinical practice are discussed.

Figure 1. Models of CD8⁺ T cell differentiation to distinct memory cell subsets.

(A) In the linear differentiation model, an autonomous antigen-triggered differentiation process consisting of conversion from naive to effector to T_EM cell occurs, followed by the appearance of T_CM cells after antigen clearance through a process of dedifferentiation (27). (B) The signal strength model proposes that naive T cells progress through hierarchical thresholds for proliferation and differentiation as the strength and duration of the interaction with APCs is increased (28, 30). T cells receiving the weakest signals do not survive, whereas high-intensity signaling causes the development of terminally differentiated effector T cells that cannot survive into the memory phase. The T_CM cells, being the least differentiated of the antigen-stimulated T cells, retain the developmental options of naive T cells, including their capacity for marked clonal expansion. (C) The memory stem cell model proposes that the cells within the T_CM cell compartment are self renewing and serve as a source of effector T cells (29, 43).

Figure 2. General approaches for ex vivo T cell expansion.

Input T cells are obtained from various anatomic sites, including peripheral blood and the tumor itself. Antigen-specific CTLs can be selected and expanded by repeated stimulation with antigen pulsed APCs or tumor cells. This process requires several rounds of stimulation (left). Alternatively, the starting T cell population can be numerically expanded by polyclonal stimulation by several methods to generate cells with enhanced effector function, to deplete Tregs, and to genetically modify T cells while maintaining the TCR repertoire of the input population (right). TIL, tumor-infiltrating lymphocyte.

Figure 3. Telomeres and telomerase function in T cell subsets.

(A) In mammalian cells, telomeres are structures at the ends of all linear chromosomes that consist of hexanucleotide repeats [(TTAGGG)n] and several associated protein complexes. The two components of telomerase are illustrated — TERC and TERT. NBS, Nijmegen breakage syndrome; MRE, meiotic recombination 11 homolog; L22, ribosomal L22 protein; TEP1, telomerase-associated protein 1. (B) The relationship of telomere length to cell division is not constant. There is a relatively constant loss of telomere length during normal cell division in the absence of compensatory mechanisms in most cells. However, telomere length can also increase with cell division in some lymphocyte subsets. Human T cells can partially sustain telomere length during cell division. Cellular stress can accelerate telomere loss rates.