Adoptive T‐Cell Transfer: Harnessing Immune Cells to Combat Disease

Abstract

Immunotherapies have recently shown great clinical potential as medical treatment in cancer patients. The majority of these therapies aim to stimulate a selective robust immune response that eliminates what is harmful, while not damaging normal tissues. Only with careful investigation of immunity and disease can we understand how to harness the selectivity and memory of the immune system. The majority of currently approved immunotherapeutic agents consist of antibodies that require multiple infusions. In order to generate memory, the cellular component of the immune system is required. These can either be engaged in the patient directly (a vaccine approach) or manipulated and given back to the patient in a process known as adoptive cell therapy. By manipulating these cells , they can be genetically modified to instruct complex and specific long‐term immune responses. As biotechnology rapidly improves, various aspects of adoptive T‐cell transfer are important to consider and could be optimised.

Key Concepts

  • Adoptive T‐cell therapy is the transfer of T cells that can be derived either from the same patient (autologous) or from a different person (allogeneic).
  • T cells can be collected and modified using gene transfer techniques before they are re‐infused to the patient.
  • New antigen receptors can be used to re‐direct T cells to recognise tumour proteins or infections. T cells may also be modified in other ways to harness their ability to specifically kill target cells, such as tumours.

Keywords: adoptive cell therapy; CAR T cells; TCR; gene transfer; viral vectors; immunotherapy

Figure 1. Comparing structure and functionality of antibodies, TCRs and CARs. (a) Antibodies are composed of two sets of identical heavy and light chains. The variable domain within the heavy chain (VH) contains three complementarity‐determining regions (CDR) with the combination with the three CDR domains within the variable domain of the light chain (VL) forms the antigen recognition site (shown in blue). The light chain variable domain is fused to a single constant domain, whereas the heavy chain variable domain is fused to a single constant domain (shown in red), fused to a hinged domain, fused to two more constant regions (shown in green). (b) The T‐cell receptor (TCR) is a heterodimer composed of alpha and beta chains that confer an antigen recognition site fused to a transmembrane domain (shown in blue). Upon antigen binding, multiple chains of the CD3 complex (delta, epsilon, gamma and zeta) cluster to the binding TCR facilitating signalling (shown in purple, green, orange and white, respectively). (c) Chimeric antigen receptors (CARs) fuse the light and heavy variable chains (shown in blue) from antibodies to allow for antigen recognition that is fused to a transmembrane domain (shown in white) and signalling moieties (shown in blue and white). By supplying CD3zeta, first‐generation CARs were generated, subsequently by second‐generation CARs that supply both CD3zeta with a co‐stimulatory signal 4‐1BB or CD28 and then by third‐generation CARs that supply all three signals. Reproduced with permission from Maus et al. (2014a) © American Society of Hematology.
Figure 2. Immunotherapeutic methods for cancer. Non‐cell‐based immunotherapies: (a) Monoclonal antibody therapy against immune checkpoint receptors such as PD1 or CTLA‐4. Monoclonal antibodies can also be utilised by fusing, for example, an anti‐CD3 antibody to an anti‐CD19 antibody together to form a moiety known as a Bi‐specific T‐cell engager (BiTE) that brings T cells to tumour‐associated antigens (shown in blue and green). (b) Cytokine therapy stimulates immune cells to respond to tumour. (c) Various agents can be used to deliver tumour antigen peptides to the immune system in combination. (d) Chemotherapy in combination with immunotherapy can be efficacious to not only treat the tumour but also by removing myeloid‐derived suppressor cells (MDSCs) that induce immunosuppression. (e) Directed chemotherapy and radiotherapy with antibody‐drug conjugates allows for more specific therapies. Cell‐based immunotherapies: (f) T‐cell clones are naturally tumour‐specific lymphocytes isolated from tumours that have been stimulated and expanded for infusion. (g) TCR Engineered T cells utilise genetic modification to express an exogenous TCR specific for desired antigen. (h) CAR‐modified T cells are genetically modified to express a CAR as described in Figure. 'M.V. Reproduced with permission from Maus et al. (2014a) © American Society of Hematology.
Figure 3. Barriers to overcome for successful T‐cell immunotherapy. (1) Source of cells and migration of T cells to the site of tumour. (2) Infiltration into the tumour. (3) Sufficient signalling, specificity and overcoming immunosuppresion. (4) Induction of an anti‐tumour innate immune response. (5) Avoid damage to normal tissues and cytokine release syndrome (CRS).
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Kloss, Christopher C, and Maus, Marcela V(Nov 2015) Adoptive T‐Cell Transfer: Harnessing Immune Cells to Combat Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026238]