Immunological inhibition of carcinogenesis

Abstract

The combination of new information provided by fundamental immunology, along with the refinement of genetic engineering techniques has given scientists the capacity to produce vaccines able to inhibit the growth of most if not every transplantable tumor. However, when faced with already established tumors, vaccines fail to afford any significant protection. Many studies are underway which seek to overcome this gloomy situation. However, another possibility is to follow the indications provided by a large quantity of experimental data and to evaluate the possibility of using immunotherapy to prevent the initial stages of tumor growth. Is it possible to prevent an autologous tumor by means of a vaccination performed before tumor onset? Could antitumor vaccines be a new form of preventive medicine in the wake of Jenner, Pasteur, and other pioneers? In this paper it is our intention to review the results obtained by our laboratory in the attempt to use natural and adaptive immunity in the control of carcinogenesis. Natural immunity boosted by IL-12 and IL-2 significantly hampers the progression of mammary lesions occurring in HER-2/neu transgenic mice genetically predestined to develop lethal mammary carcinomas. Specific immunity elicited by DNA vaccination provides a much stronger inhibition of the development of mammary lesions, and a significant number of transgenic mice are tumor free at 1 year of age. These experimental data suggest the possibility of using immunity as a means of controlling preneoplastic lesions and protecting healthy persons at risk of developing cancer.

Fig. 1

Genetic instability and clonal heterogeneity limit the curative potential of a vaccine. Therapeutic vaccination deals with a typically Darwinian selection and competition between the distinct clones and the elicited immune response

Fig. 2

Interpretation of a few of the main events leading to rIL-12–provoked tumor inhibition in vivo. The three major cell populations involved are underlined. A few of the factors whose activity has been established are italicized. Arrows suggest causal and temporal relationships (Reproduced with permission from [15])

Fig. 3

Liposomes composed of cationic lipid (DOTMA) and cholesterol at a 1:1 mole ratio were prepared at a 1:3 −/+ charge ratio in 10% (w/v) lactose by mixing the IL-2 cDNA plasmid under controlled conditions

Fig. 4

BALB-neuT mice were vaccinated with different plasmids, coding for various portions of the rat p185neu protein. All cDNA were cloned into a pcDNA3 vector. The most effective plasmid was the one coding for the ECD-TM domain of rat p185neu. The plasmids coding for the full length and ECD plus IL-1β were less effective, while the ECD alone was the least effective

Fig. 5

Inhibition of mammary carcinogenesis in BALB-neuT mice at 33 weeks of age. Mice are vaccinated intramuscularly at the 4th and the 7th week with 100 μg of pcDNA3 or ECD-TM plasmid. Percentages of tumor-free mice are calculated as the cumulative number of incident tumors / total number of mice

Fig. 6

Longer protection by DNA vaccination and mLAG-3Ig. BALB-neuT mice were immunized with 100-μg ECD-TM plasmid alone or in association with 20 μg of mLAG-3Ig. At 52 weeks of age, 20% of mice vaccinated with ECD-TM and about 80% of those with ECD-TM + mLAG-3Ig are tumor free

Fig. 7

The T820 electroporator was used to improve DNA uptake. Two minutes after DNA injection, we covered the legs of the anesthetized mouse with a conductive gel, and then applied electrodes at the end of the caliper to the leg muscle. We used two electric pulses of 25 ms each and at an intensity of 375 V/cm

Fig. 8

Sera of BALB-neuT–vaccinated mice have specific anti-p185neu antibodies able to down-regulate rat p185neu from the membrane of TUBO cells. When TUBO cells are incubated with Abs specific for p185neu at 37°C the receptor is internalized while at 4°C the down-regulation is blocked, as indicated by confocal microscopy studies. Their activity appears to be similar to that of passively administered anti-rat p185neu monoclonal antibodies