The introduction and development of T cell-based therapies to treat a variety of both hematological and solid tumors have led to substantial clinical benefits in some patients. In this brief review we introduce the different T cell modalities used and some of their key features and limitations. Emerging avenues to overcome current bottlenecks are put into perspective, especially the issues of limited persistence and efficacy that make it challenging to achieve durable clinical responses in solid tumor indications.
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References
1.
MoradG, HelminkBA, SharmaP, et al.Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2022; 185:576. DOI: 10.1016/j.cell.2022.01.008.
Bausch-FluckD, GoldmannU, MullerS, et al.The in silico human surfaceome. Proc Natl Acad Sci U S A. 2018; 115:E10988–E10997. DOI: 10.1073/pnas.1808790115.
4.
LytheG, CallardRE, HoareRL, et al.How many TCR clonotypes does a body maintain?. J Theor Biol. 2016; 389:214–224. DOI: 10.1016/j.jtbi.2015.10.016.
5.
GuedanS, RuellaM, JuneCH. Emerging cellular therapies for cancer. Annu Rev Immunol. 2019; 37:145–171. DOI: 10.1146/annurev-immunol-042718-041407.
6.
AlizadehD, WongRA, GholaminS, et al.IFNgamma is critical for CAR T cell-mediated myeloid activation and induction of endogenous immunity. Cancer Discov. 2021; 11:2248–2265. DOI: 10.1158/2159-8290.CD-20-1661.
7.
MajznerRG, RamakrishnaS, YeomKW, et al.GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature. 2022; 603:934–941. DOI: 10.1038/s41586-022-04489-4.
8.
HawkinsER, D'SouzaRR, KlampatsaA. Armored CAR T-cells: The next chapter in T-Cell cancer immunotherapy. Biologics. 2021; 15:95–105. DOI: 10.2147/BTT.S291768.
9.
HouAJ, ChenLC, ChenYY. Navigating CAR-T cells through the solid-tumour microenvironment. Nat Rev Drug Discov. 2021; 20:531–550. DOI: 10.1038/s41573-021-00189-2.
10.
WeberEW, MausMV, MackallCL. The emerging landscape of immune cell therapies. Cell. 2020; 181:46–62. DOI: 10.1016/j.cell.2020.03.001.
11.
WeberEW, ParkerKR, SotilloE, et al.Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science. 2021; 372:eaba1786. DOI: 10.1126/science.aba1786.
12.
ZhangQ, DingJ, SunS, et al.Akt inhibition at the initial stage of CAR-T preparation enhances the CAR-positive expression rate, memory phenotype and in vivo efficacy. Am J Cancer Res. 2019; 9:2379–2396.
13.
UrakR, WalterM, LimL, et al.Ex vivo Akt inhibition promotes the generation of potent CD19CAR T cells for adoptive immunotherapy. J Immunother Cancer. 2017; 5:26. DOI:10.1186/s40425-017-0227-4.
14.
ZhaoJ, LinQ, SongY, et al.Universal CARs, universal T cells, and universal CAR T cells. J Hematol Oncol. 2018; 11:132. DOI:10.1186/s13045-018-0677-2.
15.
NagarshethNB, NorbergSM, SinkoeAL, et al.TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med. 2021; 27:419–425. DOI: 10.1038/s41591-020-01225-1.
16.
DoranSL, StevanovicS, AdhikaryS, et al.T-cell receptor gene therapy for human papillomavirus-associated epithelial cancers: A first-in-human, phase I/II study. J Clin Oncol. 2019; 37:2759–2768. DOI: 10.1200/JCO.18.02424.
17.
WelshJ, KeD, OsorioNP, et al.376 Radiation sub-study to characterize safety and tolerability of low-dose radiation in combination with afami-cel in patients with advanced cancers (NCT03132922). J Immunother Cancer. 2021; 9:A407. DOI:10.1136/jitc-2021-SITC2021.376.
18.
D'AngeloSP, TineBAV, AttiaSet al.SPEARHEAD-1: A phase 2 trial of afamitresgene autoleucel (Formerly ADP-A2M4) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma. J Clin Oncol. 2021; 39:11504–11504. DOI: 10.1200/JCO.2021.39.15_suppl.11504.
19.
Adaptimmune. SURPASS Phase 1 studies of ADP-A2M4CD8 in MAGE-A4+ HLA-A*02:01+ solid tumors. Corporate Slide Deck. 2021. www.adaptimmune.com
20.
SchmidtE, MardilovichK, BathN, et al.373 Enhancement of TCR-engineered T-cells targeting MAGE-A4 antigen by co-expression of CD8α and inhibition of AKT signaling during ex vivo T-cell expansion. J Immunother Cancer. 2021; 9:A401. DOI:10.1136/jitc-2021-SITC2021.373.
21.
D'AngeloSP, DrutaM, Van TineBA, LiebnerD, SchuetzeS, HasanAN, HolmesAP, HuffA, KapoorG, ZajicS, SomaiahN. Safety and efficacy of letetresgene autoleucel (lete-cel; gsk3377794) in advanced myxoid/round cell liposarcoma (mrcls) following high lymphodepletion (cohort 2): interim analysis. CTOS Virtual AnnualMeeting. 2021, Paper 31. www.eventscribe.net/2021/CTOS/index.asp
22.
WermkeM, TsimberidouA-M, MohamedA, et al.959 Safety and anti-tumor activity of TCR-engineered autologous, PRAME-directed T cells across multiple advanced solid cancers at low doses—Clinical update on the ACTengine® IMA203 trial. J Immunother Cancer. 2021; 9:A1009. DOI:10.1136/jitc-2021-SITC2021.959.
23.
ZhaoL, CaoYJ. Engineered T cell therapy for cancer in the clinic. Front Immunol. 2019; 10:2250. DOI:10.3389/fimmu.2019.02250.
24.
ZhangJ, WangL. The emerging world of TCR-T cell trials against cancer: A systematic review. Technol Cancer Res Treat. 2019; 18:1–13. DOI: 10.1177/1533033819831068.
25.
EcsediM, McAfeeMS, ChapuisAG. The anticancer potential of T cell receptor-engineered T cells. Trends Cancer. 2021; 7:48–56. DOI: 10.1016/j.trecan.2020.09.002.
26.
OliveiraG, StromhaugK, KlaegerS, et al.Phenotype, specificity and avidity of antitumour CD8(+) T cells in melanoma. Nature. 2021; 596:119–125. DOI: 10.1038/s41586-021-03704-y.
27.
HebeisenM, OberleSG, PresottoD, et al.Molecular insights for optimizing T cell receptor specificity against cancer. Front Immunol. 2013; 4:154. DOI:10.3389/fimmu.2013.00154.
28.
SpearTT, EvavoldBD, BakerBM, et al.Understanding TCR affinity, antigen specificity, and cross-reactivity to improve TCR gene-modified T cells for cancer immunotherapy. Cancer Immunol Immunother. 2019; 68:1881–1889. DOI: 10.1007/s00262-019-02401-0.
DudleyME, WunderlichJR, RobbinsPF, et al.Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002; 298:850–854. DOI: 10.1126/science.1076514.
31.
RohaanMW, van den BergJH, KvistborgP, et al.Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: A viable treatment option. J Immunother Cancer. 2018; 6:102. DOI:10.1186/s40425-018-0391-1.
32.
SchoenfeldA, LeeS, Paz-AresL, et al.458 First phase 2 results of autologous tumor-infiltrating lymphocyte (TIL; LN-145) monotherapy in patients with advanced, immune checkpoint inhibitor-treated, non-small cell lung cancer (NSCLC). J Immunother Cancer. 2021; 9:A486–A487. DOI: 10.1136/jitc-2021-SITC2021.458.
33.
O'MalleyD, LeeS, PsyrriA, et al.492 Phase 2 efficacy and safety of autologous tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab in immune checkpoint inhibitor-naïve patients with advanced cancers. J Immunother Cancer. 2021; 9:A523–A524. DOI: 10.1136/jitc-2021-SITC2021.492.
34.
CreelanBC, WangC, TeerJK, et al.Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: A phase 1 trial. Nat Med. 2021; 27:1410–1418. DOI: 10.1038/s41591-021-01462-y.
35.
VeatchJR, SimonS, RiddellSR. Tumor-infiltrating lymphocytes make inroads in non-small-cell lung cancer. Nat Med. 2021; 27:1339–1341. DOI: 10.1038/s41591-021-01445-z.
36.
KrishnaS, LoweryFJ, CopelandAR, et al.Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science. 2020; 370:1328–1334. DOI: 10.1126/science.abb9847.
37.
LuYC, JiaL, ZhengZ, et al.Single-cell transcriptome analysis reveals gene signatures associated with T-cell persistence following adoptive cell therapy. Cancer Immunol Res. 2019; 7:1824–1836. DOI: 10.1158/2326–6066.CIR-19-0299.
38.
ChapuisAG, RobertsIM, ThompsonJA, et al.T-cell therapy using interleukin-21-primed cytotoxic T-cell lymphocytes combined with cytotoxic T-cell lymphocyte antigen-4 blockade results in long-term cell persistence and durable tumor regression. J Clin Oncol. 2016; 34:3787–3795. DOI: 10.1200/JCO.2015.65.5142.
39.
VasileiouS, LullaPD, TzannouI, et al.T-cell therapy for lymphoma using nonengineered multiantigen-targeted T cells is safe and produces durable clinical effects. J Clin Oncol. 2021; 39:1415–1425. DOI: 10.1200/JCO.20.02224.
40.
HontAB, CruzCR, UlreyR, et al.Immunotherapy of relapsed and refractory solid tumors with ex vivo expanded multi-tumor associated antigen specific cytotoxic T lymphocytes: A phase I study. J Clin Oncol. 2019; 37:2349–2359. DOI: 10.1200/JCO.19.00177.
41.
LiT, ZhaoL, YangY, et al.T cells expanded from PD-1(+) peripheral blood lymphocytes share more clones with paired tumor-infiltrating lymphocytes. Cancer Res. 2021; 81:2184–2194. DOI: 10.1158/0008-5472.CAN-20-2300.
42.
LullaPD, TzannouI, VasileiouS, et al.The safety and clinical effects of administering a multiantigen-targeted T cell therapy to patients with multiple myeloma. Sci Transl Med. 2020; 12:eaaz3339. DOI:10.1126/scitranslmed.aaz3339.
43.
KishtonRJ, VodnalaSK, VizcardoR, et al.Next generation immunotherapy: Enhancing stemness of polyclonal T cells to improve anti-tumor activity. Curr Opin Immunol. 2022; 74:39–45. DOI: 10.1016/j.coi.2021.10.001.
44.
ConlonKC, MiljkovicMD, WaldmannTA. Cytokines in the treatment of cancer. J Interferon Cytokine Res. 2019; 39:6–21. DOI: 10.1089/jir.2018.0019.
45.
ChapuisAG, DesmaraisC, EmersonR, et al.Tracking the fate and origin of clinically relevant adoptively transferred CD8(+) T cells in vivo. Sci Immunol. 2017; 2:eaal2568. DOI:10.1126/sciimmunol.aal2568.
46.
TangL, ZhengY, MeloMB, et al.Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat Biotechnol. 2018; 36:707–716. DOI: 10.1038/nbt.4181.
47.
JonesDS, 2nd, NardozziJD, SacktonKL, et al.Cell surface-tethered IL-12 repolarizes the tumor immune microenvironment to enhance the efficacy of adoptive T cell therapy. Sci Adv. 2022; 8:eabi8075. DOI:10.1126/sciadv.abi8075.
48.
LiJ, LinW, ChenH, et al.Dual-target IL-12-containing nanoparticles enhance T cell functions for cancer immunotherapy. Cell Immunol. 2020; 349:104042. DOI:10.1016/j.cellimm.2020.104042.
49.
JinY, DongY, ZhangJ, et al.The toxicity of cell therapy: Mechanism, manifestations, and challenges. J Appl Toxicol. 2021; 41:659–667. DOI: 10.1002/jat.4100.
50.
RaffinC, VoLT, BluestoneJA. Treg cell-based therapies: Challenges and perspectives. Nat Rev Immunol. 2020; 20:158–172. DOI: 10.1038/s41577-019-0232-6.
51.
BarrettDM, SinghN, PorterDL, et al.Chimeric antigen receptor therapy for cancer. Annu Rev Med. 2014; 65:333–347. DOI: 10.1146/annurev-med-060512-150254.
52.
ZhongS, MalecekK, JohnsonLA, et al.T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy. Proc Natl Acad Sci U S A. 2013; 110:6973–6978. DOI: 10.1073/pnas.1221609110.
RathJA, ArberC. Engineering strategies to enhance TCR-based adoptive T cell therapy. Cells. 2020; 9:1485. DOI:10.3390/cells9061485.
55.
HouB, TangY, LiW, et al.Efficiency of CAR-T therapy for treatment of solid tumor in clinical trials: A meta-analysis. Dis Markers. 2019; 2019:3425291. DOI:10.1155/2019/3425291.
56.
Weingarten-GabbayS, KlaegerS, SarkizovaS, et al.Profiling SARS-CoV-2 HLA-I peptidome reveals T cell epitopes from out-of-frame ORFs. Cell. 2021; 184:3962.e17–3980.e17. DOI: 10.1016/j.cell.2021.05.046.
57.
FrancisJM, Leistritz-EdwardsD, DunnA, et al.Allelic variation in class I HLA determines CD8(+) T cell repertoire shape and cross-reactive memory responses to SARS-CoV-2. Sci Immunol. 2022; 7:eabk3070. DOI:10.1126/sciimmunol.abk3070.
