Immunologic special forces: anti-pathogen cytotoxic T-lymphocyte immunotherapy following hematopoietic stem cell transplantation

Figures & data

Figure 1 Current Good Manufacturing Practice-compliant approaches for generation of antipathogen CTL products.

Notes: Cell selection utilizes either multimers displaying a pathogen-derived peptide in the setting of a type I human leukocyte antigen molecule, or column selection utilizing ex vivo stimulation of T-cells with antigens followed by selection of interferon-gamma or CD154-expressing T-cells via antibody-coated immunomagnetic beads. Ex vivo cell culture utilizes stimulation of T-cells by antigen-displaying antigen-presenting cells, which can be produced via antigenic peptide pools, viral transduction, or nucleofection. A rapid protocol can produce cytotoxic T-lymphocytes in 10–12 days from virus-seropositive donors after a single stimulation, whereas production of cytotoxic T-lymphocytes derived from cord blood requires three stimulations over a minimum of 28 days.
Abbreviations: CTL, cytotoxic T-lymphocyte; IFN, interferon.

Table 1 Previous clinical trials of pathogen-specific T-cell therapy

Strategy	Study	Pathogen specificity	Donor	Methodology	Patient accrual	Centers (n)	Advantages/disadvantages
Cell selection	Cobbold et al^Citation38	CMV	HSCT donor or third-party	Tetramer selection	9	1	Advantages Rapid development
	Feuchtinger et al^Citation39	CMV	HSCT donor or third-party	Interferon-gamma column selection	18	1	Uses existing GMP compliant technology
	Peggs et al^Citation40	CMV	HSCT donor	Interferon-gamma column selection	18	1
	Schmitt et al^Citation25	CMV	HSCT donor	Reversible Streptamer selection	2	1	Disadvantages Limited repertoire with multimer use (low cell yield)
	Feuchtinger et al^Citation41	Adv	HSCT donor	Interferon-gamma column selection	9	1
	Uhlin et al^Citation42	EBV	Related haploidentical donor	Multimer selection	1	1	Requires presence of pathogen-specific memory T-cells
	Moosman et al^Citation43	EBV	HSCT donor	Interferon-gamma column selection	6	1
	Qasim et al^Citation54	Adv	Third party	Interferon-gamma column selection	1	1
	Uhlin et al^Citation52	CMV/EBV/Adv	HSCT donor or third-party	Pentamer selection	8	1
Cell culture	Perruccio et al^Citation69	CMV or Aspergillus	HSCT donor	Stimulation of PBMC with CMV antigen or inactivated conidia	10	1	Advantages Yields large number of polyclonal CTL
	Leen et al^Citation17	CMV/EBV/Adv	HSCT donor	Ad5f35pp65 transduced LCL	26	3	Allows CTL development from pathogen-naïve donors
	Micklethwaite et al^Citation45	CMV/Adv	HSCT donor	Ad5f35pp65 transduced DC	12	1
	Leen et al^Citation44	EBV/Adv	HSCT donor	Ad5f35 null transduced LCL	13	3
	Barker et al^Citation50	EBV	Third-party donor	EBV-LCL stimulation	2	1	Disadvantages Time-intensive (2–5 weeks)
	Rooney et al 2010^Citation31	EBV	HSCT donor	Irradiated EBV-LCL	114	3
	Balduzzi et al^Citation55	JCV	HSCT donor	Pepmix-pulsed PBMC	1	1
	Leen et al^Citation51	CMV/EBV/Adv	Third-party donor	Ad5f35pp65 transduced LCL	47	8	Regulatory requirements for GMP culturing
	Gerdemann et al 2013^Citation72	CMV/EBV/Adv	HSCT donor	Nucleofection of DCs	12	2
	Blythe et al 2013^Citation46	CMV or CMV/Adv	HSCT donor	NLV-peptide pulsing or Ad5f35pp65 transduction of DCs	50	2

Abbreviations: Adv, adenovirus; CMV, cytomegalovirus; CTL, cytotoxic T-lymphocyte; DC, dendritic cells; EBV, Epstein Barr virus; GMP, Good Manufacturing Practice; LCL, lymphoblastoid cell lines; HSCT, hematopoietic stem cell transplantation; PBMCs, peripheral blood mononuclear cells; JCV, John Cunningham virus.

Table 2 Preclinical studies of novel antipathogen T-cell therapies

Study	Pathogen specificity	Donor	Methodology
Beck et al^Citation64	Aspergillus	Healthy donors	Interferon-gamma selection after stimluation of PBMCs with Aspergillus extracts
Khanna et al^Citation66	Aspergillus, Candida, Rhinopus	Healthy donors	CD154 selection after stimulation of PBMCs with fungal extracts
Gerdemann et al^Citation34	CMV/EBV/Adv/HHV6/RSV/BK/influenza	Healthy donors	Nucleofection or Pepmix stimulation of DCs
Ramos et al^Citation56	HPV13	Cervical or nasopharyngeal cancer patients	Pepmix stimulation of DCs
Tramsen et al^Citation65	Aspergillus, Candida, Rhinopus	Healthy donors	Interferon-gamma selection after stimluation of PBMCs with fungal extracts

Abbreviations: Adv, adenovirus; CMV, cytomegalovirus; DCs, dendritic cells; EBV, Epstein Barr virus; PBMCs, peripheral blood mononuclear cells; HHV, human herpesvirus 6; HPV, human papillomavirus; RSV, respiratory syncytial virus.

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