Medical Grand Rounds

Bench-to-bedside challenges in developing immune protection against breast cancer

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ABSTRACTDespite the success of childhood vaccination against infectious diseases, vaccines are lacking against diseases that occur with age. We are developing a vaccine to prevent breast cancer. This article explains the vaccine strategy, how we think the vaccine will work, and how we plan to move forward through clinical trials.

KEY POINTS

  • “Retired” tissue-specific self proteins may substitute for unavailable pathogens as vaccine targets for mediating immune prevention of adult-onset cancers.
  • Vaccination against the retired breast-specific protein alpha-lactalbumin provides safe and effective immune protection against the development of breast tumors in several mouse models.
  • Alpha-lactalbumin is overexpressed in most human triple-negative breast cancers (TNBC), the most aggressive and lethal form of human breast cancer.
  • Forthcoming are clinical trials designed to prevent the initiation of TNBC in otherwise healthy cancer-free women, as well as trials designed to prevent recurrence of TNBC in women already diagnosed with this disease.


 

References

The most proven, effective way to control disease is through prophylactic vaccination. The childhood vaccination program is a testament to this disease prevention approach, and in its current form protects us from diseases caused by 16 different pathogens.1

Childhood immunization ends in the teen years with recommended vaccination against multiple strains of human papillomavirus that are associated with several cancers, most notably cervical carcinoma.2 However, even though we have known for over 30 years that the immune system can provide considerable vaccine-induced protection against the development of cancer,3 we have not produced any vaccines that prevent cancers that commonly occur with age, such as breast and prostate cancer, which afflict 1 of 8 women and 1 of 6 men, respectively.4,5

The lack of an adult vaccine program that provides protection against such commonly occurring adult-onset cancers represents a glaring health care deficiency and a challenge for this current generation to protect coming generations.

THE ‘RETIRED’ PROTEIN HYPOTHESIS

Given that most cancers are not associated with any disease-inducing pathogens, at what targets can we aim our immune system to induce safe and effective protection against these commonly occurring adult-onset cancers?

Perhaps an understanding of the natural aging process may provide us with insights regarding possible vaccine targets. As we age, there is a decline in expression of many tissue-specific proteins, often to the point where they may be considered “retired” and no longer found at detectable or immunogenic levels in normal cells. Examples of this natural aging process include the pigment proteins as our hair whitens, certain lactation proteins when breastfeeding ceases, and some ovarian proteins as menopause begins and production of mature egg follicles ceases. If these retired proteins are expressed in invigorated emerging tumors, then preemptive immunity directed against these retired proteins would attack and destroy the emerging tumors and ignore normal tissues, thereby avoiding any complicating collateral autoimmune damage.

Thus, we propose that retired tissue-specific self-proteins may substitute for unavailable pathogens as targets for mediating safe and effective immune protection against adult-onset cancers such as breast cancer.

SAFE AND EFFECTIVE PREVENTION OF BREAST CANCER IN MICE

To test this retired-protein hypothesis for immunoprevention of breast cancer, we selected alpha-lactalbumin as our vaccine target, for two reasons:

  • Alpha-lactalbumin is a protein expressed exclusively in lactating breast tissue and is not expressed at immunogenic levels in either normal nonlactating breast tissues or in any of 78 other normal human tissues examined.6–8
  • Alpha-lactalbumin is expressed in most human triple-negative breast cancers (TNBC),9,10 the most aggressive and lethal form of breast cancer, and the predominant form that occurs in women with mutations in the breast cancer 1, early-onset gene (BRCA1).11,12

We found that alpha-lactalbumin vaccination consistently inhibited the formation and growth of breast tumors in three different mouse models commonly used in breast cancer research.13 More importantly, the observed immune protection against the development of breast cancer in mice occurred in the absence of any detectable autoimmune inflammatory damage in any normal tissues examined. Thus, we concluded that alpha-lactalbumin vaccination could provide healthy women with safe and effective immune protection against the more malignant forms of breast cancer.

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