The potential applications of T cell receptor (TCR)-like antibody in cervical cancer immunotherapy

Figures & data

Figure 1. The virion and genome map of human papillomavirus (HPV). (Adapted from (Robboy et al.).⁸

Table 1. Monoclonal antibodies under clinical trial investigation for cervical cancer therapeutics

Antibody	Combination therapy	Mechanism	Status	Reference
Bevacizumab	Chemotherapy Cisplatin + paclitaxel Topotecan + paclitaxel	VEGF inhibitor	Phase-III trial	[19]
Nimotuzumab	Radiochemotherapy	EGFR inhibitor	Phase-II trial	[102]
	ChemotherapyCisplatin + paclitaxelRadiotherapy			[103]
Cetuximab (Chimeric antibody)	Chemotherapy (Cisplatin)	EGFR inhibitor	Phase-II trial	[104]
Tisotumab vedotin (Antibody-drug conjugate)	Monotherapy	Angiogenesis inhibitor (Tissue factor (TF) activatated factor VII inhibitor and TF-expressing cell cytotoxicity)	PhaseI/II	[105]
Ipilimumab	Chemotherapy (Cisplatin)Radiotherapy	Programmed cell death 1 (PD-1) checkpoint inhibitor	Phase I/II	[106]
Nivolumab	Monotherapy1^st treatment:Radio-chemotherapy (Cisplatin)2^nd treatment:Chemotherapy (Carboplatin + paclitaxel) and bevacizumab3^rd treatment:Nivolumab	PD-1 inhibitor	Phase I/IICase report	[107]
Cemiplimab	Monotherapy or with Hypofractionated radiotherapy (hfRT)	PD-1 inhibitor	Phase IPhase III(Ongoing)(NCT03257267)	[108]
	Monotherapy or with Radiotherapy and/or Chemotherapy (Cyclophosphamide)		Phase I	[109]
Avelumab	Platinum-based chemotherapy (Prior to antibody administration) and Axitinib (tyrosine kinase inhibitor)	PD-1 inhibitor	Phase I(Ongoing)(NCT03826589)	[110]
Durvalumab	Chemotherapy (Cisplatin + carboplatin) Radiation (External beam radiation therapy (EBRT) + brachytherapy)	PD-L1 inhibitor	Phase III(Ongoing)(NCT03830866)	[111]
Atezolizumab	MonotherapyTiragolumab(TIGIT inhibitor)	PD-L1Inhibitor	Phase II (Ongoing) (NCT04300647	[112]
	Bevacizumab		Phase II (Ongoing) (NCT02921269)	[113]
	Platinum chemotherapy (Paclitaxel) + Bevacizumab		Phase III (Ongoing) (NCT03556839)	[114]

Table 2. Current adoptive cell therapy (ACT) under investigation for cervical cancer treatment

Type of therapy	Component	Mechanism	Limitations	Current status	Ref
Adoptive T cell therapy	Tumor infiltering lymphocyte (TIL)CD4^+, CD8^+, Treg cells	T cell response specific for HPV 16 and HPV 18 E6, E7 was determined by systemic tumor focused immunity.	N/A	Absence of metastases in lymph node indicates good progress in cervical cancer treatment.CD8^+ infiltration showed better prognosis.	[115]
ATC	TIL(LN-145) that undergone clonal expansion ex vivo.	N/A	LN-145 is very much polyclonal.Difficult to determine a single T cell that is highly specific.	N/A	[116]
ATC	TIL	N/A	N/A	Clinical trial C-145-04 testing LN-145, TIL against metastatic, recurrent and advanced cervical cancer.	[117]

Figure 2. Overview of T cell receptor (TCR)-like antibody applications in cervical cancer immunotherapy. (a) TCR-like antibody-dependent cell cytotoxicity (ADCC); (b) Complement-dependent cytotoxicity (CDC) mediated by TCR-like antibody; (c) TCR-like antibody-dependent cellular phagocytosis (ADCP); (d) Induction of tumor cell apoptosis by TCR-like antibody; (e) TCR-like antibody-based CAR for tumor cell lysis by T cells; (f) TCR-like antibody conjugated with drug/toxin (Immunotoxin)

Table 3. List of generated TCR-like antibodies developed for therapeutic purpose

TCR-like Antibody Clone	HLA Allele	Epitope Sequence	Target	Antigen	Reference for gene expression in cervical cancer	Research Approach		Reference
2A5-MMAE2E8-MMAE	HLA-A*0201	KLVVVGAVGV (G12V)KLVVVGADGV (G12D)	Cancer	KRAS G12V and G12D oncogene	[118,119]	TCR-like antibody-drug conjugatesIn vitro and In vivo	[120]
D10 scFv D10 MANAbody	HLA-A2	KLVVVGAVGV (G12V)	Cancer	KRAS oncogene	[118,119]	In vitro CDC	[121]
#21-3	HLA-A*24	AYACNTSTL (SV2B80-88)	Cancer	Survivin-2B (Tumor-associated antigen)	[122]	Hybridoma technologyIn vitro cytotoxicity	[70]
Clone 38 Clone 38–2	HLA-A*0201	C426LGGLLTMV434	CancerEBV Malignancies	LMP2A	[123]	(DiBsAb) In vitro and In vivo	[124]
3M4E5 FabHyb3.3 FabESK-1 Fab	HLA-A*0201HLA-A*0101	SLLMWITQCEADPTGHSY (A1-EAD) and EVDPIGHLY (A1-EVD)	Cancer	NY-ESO-1157–165MAGE-A1161–169/MAGE3-A3168–176	[125]	BioinformaticsIn vitro	[126]
P1C1TM	HLA-A2402	P53125-134	Cancer	Mutant p53	[127]	In vitro and In vivoADCCTCR-like antibody drug conjugate (pHrodo Red)	[128]
AH5	HLA-A2	ELEYRQVPV	Cancer	MAGE-A antigen	[125]	In vitro	[129]
3F91B10	HLA-A201	TMT(40–48)GVL (47–55)	Cancer	hCGbeta	[130]	In vitro (Vaccine potency)	[131]
Foxp3-#32	HLA-A201	TLIRWAILEA	Cancer	Foxp3	[132]	In vitro	[133]
Pr20M	HLA-A201	ALYVDSLFFL	Cancer	PRAME	[78]	In vitro and In vivo	[134]

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