Adoptive cellular therapy in solid tumor malignancies: review of the literature and challenges ahead

Abstract

While immune checkpoint inhibitors (ICIs) have ushered in major changes in standards of care for many solid tumor malignancies, primary and acquired resistance is common. Insufficient antitumor T cells, inadequate function of these cells, and impaired formation of memory T cells all contribute to resistance mechanisms to ICI. Adoptive cellular therapy (ACT) is a form of immunotherapy that is rapidly growing in clinical investigation and has the potential to overcome these limitations by its ability to augment the number, specificity, and reactivity of T cells against tumor tissue. ACT has revolutionized the treatment of hematologic malignancies, though the use of ACT in solid tumor malignancies is still in its early stages. There are currently three major modalities of ACT: tumor-infiltrating lymphocytes (TILs), genetically engineered T-cell receptors (TCRs), and chimeric antigen receptor (CAR) T cells. TIL therapy involves expansion of a heterogeneous population of endogenous T cells found in a harvested tumor, while TCRs and CAR T cells involve expansion of a genetically engineered T-cell directed toward specific antigen targets. In this review, we explore the potential of ACT as a treatment modality against solid tumors, discuss their advantages and limitations against solid tumor malignancies, discuss the promising therapies under active investigation, and examine future directions for this rapidly growing field.

Keywords: adoptive; chimeric antigen; immunotherapy; lymphocytes; receptors; tumor-infiltrating.

Figure 1

Differences between chimeric antigen receptor (CAR) T cells and re-engineered T-cell receptors (TCRs). CAR T cells recognize antigens expressed on the cell surface via an antigen-recognition domain (signal-chain variable fragment). This domain is connected to a spacer, transmembrane domain, and a single or multiple costimulatory domains which then trigger downstream T-cell activation via a signaling domain. TCRs are heterodimers with an α and β subunit which recognizes intracellular peptide antigens presented to it by the major histocompatibility complex (MHC). The heterodimer is connected to a CD3 signal transduction complex which acts to activate downstream T-cell activation. Created with http://www.biorender.com/.

Figure 2

Challenges for adoptive cell therapy (ACT) in solid tumors. Tumor heterogeneity, antigen escape, T-cell trafficking, and an immunosuppressive tumor microenvironment represent some of the most challenging obstacles in solid tumor ACT development. Adapted from ‘Challenges for CAR T-cell immunotherapy in solid tumors’, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates. IL-10, interleukin-10.