Harnessing DNA-induced immune responses for improving cancer vaccines

Figures & data

Figure 1. Signaling pathways of innate immunity involved in DNA-sensing. DNA can be recognized by different sensors, including TLR9, DAI, AIM2, IFI16 and LRRFIP1. As result of downstream signaling, NF-κB and IRF transcription factors become activated to promote the expression of different proinflammatory cytokines, and IFN-α/β.

Table 1. DNA vaccination clinical trials targeting cancer

Tumor	Target	Site of administration	Device	DNA dose	Treatment dose	Immunological Response	NCT Listing
Melanoma	Tyrosinase	IM + EP	TriGrid Delivery System	N.D.	5 doses	N.D.	NCT00471133
	Tyrosinase	IM	N.D	0.5, 2.0, 4.0, 8.0 mg	6 doses	N.D.	NCT00680589
	gp100	IM or PMED	Biojector2000 or PowderMed	1 mg (IM) or 0.002 mg (PMED)	16 doses	5/27 CD8+ tetramer+ response, PMED shows trend to increased CD8+ IFN-γ generation (Ginsberg et al., 2010)	NCT00398073
	gp100	IM	Biojector2000	0.1, 0.5, 1.5 mg	6 doses	5/19 CD8+ tetramer+ response	NCT00104845
						(Yuan et al., 2009)
	Tyrosinase	IM	Biojector2000	0.1, 0.5, 1.5 mg	6 doses	7/18 CD8+ tetramer+ response	NCT00698100
						(Wolchok et al., 2007)
Cervical Intraepithelial Neoplasia	HPV16/18 E6/E7	IM + EP	Cellectra	0.6, 2.0, 6.0 mg	3 doses	N.D.	NCT00685412
	HPV16 E7	ID or IM or IL	GeneGun	0.008 or 0.016 mg (ID), 1 or 3 mg (IM), 1 or 3 mg (IL)	4 doses	N.D.	NCT00988559
	HPV16 E7	IM	N.D.	0.5, 1.0, 3.0 mg	3 doses	No Vaccine induced antibodies,
						5/9 IFN-γ Elispot (Trimble et al., 2009)
Prostate Cancer	PSA	ID + EP	DermaVAX	0.05, 0.15, 0.4, 1.0 mg	5 doses	N.D.	NCT00859729
	PSMA	IM + EP	Elgen Twinjector	0.8, 1.6, 3.2 mg	3 doses	16/32 PSMA specific CD8+ response, 21/32 vaccine induced antibodies, trend to improved clinical outcome (Chudley et al., 2012)
	PAP	ID	N.D.	0.1, 0.5, 1.5 mg	6 doses	3/22 CD8 antigen specific IFNg	NCT00582140
						(McNeel et al., 2009)
	PSA	ID + IM	N.D.	0.1, 0.3, 0.9 mg	5 doses	PSA specific antibodies, 2/9 IFN gamma response to PSA (Pavlenko et al., 2004)
Ovarian and Breast Cancer	Her-2/Neu	ID	N.D.	0.01, 0.1 mg	3 doses	13/21 Her2 specific Tcell response	NCT00436254
						J Clin Oncol 27:15s, 2009 (suppl; abstr 3054)
	Her-2/Neu	IM + IC	N.D.	0.03 (IC) and 0.27 (IM)	3 doses	Measurable T cell response, increased Her-2 specific binding antibodies
						(Norell et al., 2010)
Hematological Malignancy	WT1	IM + EP	N.D.	1 mg	6 x 4 doses	N.D.	NCT01334060
	Idiotype	IM + ID	Biojector	0.2, 0.6, 1.8 mg	3 doses	8/12 T-cell or Antibody specific response to MsIG(Timmerman et al., 2002)

IM, intramuscular; ID, intradermal; IL, intralesional; IC, intracutaneous; EP, electroporation; N.D., not described; PMED, particle-mediated epidermal delivery; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; PAP, prostatic acid phosphatase.

Figure 2. Genetic adjuvants for enhancing the potency of DNA vaccines against cancer: Overexpression vs. silencing. Genetic (DNA-encoded) adjuvants used for DNA vaccines can be designed to either overexpress immune-stimulatory molecules (left side of the scale), or downregulate the gene expression of inhibitory molecules (right side of the scale).