A guide to cancer immunotherapy: from T cell basic science to clinical practice

Abstract

The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.

Fig. 1. Peripheral T cell fates after antigenic activation.

Resting T cells become activated after stimulation by cognate antigen in the context of an antigen-presenting cell and co-stimulatory signals. Activated T cells produce and consume proliferative/survival cytokines, for example, IL-2, IL-4 and IL-7, and begin to expand in number. If CD4⁺CD25⁺ regulatory T (T_reg) cells are present, they can deprive the cycling T cells of proliferative/survival cytokines, especially IL-2, causing them to undergo apoptosis. Once cells are proliferating rapidly, they have different fates depending on their environment. If they receive acute strong antigenic stimulation, especially if it is encountered repeatedly, the cells will undergo restimulation-induced cell death. By contrast, if they receive chronic weak antigenic stimulation, the cells will survive but become reprogrammed into a specific unresponsive transcriptional state known as ‘T cell exhaustion’. Finally, as the antigen and cytokine stimulation diminishes as the immune response wanes, usually once the pathogen has been cleared, cytokine withdrawal can occur passively to contract the expanded population of antigen-specific T cells. A small fraction of cells will be reprogrammed to enter a ‘memory’ phenotype, and this differentiation step is facilitated by IL-7 and IL-15. Memory T cells will continue to persist in the immune system and form the basis of anamnestic responses. In these regulatory processes, T cell death usually takes the form of apoptosis.

Fig. 2. Mechanisms of T cell activation and regulation.

Before activation, antigen-presenting cells (APCs) load antigen onto MHC molecules to prepare for contact with a T cell that displays a cognate T cell receptor (TCR) while also providing necessary co-stimulatory ligands B7-1 and B7-2. The inhibitory molecule cytotoxic T lymphocyte antigen 4 (CTLA4) is contained within intracellular vesicles in naive T cells, whereas it is constitutively expressed on the cell surface of CD4⁺CD25⁺ regulatory T (T_reg) cells. Both classes of T cells express the co-stimulatory receptor CD28. Early after activation, generally in the lymphoid tissue, T cells are activated when their TCRs bind to their cognate antigen presented by APCs in conjunction with CD28 binding to B7-1/B7-2. Also, the activated T cells begin the process of displaying CTLA4 on the cell surface. T cells within peripheral tissues upregulate PD1 at the mRNA level early after activation. Late after activation, in lymphoid tissue, CTLA4 expressed by activated T cells binds to the B7-1 and B7-2 molecules on APCs, thereby preventing their binding to CD28 and promoting anergy by decreasing the T cell activation state. At the same time, constitutive expression of CTLA4 on T_reg cells leads to trans-endocytosis of B7 ligands and interferes with the CD28 co-stimulatory ability of APCs. Late after activation in peripheral tissues, PD1 is further upregulated transcriptionally, leading to greater surface expression of programmed cell death 1 (PD1), which binds to its ligands PDL1 and PDL2, thereby promoting T cell exhaustion at sites of infection or when confronted with neoplasms. Image courtesy of the National Institute of Allergy and Infectious Diseases.

Fig. 3. Effects of CTLA4-blocking antibodies.

Cytotoxic T lymphocyte antigen 4 (CTLA4)-blocking antibodies (α-CTLA4), especially when bound to an Fc receptor (FcR) on an antigen-presenting cell (APC), can promote antibody-dependent cellular cytotoxicity (ADCC). CD4⁺CD25⁺ regulatory T (T_reg) cells express higher amounts of CTLA4 than conventional T cells and are therefore more prone to α-CTLA4-induced ADCC than conventional T cells. In addition, α-CTLA4 can bind to CTLA4 on the surface of the T_reg cell and prevent it from counter-regulating the CD28-mediated co-stimulatory pathways that are playing a role in T cell activation. At the same time, α-CTLA4 can also promote T cell responses by blocking CTLA4 on the surface of conventional T cells as they undergo activation. TCR, T cell receptor. Adapted from ©2019 Fritz, J. M. & Lenardo, M. J. Originally published in J. Exp. Med. 10.1084/jem.20182395 (ref.).

Fig. 4. Mechanisms of PD1 axis inhibition.

Activated T cells express programmed cell death 1 (PD1), which engages with its specific ligand (PDL1 or PDL2) to dampen activation. Blocking of the PD1 axis through the administration of an anti-PD1 (or anti-PDL1 or anti-PDL2) antibody prevents this inhibitory interaction and unleashes antitumoural T lymphocyte activity by promoting increased T cell activation and proliferation, by enhancing their effector functions and by supporting the formation of memory cells. Consequently, more T cells bind to tumour antigens presented on tumour cells by MHC molecules via their T cell receptors (TCRs). This ultimately leads to the release of cytolytic mediators, such as perforin and granzyme, causing enhanced tumour killing. APC, antigen-presenting cell. Adapted from ©2019 Fritz, J. M. & Lenardo, M. J. Originally published in J. Exp. Med. 10.1084/jem.20182395 (ref.).

Fig. 5. Adoptive T cell therapy.

a | Tumour-infiltrating lymphocytes (TILs) are isolated from a patient tumour biopsy and expanded ex vivo with IL-2. TILs are then infused into a patient who has undergone lymphodepletion to provide a niche for the transferred TILs to expand, act as effector cells and generate immunological memory. As the T cells were derived from the tumour, it is assumed that a good proportion can recognize tumour-associated antigens (TAAs) or neoantigens. b | The physiological T cell receptor (TCR) complex gains its specificity from polymorphic α- and β-glycoprotein chains that have an antigen-binding portion and a conserved domain that associate with and signal through a group of non-polymorphic proteins, CD3 γ, δ, ε and ζ. Bioengineering of the TCR α- and β-glycoprotein antigen-binding domain (purple), while preserving the conserved domains (Cα and Cβ), allows for the development and expansion of T lymphocytes with specificity to tumour neoantigens. c | Originally, chimeric antigen receptors (CARs) were composed of an extracellular single-chain fragment of an antibody variable region coupled to a CD3 ζ-signalling domain. Poor expansion and functionality of these first-generation CARs led to the development of second and third-generation CARs containing intracellular modules from co-stimulatory molecules (CD28 and/or 4-1BB) that provide additional signals necessary to fully activate the T cell. Subsequent generations of CAR T cells contain further modifications to improve antitumour efficacy. For example, fourth-generation ‘armoured’ CAR T cells have been engineered to secrete pro-inflammatory cytokines, such as IL-12, to overcome immunosuppression in the tumour microenvironment. The chimeric cytokine receptor 4αβ, comprising the ectodomain of IL-4Rα fused to the IL-2/IL-15Rβ chain, signals in response to IL-4, an abundant cytokine in numerous tumour types. V_H, variable heavy chain; V_L, variable light chain.

Fig. 6. Personalized vaccine development.

Healthy tissue and tumour tissue from a patient with cancer are submitted for DNA sequencing and bioinformatic analyses to identify gene variants that encode peptides that are specific to the tumour (neoantigens). Prediction algorithms are then used to screen for neoantigens that are likely to stably bind to the patient’s MHC (also known as HLA in human) molecules and their expression is validated by sequencing tumour mRNA. Multiple predicted neoantigens are then formulated into vaccines, which are administered to the patient together with adjuvants. Post treatment, the patient is regularly monitored for neoantigen-specific immune responses and tumour growth.