T Cell Based Immunotherapy for Cancer: History
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Contributor:
Muzamil Y. Want
,
Zeenat Bashir
,
Rauf A. Najar
,
Muzamil Yaqub Want

T cells are critical in destroying cancer cells by recognizing antigens presented by MHC molecules on cancer cells or antigen-presenting cells. Identifying and targeting cancer-specific or overexpressed self-antigens is essential for redirecting T cells against tumors, leading to tumor regression. This is achieved through the identification of mutated or overexpressed self-proteins in cancer cells, which guide the recognition of cancer cells by T-cell receptors. There are two main approaches to T cell-based immunotherapy: HLA-restricted and HLA-non-restricted Immunotherapy. 

  • T cells
  • immunotherapy
  • neoantigens
  • cancer antigens
  • TCR engineering

1. Introduction

Cancer is a major public health challenge, affecting millions of people worldwide. Despite significant advances in cancer therapy, cancer remains a leading cause of death, accounting for approximately 10 million deaths annually. The immune system plays a vital role in protecting the host from malignant cells, and harnessing its potential has been a focus of cancer therapy research for decades. T cells are a critical component of the adaptive immune system, and their ability to recognize and eliminate cancer cells has led to significant advances in cancer immunotherapy. In the mid-twentieth century, the concept of lymphocytes as mediators of anti-tumor surveillance was first proposed by Thomas and Burnett, but it was not until later that T cells were identified as the major mediators of adaptive immunity [1][2][3][4][5][6][7]. Today, the role of T cells in cancer immunotherapy is a rapidly expanding area of research.
The development of T cells begins in the bone marrow, where they originate from progenitors that migrate to the thymus for maturation. Upon maturation in the thymus, T cells differentiate into two main lineages—conventional αβ T cells and unconventional γδ T cells—that can be distinguished by the expression of αβ or γδ T cell receptors, respectively. Conventional αβ T cells comprise various subsets, including cytotoxic T cells, helper T cells, regulatory T cells, natural killer T cells, and memory T cells, each with distinct functions in immune response. While the thymus output of naive T cells decreases with age, human naive T cells have a long intrinsic lifespan and turnover rate, making them a promising candidate for immunotherapy [8][9][10][11][12].
T cells have revolutionized cancer treatment, and their use as adoptive T cell therapy has shown great success for some cancers. However, the success of adoptive T cell therapy depends on various factors, such as the choice of T cell subset, target antigen, and immune evasion mechanisms employed by cancer cells. Additionally, the tumor microenvironment can influence T cell function and promote immune escape, highlighting the need for combination therapies targeting both the cancer cells and the immune system. Nevertheless, the potential of T cells to recognize and eliminate cancer cells has opened new avenues for cancer immunotherapy, providing hope for a future where cancer can be effectively treated and cured. 

2. Antigenic Targets for T Cell Immunotherapy

Antigenic targets for T cell immunotherapy are crucial for the development of effective cancer treatments. The first human tumor antigen was discovered by Van der Bruggen et al. in 1991; it was named MZ2-E and was expressed in melanoma cells [7]. Consequently, cytotoxic T lymphocytes from melanoma patients recognized the melanoma cell line of HLA-A1 patients expressing the MZ2-E. Therefore, their group proposed that precise immunotherapy could be provided to HLA-A1+ melanoma patients expressing the MZ2-E antigen. Since then, various biochemical and genetic approaches have been developed to identify tumor antigens recognized by T cells. The biochemical approach involves eluting the HLA-peptide complex from tumor cells, followed by mass spectrometric sequencing to identify the antigenic peptides presented by the HLA molecules. In contrast, the genetic approach comprises two strategies: forward immunology and reverse immunology. The forward immunology approach involves cloning tumor-reactive T cells from patients and screening a cDNA library from patient-derived tumor cells to identify the antigens recognized by these T cells. On the other hand, the reverse immunology approach uses genome sequencing to identify mutations and predict potential HLA-binding antigens in the patient’s tumor. The peptide candidates are then screened for their ability to activate T cells in vitro [13]. T cells can target both HLA-restricted and HLA-non-restricted antigens found on the target cells. HLA-independent T cell immunotherapy targets antigens expressed on the surface of tumor cells. In contrast, HLA-dependent T cell immunotherapy targets antigens bound to HLA molecules on the surface of cells, known as the immunopeptidome.

2.1. Identification of Tumor Antigenic Epitopes for T Cell Immunotherapy

T cell immunotherapy is a promising approach for cancer treatment, but identifying tumor-reactive T cells and their target antigens is crucial for its success. There are two approaches to identifying these antigens: the indirect method, which involves screening candidate antigen targets of T cells from tumors in the laboratory, and the direct method, which involves isolating and identifying tumor-reactive T cells from tumor-infiltrating lymphocytes (TILs) or peripheral blood lymphocytes (PBLs) in patients. It is crucial to validate the reactivity of T cells towards tumors by studying the interactions between cancer cells and T cells in more depth. However, identifying T cells and their corresponding receptors with the ideal affinity for cancer antigens is challenging, as these antigens are often unmutated self-proteins expressed at higher levels in cancer cells than in normal tissues.
To generate antitumor T cells with optimal affinity of T cell receptor (TCR) to cancer-associated antigens, Obenaus et al. (2015) reported the potential of using antigen-negative humanized mice to generate T cells with a diverse human TCR repertoire and isolated the TCR specific to cancer antigens MAGE-A1 and NY-ESO-1, which have better affinity compared to human-derived TCRs [14]. Several other studies have attempted to enrich naturally occurring T cells from cancer patients by co-culturing TILs or PBLs with autologous tumors and expanding tumor-specific T cells before infusing them back into the patient [15][16][17][18]. However, the low frequency of T cells specific for these antigens makes it difficult to identify TCR T cells specific for cancer antigens. More recently, Arnaud et al. (2022) described a prediction method called NeoScreen that potentially identifies rare tumor antigens and their cognate TCR from TILs, enabling the selective expansion of antigen-specific T cells [19]. They reported that T cells transduced with target specific TCR identification via NeoScreen mediate tumor regression in preclinical models of cancer. Several T cell-based strategies have been developed to target tumor antigens that are well tolerated and show clinical promise in cancer patients. Overall, identifying tumor antigenic epitopes for T cell immunotherapy is crucial for the success of this promising approach to cancer treatment.

2.2. HLA Restricted T Cell-Based Immunotherapy

HLA dependent T cell-based immunotherapy employs the use of lymphocytes with minimally modified TCR or naturally occurring TCR directed against the tumor-specific antigen processed and presented by antigen-presenting cells via HLA molecules. This approach utilizes the ability of T cells to recognize the tumor antigens including cancer-associated or tumor-specific antigens presented by the antigen-presenting molecules on the cell surface. Many approaches have been employed for cancer immunotherapy in patients, such as endogenous T cells targeting undefined or defined antigens including cancer-associated or cancer-specific antigens.

2.3. Non-HLA Restricted T Cell-Based Immunotherapy

HLA-independent TCR-based T cell immunotherapy employs use of lymphocytes modified with TCR that are directed against the tumor antigens directly presented on the tumor cells. This approach utilizes a chimeric receptor introduced into the immune effector cells, such as T cells, natural killer cells or gamma delta (γδ) T cells to recognize tumor cell surface proteins and are commonly called as chimeric antigen receptor T or natural killer cells.

This entry is adapted from the peer-reviewed paper 10.3390/vaccines11040835

References

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