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Review
. 2020 Jul 24;12(8):2030.
doi: 10.3390/cancers12082030.

The Great War of Today: Modifications of CAR-T Cells to Effectively Combat Malignancies

Andriy Zhylko  1 , Magdalena Winiarska  1 , Agnieszka Graczyk-Jarzynka  1
Affiliations
Review

The Great War of Today: Modifications of CAR-T Cells to Effectively Combat Malignancies

Andriy Zhylko et al. Cancers (Basel). .

Abstract

Immunotherapy of cancer had its early beginnings in the times when the elements of the immune system were still poorly characterized. However, with the progress in molecular biology, it has become feasible to re-engineer T cells in order to eradicate tumour cells. The use of synthetic chimeric antigen receptors (CARs) helped to re-target and simultaneously unleash the cytotoxic potential of T cells. CAR-T therapy proved to be remarkably effective in cases of haematological malignancies, often refractory and relapsed. The success of this approach yielded two Food and Drug Administration (FDA) approvals for the first "living drug" modalities. However, CAR-T therapy is not without flaws. Apart from the side effects associated with the treatment, it became apparent that CAR introduction alters T cell biology and the possible therapeutic outcomes. Additionally, it was shown that CAR-T approaches in solid tumours do not recapitulate the success in the haemato-oncology. Therefore, in this review, we aim to discuss the recent concerns of CAR-T therapy for both haematological and solid tumours. We also summarise the general strategies that are implemented to enhance the efficacy and safety of the CAR-T regimens in blood and solid malignancies.

Keywords: T cells; chimeric antigen receptor; immunotherapy.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The CAR structure and general strategies to enhance CAR-T cell therapy. (A) Three generations of chimeric antigen receptors are based on the composition of the intracellular part. First-generation CARs contain one stimulation domain, whereas second and third generations have one or two additional costimulatory domains, respectively. Besides scFv, other molecules (ligands or receptors) are used as antigen recognition domains. (B–F) Strategies to increase CAR-T cell efficacy and selectivity against tumour cells. (B) Epitopes, located adjacent to the cell membrane, require a longer and more flexible hinge than those easily accessible for CARs. (C) In universal CARs, by targeting an epitope fused with an antibody, specificity relies mostly on antibody selectivity. (D) The use of a ligand instead of scFv as an antigen recognition domain could increase the specificity of CAR-T cells. (E) TCR-like CAR-T cells target intracellular cancer-specific antigens that are presented by MHC. (F) Tandem CARs are designed to target more than one antigen simultaneously. They recognise two different antigens and provide effective lysis of malignant cells expressing one or both cognate antigens. (G–K) Strategies to decrease on-target off-tumour toxicity and the probability of healthy cells lysis. (G) Decreased affinity toward cognate antigen enables CAR-T cells to distinguish healthy cells with a low expression level of TAAs from malignant cells with a high level of TAAs. (H) The division of the full activation signal to two independent CARs with different antigen specificities restrict the CAR-T cell’s cytotoxicity to malignant cells that express both targeted antigens while sparing healthy cells with only one antigen on their surface. (I) Additional co-modification of CAR-T cells with iCAR enables specific recognition of non-malignant cells and inhibition of toxicity against them. (J) The expression of the “effector” CAR is regulated by the synNotch receptor redirected against another TAA. (K) CAR “off-switches” are based on the co-modification of CAR-T cells with antibody-recognised molecules or with iCas9. This enables selective CAR-T cell clearance while CAR-related life-threatening side effects occur. Abbreviations: CAR—chimeric antigen receptor, scFv—single-chain variable fragment, mAb—monoclonal antibody, Ag—antigen, iCas9—inducible caspase 9, TCR—T-cell receptor, MHC—major histocompatibility complex, TAA—tumour-associated antigen, iCAR—inhibitory CAR, synNotch receptor—synthetic Notch receptor.
Figure 2
Figure 2
Remaining issues of CAR-T cell therapies in haemato-oncology. Relapses in a long-term observation after CAR-T cell infusion have two primary sources: CAR-T cells persistence (A1,A2) and the escape of malignant cells from immune surveillance (B–E). (A1) The persistence and proliferation rate of CAR-T cells depends on the co-stimulation domains. Additionally, (A2) subpopulation composition of the CAR-T cell infusion, as well as the phenotype of lymphocytes, influence the proliferation and persistence of modified effector cells. (B–E) Mechanisms of immune escape of neoplastic cells from CAR-T cells. (B) Targeted antigen changes as a result of mutation or splicing alteration. (C) Unintentional modification of neoplastic B cells with a CAR that masks the targeted epitope, rendering it undetectable by CAR-T cells. (D) Infusion of CAR-T cells triggers the selection of malignant cells with low antigen density that are resistant to effector cells. (E) The decrease of antigen surface level results from CAR-T cell-mediated trogocytosis, with subsequent induction of fratricide T cell killing and CAR-T cells with an exhausted phenotype. Abbreviations: Th—helper T cell, Tc—cytotoxic T cell, ICOS-based CAR—inducible co-stimulator-based CAR.
Figure 3
Figure 3
Examples of preclinical concepts supporting CAR-T cell anti-tumour activity in solid tumours. The effective eradication of solid tumours by CAR-T cells is jeopardised by impaired trafficking and infiltration into the tumour mass (A,B), competition with inhibitory signals (C) and reduced survival within the TME. (A) CAR-T cells additionally co-modified with a chemokine receptor (CCR) migrate towards and infiltrate solid masses in response to the chemokine gradient. (B) Forced expression of heparanase (HSPE) and redirection of CAR-T cells against fibroblast activation protein (FAP) further enhances the infiltration of solid masses. Blocking inhibitory molecules, such as PD-L1, by CAR-T cells secreting antibodies (C, top) or modified with switch receptors (C, bottom) providing activation signals leads to increased anticancer efficacy of the therapy. (D) Preconditional therapy with cyclophosphamide and fludarabine (Cy/Flu) decreases the expression level of IDO that inhibits T cell functions. (E) Modification of CAR-T cells with dominant-negative (DN) receptors for FasL leads to the resistance of CAR-T cells to proapoptotic signals present in the TME. (F) Armoured CARs (TRUCKs) engineered to secrete proinflammatory cytokines have enhanced anticancer efficacy and increase the activation of tumour infiltrating lymphocytes (TILs). Abbreviations: TME—tumour microenvironment, PD-L1—programmed death-ligand 1, IDO—indoleamine 2,3 dioxygenase, TRUCK—T cells redirected for universal cytokine killing, CASC—cancer-associated stromal cell, PD-1—program cell death 1, FasL—Fas ligand.
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