Adoptive Immunotherapy beyond CAR T-Cells
<p>The diverse nature of adoptive immunotherapy. Infusion of tumor infiltrating lymphocytes (TILs) is one of the oldest clinical approaches in T-cell-based immunotherapy. The isolated TILs are expanded ex vivo and infused back to the patient. In addition, TILs and other T-cells may be used for isolation of T-cell receptors (TCRs) for further genetic engineering and generation of transgenic TCR therapies. Alternatively, to widespread CAR T-cells, other cell populations (e.g., NK-cells, macrophages) may be transduced to produce CAR NK-cells and CAR M-cells, respectively. Cellular therapies that are primarily applied for the treatment of solid tumors (*) or hematological malignancies (+).</p> "> Figure 2
<p>The structure of TCR α and β chains. The TCR constant domains are responsible for the correct complex assembly and binding to CD3 chains, whereas the variable domains are involved in recognition of the peptide–MHC complex. Complementary Determining Regions 3 of α (CDR3α) and β (CDR3β) chains are assembled during somatic mutagenesis and V(D)J recombination and are the most important for antigen recognition. The other CDRs (V-gene specific) are germline encoded and contribute to peptide–MHC recognition.</p> "> Figure 3
<p>The strategies for neoantigen discovery. (1) A laborious approach that includes: (a) tumor genome and RNA sequencing; followed by (b) MS analysis of the immunopeptidome (peptides dissociated from peptide–MHC complex) and (c) mapping of these peptides to the source genome/transcriptome. (2) Analysis of the sequencing data allows computational prediction of putative HLA-binding peptides by NetMHCPan, SYFPEITHI, or HLAthena algorithms. (3) Novel approaches for epitope screening based on human genome-wide libraries. Approaches 1 and 2 require subsequent validation to confirm correct processing and presentation of the identified peptides (for approach 2), as well as their potential immunogenicity (for both approaches). The validation step includes ex vivo expansion of T-cells in presence of peptide- or minigene-pulsed dendritic cells (DCs) or using approach 3.</p> "> Figure 4
<p>Addressing mispairing issues. The top semicircle (rose) depicts modifications of transgenic TCRs that facilitate correct pairing of ɑ and β chains. The bottom semicircle (green) outlines regulation of the endogenous TCR expression.</p> "> Figure 5
<p>The differences and similarities in the design of transgenic receptors for adoptive immunotherapy.</p> "> Figure 6
<p>Evolution of the bioreactor platforms. The most advanced systems include G-Rex<sup>®</sup> by Wilson Wolf, Z<sup>®</sup>RP by Zellwerk, Xuri<sup>®</sup> (WAVE<sup>®</sup>) by Cytiva, CliniMACS Prodigy<sup>®</sup> by Miltenyi Biotec, Cocoon<sup>®</sup> by Lonza (Basel, Switzerland), and Quantum<sup>®</sup> by Terumo (Tokyo, Japan).</p> ">
Abstract
:Simple Summary
Abstract
1. Introduction
2. The Importance of Cell Source for Production of Conventional CAR T-Cells
3. CAR Cells, but Not CAR αβ T-Cells
3.1. γδ. T-Cells
3.2. NK-Cells
3.3. CAR M-Cells
4. T-Cells, but Not CAR T-Cells. TCR-Based Therapies
4.1. The Basis of the TCR Machinery
4.2. TILs—Not-Engineered T-Cells
4.3. Strategies for Selection of TCR-Dependent Epitopes
4.3.1. Sequencing Strategies
4.3.2. Bioinformatic Selection
4.3.3. Library-Associated Epitope Screening
4.4. Transgenic TCRs
4.5. Exploiting Alternatives to Conventional TCRs
4.5.1. NK-Cell Receptors
4.5.2. Non-Conventional TCRs
5. Evolution of Manufacturing Therapeutic T-Cells
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ACT | Adoptive Cell Transfer |
APC | Antigen-Presenting Cell |
BTLA | B- and T-lymphocyte attenuator |
BTN2A1 | Butyrophilin-2A1 |
CAR | Chimeric Antigen Receptor |
CR | Complete Remission |
DC | Dendritic Cell |
FACS | Fluorescence-Activated Cell Sorting |
GMP | Good Manufacturing Practice |
GvHD | Graft versus Host Disease |
HF | Hollow Fiber |
HLA | Human Leukocyte Antigen |
HSCT | Hematopoietic Stem Cell Transplantation |
IL | Interleukin |
Mel | Melanoma |
KIR | Killer Cell Immunoglobulin-Like Receptor |
MHC | Major Histocompatibility Complex |
MRD | Minimal Residual Disease |
MS | mass spectrometry |
MSC | mesenchymal stem cell |
MR1 | major histocompatibility complex class I-related gene protein |
NK | Natural Killer |
NOD/SCID | Nonobese Diabetic/Severe Combined Immunodeficiency |
NR | No Response |
ORF | Open Reading Frame |
PBMC | Peripheral Blood Mononuclear Cell |
pMHC | Peptide-loaded Major Histocompatibility Complex |
PD | Progressive Disease |
PoC | Point-of-Care |
PR | Partial Remission |
Pt/pts | patient/patients |
RNA | Ribonucleic Acid |
scTCR | single chain T-Cell Receptor |
SD | Stable Disease |
shRNA | short hairpin RNA |
SCS | Synovial Cell Sarcoma |
TCM | Central Memory T-cell |
TIL | Tumor Infiltrating Lymphocyte |
TM | TransMembrane |
TMB | Tumor Mutation Burden |
TME | Tumor Microenvironment |
Treg | T regulatory cells |
TSCM | Stem Memory T-cell |
VGPR | Very Good Partial Remission |
WIM | Wave-Induced Motion |
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Modification | Commentary |
---|---|
| May impact T-cell avidity and recognition of non-target cells with low target antigen levels |
| Prevents cross-reactivity by formation of hybrid TCRs with unknown specificity |
| Unknown additional specificity |
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Titov, A.; Zmievskaya, E.; Ganeeva, I.; Valiullina, A.; Petukhov, A.; Rakhmatullina, A.; Miftakhova, R.; Fainshtein, M.; Rizvanov, A.; Bulatov, E. Adoptive Immunotherapy beyond CAR T-Cells. Cancers 2021, 13, 743. https://doi.org/10.3390/cancers13040743
Titov A, Zmievskaya E, Ganeeva I, Valiullina A, Petukhov A, Rakhmatullina A, Miftakhova R, Fainshtein M, Rizvanov A, Bulatov E. Adoptive Immunotherapy beyond CAR T-Cells. Cancers. 2021; 13(4):743. https://doi.org/10.3390/cancers13040743
Chicago/Turabian StyleTitov, Aleksei, Ekaterina Zmievskaya, Irina Ganeeva, Aygul Valiullina, Alexey Petukhov, Aygul Rakhmatullina, Regina Miftakhova, Michael Fainshtein, Albert Rizvanov, and Emil Bulatov. 2021. "Adoptive Immunotherapy beyond CAR T-Cells" Cancers 13, no. 4: 743. https://doi.org/10.3390/cancers13040743