Primary Immunoprevention: The Great Unmet Need for Controlling Breast Cancer

May 15, 2016

Perhaps we can now hope that primary immunoprevention of cancers that are engaged as people age may receive the attention, support, and legitimacy that will soon result in similar breakthrough stature.

Since their inception in the late 18th century, vaccines have been used predominantly as prophylactic agents, and their greatest clinical benefit has been in preventing diseases caused by pathogens.[1,2] In fact, when used as treatment after symptoms manifest, traditional pathogen-targeted vaccines fail to enhance pathogen clearance or alleviate disease activity.[3] Thus, it appears safe to say that vaccines work best when providing pre-emptive immunity.

Despite the fact that the effectiveness of vaccines for disease prevention has been repeatedly proven, cancer vaccines have been used predominantly as treatment agents administered after the emergence of established growing tumors. The notable exceptions to the dominance of the treatment paradigm for cancer vaccination seem confined to cancers such as those in the liver and cervix that are caused by pathogens.[4,5]

Breast cancer vaccination is particularly dominated by this treatment paradigm in that vaccine researchers use the word “prevention” almost exclusively “…to avoid or defer the complications of diseases after they have developed…,”[6] and apply such tertiary prevention strategies to prevent recurrence or invasiveness of pre-existing breast tumors. Despite the need for such tertiary prevention strategies, one could argue that the greatest unmet need for controlling breast cancer is the development of a vaccine that provides primary prevention of breast tumor growth for healthy, tumor-free women.

It is a matter of speculation as to why primary immunoprevention is not a high priority for control of breast cancer, but there is no doubt about its nonpriority status as reflected by the established funding structure that clearly favors cancer treatment over cancer prevention. The most recent available fiscal data from the National Cancer Institute indicate that actual spending for treatment research was 3.4 times greater than spending for cancer prevention.[7] Even though primary immunoprevention for breast cancer often fails to get the funding support that its potential impact may command, it is still an active area of investigation involving a handful of diehard enthusiasts, so perhaps a brief overview of actively pursued approaches may be in order here.

Human mammary tumor viruses (HMTV) have been proposed as potential targets for inducing primary immunoprevention of breast cancer, and perhaps the most studied variant of HMTV is a nongenomic infectious retrovirus that has > 95% homology with the oncogenic mouse mammary tumor virus and is detected in about 38% of human breast tumor tissues.[8,9] The endogenous retrovirus type K (HERV-K) family members whose envelope proteins are expressed on the surface of human breast cancer cells may also serve as potential vaccine targets for primary prevention.[10] As suggested by Salmons et al in 2013,[11] resolution of a possible viral role in human breast cancer tumorigenesis awaits definitive studies showing viral-induced malignant transformation and tumor formation in vivo.

Given the current uncertainty implicating a definitive oncogenic virus for human breast cancer, what nonpathogenic proteins can substitute as vaccine targets for developing primary immunoprevention of breast cancer? To this end, Dr. Olivera Finn has pioneered the concept of vaccinating against immunologically available primary peptide sequences of MUC1, a protein expressed with a low level of glycosylation in many human tumors and also expressed ubiquitously in many normal tissues but at heavily glycosylated levels that preclude immunologic availability.[12] Tiriveedhi and colleagues have proposed vaccination against mammaglobin A expressed in the majority of human estrogen receptor–positive breast tumors, as well as in a small handful of normal tissues.[13] Several investigators have proposed vaccination against human epidermal growth factor receptor 2 (HER2) and a variety of other similar ubiquitously found proteins that are expressed at high levels in some breast tumors, but are presumably expressed at low nonimmunogenic levels in many normal tissues.[14] Dr. Stephen Johnston has proposed vaccination against a finite number of immunogenic frameshift neoantigens suspected to be broadly expressed in most human breast tumors.[15,16] We have proposed that tissue-specific self-proteins that are “retired” from expression in normal tissues as we age, but are expressed in emerging tumors, may substitute as vaccine targets for unavailable pathogens for primary immunoprevention of breast cancer.[17] To this end, we have identified α-lactalbumin as a retired breast-specific self-protein not expressed at immunogenic levels in any normal tissues with age, but expressed in the majority of triple-negative breast cancers (TNBCs), the most aggressive form of breast cancer and the most predominant form occurring in women with BRCA1 mutations who have high genetic risk and thus the greatest need for a preventive vaccine.[18,19]

Each of these approaches for primary immunoprevention of breast cancer has strengths and weaknesses, and it is far from clear at this early point which of these proposed approaches will prove to be most successful in providing safe and effective pre-emptive immunity and protection against the development of breast cancer. However, it may be worth considering several issues as these different approaches proceed through clinical testing. First, breast cancer is clearly a complex disease involving many subtypes,[20] and this complexity may predispose to a need for a multivalent preventive vaccine against sufficient targets expressed in the known multitude of different breast cancer variants. For example, one vaccine target may be effective in preventing estrogen receptor–positive breast cancer (eg, mammaglobin A), whereas another may be useful in preventing TNBC (eg, α-lactalbumin). A single vaccine that incorporates multiple targets may be necessary to control a broader array of breast cancer subtypes, as indicated by Shen et al in their common pooled neoantigen strategy.[16]

In addition, it is difficult to ignore the substantial emphasis on vaccinating against HER2 and other self-proteins that are ubiquitously expressed in numerous normal tissues. The immune response elicited to such globally expressed self-proteins is often subdominant or cryptic because of efficient self-reactive T-cell repertoire deletion, resulting in a predominance of low-affinity T cells incapable of targeting clinically relevant immune responses. Nevertheless, this excessive focus on HER2 and related systemically expressed self-proteins persists in the field of breast cancer vaccination, along with the common use of vaccine adjuvants that generate a predominant type 1 T helper (Th1)-like immunity that precludes the incorporation of the robust proinflammatory features of Th17 and Th9 responsiveness implicated in optimized tissue destruction in response to self-proteins.[21,22]

Finally, it remains unexplained in the Mittendorf et al review in this issue of ONCOLOGY[23] how a vaccine targeted against HER2 could be most effective against HER2-negative breast tumors. Indeed, our own direct experience indicates that increased T-cell infiltration and enhanced tissue destruction occurs when tissues express high levels of immune-targeted self-proteins.[24] In any event, cancer immunotherapy has come a long way, having been recognized for breakthrough status by the editors of Science in 2013.[25] Perhaps we can now hope that primary immunoprevention of cancers that are engaged as people age may receive the attention, support, and legitimacy that will soon result in similar breakthrough stature.

Financial Disclosure:Dr. Tuohy is the primary inventor with intellectual property related to α-lactalbumin vaccination. He has licensed his inventions to Shield Biotech, Inc, for the purpose of commercialization and stands to benefit financially if these inventions are tested successfully in clinical trials. Shield Biotech, Inc, had no role in the writing or decision to publish this commentary.


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