Table 2 Current NRT cell therapy and NRT cell relative clinical researches

NCT01174121

2014

cholangio-carcinoma

II

1

NRT

ERBB2IP-E805G CD4 + Th1 cell

SD

Vβ22 + ERBB2IP NRT cells exerted a major antitumor effect.

[155]

NCT03171220

2017

solid tumors

advanced

6

NRT

CR: 1; PR: 1; SD: 4; PFS (median): 8.6 M

De novo approach: less than 30% of the peptides can induce NRT cells; Peptide library approach: nearly 50%.

[27]

NCT01174121

2017

breast cancer

advanced (ER + HER2–)

II

1

NRT

mutSLC3A2, mutKIAA0368

CR

SLC3A2 reactivity and KIAA0368 reactivity were mediated by CD4 + and CD8 + T cells, respectively. 11 TCR clonotypes recognized the four neoantigens (SLC3A2, KIAA0368, CADPS2 and CTSB). 72.7% of the TCR of NRT cells can be detected in patient’s peripheral blood, lasting at least 17 months.

[26]

ChiCTR1800017836

2020

collecting duct carcinoma

advanced

I

1

NRT + Neovax

13 neoantigen peptides

SD

12 of 13 peptides can induce NRT cells. The frequency of mutant allele decreased after three months.

[28]

NCT03199807

2021

HCC

IV

1

NRT

KRAS-G12A, KRAS-G13D, PIK3CA-H1047L, IDH1-R132H

CR

The proportion of NRT cells in vivo reached a maximum of 4.49% in four cycle reinfusions.

[25]

NCT03935893

2022

solid tumor

advanced

II

1

NRT

KRAS-G12D TCR T cell

CR

Reinfused NRT cells represented approximately 2.4% of the total circulating T cells at 6 months.

[156]

NCT01174121 and NCT03412877

2022

solid tumor

advanced

II

13

NRT

TP53 TCR T cell

PR: 3; NR: 10

Percentage of NRT cells with a persistence of 6 weeks: 0.01%;

NRT cells showed high level exhausted phenotype (PD-1:43%, TIM3: 33%, CD39: 93%) and low-level central memory phenotype (CD62L:5.02%).

[157]

NCT03067493

2022

primary HCC

II

23(10 vaccinated)

NRT + Neo-DCVac

peptide–loaded DC

SD: 5; PD: 5; DSF(median): 18.3 M

42.5% of the neoantigen peptides induced NRT cell response; 70% of patients had neoantigen-specific immune response.

[158]

NCT02035956

2017

melanoma

III-IV

I

13

NeoVax

IVAC MUTANOME

mRNA

SD: 8; PD: 5

60% of the neoantigen peptides induced NRT cell response; each patient developed NRT cells against at least 3 mutations; 57% of NRT cells were CD4 + T cell.

[159]

NCT02287428

2018

MGMT-UG

I/Ib

I

10 (2 withdrew)

NeoVax

peptides + poly-ICLC

PD: 8; PFS(median): 7.6 M; OR: 16.8 M

Two patients who did not receive dexamethasome generated NRT cell response towards neoantigens.

[160]

NCT03480152

2019

gastrointestinal cancer

advanced

I

5(1 PD)

NeoVax

mRNA-4650

mRNA

NR

15.7% of the neoantigen peptides induced NRT cell response; 59% of NRT cells were CD4 + T cells and 41% were CD8 + T cells.

[161]

NCT03662815

2019

solid tumors

advanced

24 (22 vaccinated, 21 finish five)

NeoVax

iNeo-Vac-P01

peptides + GM-CSF

SD: 15; PD: 6; PFS(median): 4.6 M; PFS(6): 27.3%; OS(12): 55.1%;

Nearly 80% of the peptides or peptide pools induced NRT cell response.

[162]

NCT01461148

2020

colorectal cancer

III/IV

I/IIa

22(19 finished)

NeoVax

FSP (TAF1B (-1), HT001 (-1) and AIM2 (-1)

peptides

SD: 3

50% of the patients had neoantigen-specific immune response. Each patient developed NRT cells against at least 1 peptide. Some frameshift peptide neoantigens could not induce CD8 + NRT cells.

[163]

NCT02960230

2020

diffuse midline glioma

HLA-A^*02:01 + , H3.3K27 Mut

19

NeoVax

peptides + TT peptide + poly-ICLC

OS(median): 16.1 M, OS(12): 40%

Nearly 80% of the neoantigen peptides induced NRT cell response. Expansion of CD8 + NRT cells was associated with a better prognosis.

[164]

ChiCTR1900020990

2021

HCC

II-III

I

10

NeoVax

peptides + poly-ICLC

CR: 2; PD: 8; median RFS: 7.4 M;

Nearly 70% of the neoantigen peptides induced NRT cell response. 50% of the patients had neoantigen-specific immune response.

[165]

NCT01970358

2017

melanoma

IIIB/C, IVM1a/b

I

8 (6 vaccinated)

NeoVax + ICIs

ICI: pembrolizumab

peptides + poly-ICLC

CR: 2; SD: 6; PD: 2; PFS: 25 M;

47% of the neoantigen peptide pools induced NRT cell response. 20% of the neoantigen peptides induced CD4 + T cell response. The proportion of neoantigen stimulation was higher in MHC class II than in MHC class I.

[22]

NCT02897765

2020

melanoma, NSCLC, and TCC

III/IV

82(60 vaccinated)

NeoVax + ICIs

NeoVax: Neo-PV-01,ICI: Nivolumab

peptides + poly-ICLC

PFS (median): 23.5 M (melanoma), 8.5 M (NSCLC); 5.8 M (TCC). OS(1Y): 96% (melanoma),  83% (NSCLC), 67% (TCC)

52% of the neoantigen peptides induced NRT cell response in melanoma patients, 47% in NSCLC and 52% in bladder cancer patients. The average proportion of the immune response induced by neoantigen were 42% in CD4 + T cells and 24% in CD8 + T cells.

[24]

NCT01807182

2018

melanoma

III-IV

II

1

TIL

BRAF^V600E

CR

Neoantigen peptides only stimulated CD4 + T cell response.

[166]

NCT02278887

2020

melanoma

IIIc/IV

I

10

TIL

CR: 2; PR: 3; SD: 1; PD: 4

NRT cells can be detected in 66.7% of the patients with TIL infusion; The frequency of NRT cells responses peaked between 3 and 9 months.

[167]

NCT00937625

2021

melanoma

advanced

I

26

TIL

CR: 5; PR: 6; SD: 10; PD: 5

NRT cells can be detected in 69.2% of the patients with TIL infusion; 3.4% of the neoantigen peptides in TIL or peripheral blood induced NRT cell response. The median proportion of CD8 + T NRT cells was 0.63%.

[168]

NCT03215810

2020

NSCLC

IV

I

20(16 vaccinated)

TIL + ICIs

ICI: nivolumab

CR: 2; PR: 2; SD: 2; PD: 1

72.2% of the patients had neoantigen-specific immune response.

The majority of TILs were terminally differentiated and only small subsets were in the stem-like state.

[169]

NCT00683670

2013

melanoma

IV

I

7

Neo-DCVac

CR: 1; PR: 2; PD: 4

DC vaccine augmented NRT cell response and broadened neoantigen-reactive TCR repertoire. Only three neoantigens with the highest binding affinity can induce NRT cell response in each patient.

[170, 171]

NCT02956551

2020

lung cancer

IIIc/IV

I

18(12 vaccinated)

Neo-DCVac

SD: 9; PD: 3; PFS(median): 5.5 M; OS(median):7.9 M

Nearly 62% of the neoantigen peptides induced NRT cell response on average. The percentage of CD8 + NRT cells was 21.69% and that of CD4 + NRT cells was 43.72% on average.

[172]

NCT01132014

2017

ovarian cancer

IIIb-IV

I

25

Neo-DCVac + ICIs

ICI: bevacizumab

DC pulsed with oxidized autologous whole-tumor cell lysate

SD: 16; PD: 9; PFS(24 months): 25; OS(2Y, responder): 100%, OS(2Y,no responder): 25%;

Six patients who received DC vaccine generated NRT cells targeting at least one neoantigen. CD8 + NRT cells induced by DC vaccine were polyfunctional.

[173]

NCT02108652

2014

UBC

IV

II

24

ICI

Atezolizumab

Early-stage NART expansion and activation are associated with response to ICB.

Increased NRT cell response can be observed between pre-treatment to three weeks post-treatment of ICI. The phenotypes of NRT cells with PD1 + Ki67 + effector and increased CD39 levels showed positively relevant to clinical response.

[174]

NCT01903993

2019

NSCLC

IIIb-IV

II

14

ICI

Atezolizumab

Neoantigen-specific T cells phenotype change: differentiated effector phenotype, memory-like phenotypic (PD).

Patients who responded to ICI therapy showed increased frequency of NRT cells and differentiated effector phenotype of T cells.

[175]