Reengineering dendritic cell-based anti-cancer vaccines

Despite initial enthusiasm, dendritic cell (DC)-based anticancer vaccines have yet to live up to their promise as one of the best hopes for generating effective anti-tumor immunity. One of the principal reasons for the generally disappointing results achieved thus far could be that the full potential of DCs has not been effectively exploited.

Here, we argue that dramatic improvements in vaccine efficacy will probably require a careful re-evaluation of current vaccine design. The formulation of new strategies must take into account the natural history of DCs, particularly their role in helping the immune system deal with infection. Equally critical is the emerging importance of soluble factors, notably interleukin-12, in modulating the quality of immune responses.

Vaccines should also be designed to recruit helper T cells and antibody-producing Bcells rather than simply cytotoxic T lymphocytes. Finally, the judicious selection of tumor, target antigen, and disease stage best suited for treatment should serve as the foundation of trial designs. Our discussion addresses a recent clinical vaccine trial to treat early breast cancer, where many elements of this new strategy were put into practice.

Combining Innate Immunity With Radiation Therapy for Cancer Treatment

The widely shared goal of cancer immunotherapy is to stimulate an immune response of sufficient quality and magnitude to destroy primary malignancies and their metastases. Cancer immunotherapy has taken many cues from the development of successful antimicrobial vaccines.

Antimicrobial vaccines rely on the immune system’s capacity to distinguish self-tissues from infectious non-self so that invading pathogens, and the cells they might infect, could be efficiently identified and eliminated, while sparing healthy tissues. The process of discriminating self from infectious non-self is facilitated by the millions (and in some cases billions) of years of evolutionary divergence that separates vertebrates from the pathogens that infect them.

This separation has given rise to individual proteins and other generalized molecular structures that serve to distinguish microbes from men. In theory, malignant cells that express protein antigens that either are unique to the tumor, vastly over-expressed by the tumor, or whose expression is at least restricted to a narrow range of self-tissues provides a potential immunologic handle whereby tumors may be specifically recognized and destroyed.

In practice, however, it has proven unexpectedly difficult to coax the immune system into vigorously rejecting malignancies, despite repeated demonstrations that tumor-associated antigens can provoke immune responses. In this issue of Clinical Cancer Research, Mason et al. (1) shows, using a murine subcutaneous and lung metastasis sarcomatreatment model, that synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs (characteristic of bacterial DNA) could be given with conventional radiation therapy to greatly augment therapeutic efficacy through an apparent immune-mediated.

A Novel Dendritic Cell-Based Immunization

The immune system has traditionally been divided into two parts; the innate and the adaptive. The innate immune system’s components include monocytes, macrophages, granulocytes, NK and dendritic cells (DC). The adaptive immune system is composed of antibody-producing B lymphocytes, as well as CD4pos helper T cells and CD8pos cytotoxic T cells. These cells work together to sense, control and eliminate infection. Agents of innate immunity identify microbes through special pattern recognition receptors that sense biochemical structures (usually non-proteins) common to broad classes of potential pathogens

(1). On the other hand, T and B lymphocytes specialize in responding against antigens (usually proteins) specific to the individual species of microbe. DCs have a unique role in that they form a critical bridge between innate and adaptive immunity. Pattern recognition proteins belonging to the Toll-like family of transmembrane receptors (2) induce a maturation and migration program whereby various DC populations, including monocytederived DCs, convey peripherally-acquired proteins to T cells located in the regional draining lymph nodes (3).

The DCs “present” the microbial antigens to T cells in the form of processed peptides complexed with self major histocompatibility proteins (4). This supplies an important signal (signal 1) to T cells that, along with maturation-enhanced co-stimulatory molecule (CD80, CD86) expression (signal 2), can fully activate T cells (5). DCs and some other accessory cells can supply so-called “third signals” (6) that often are expressed in the form of soluble factors, for example, IL-12, IL-23, IL-6 and TGF-beta. Such signals can profoundly influence helper T cell development toward discrete functional phenotypes that include IFN-γ-secreting Th1, IL-17- secreting Th17, as well as anti-inflammatory Treg that produce TGF-beta and IL-10 (7–10).

In many instances, the precise combination of activation signals received by DC dictates whether individual 3rd signal agents will be produced, and hence which Th phenotypes will be selectively induced by the DC (11). Although the immune system evolved primarily to deal with infections, it may be possible to direct it against malignancies. An ideal strategy for inducing anti-tumor immunity must successfully accomplish several goals-some of which are overlapping with traditional antimicrobial vaccines, but others unique to the particular requirements of effective anti-tumor immunity. For example, an effective anti-tumor vaccine must overcome the immune system’s natural tendency to resist the development of strong immunity against self-proteins (i.e. tolerance).

It must also generate immunity of a quality and intensity likely to reduce or eliminate tumor burdens. In the case of therapeutic vaccines, immunity must be effectively induced when disease is already firmly established. Finally, such induced immunity should be durable, so that possible tumor recurrences can be suppressed for long per periods postimmunization.

Extracellular ATP and Toll-Like Receptor

Dendritic cells (DC) are the most potent known antigenpresenting cells and are primarily responsible for sensitizing naıve T cells to antigen. DC activate T cells by supplying antigenic (signal 1) and co-stimulatory (signal 2) signals as well as an additional set of ‘‘third signals’’ that can profoundly affect T cell function [1].

For example, if the cytokine interleukin-12 (IL-12) is present during Th sensitization it is likely that Th1 polarization will occur, resulting in T cells that produce high levels of IFN-c and correspondingly less (or no) IL-4 and IL-5 [2]. Such cells can be highly effective for dealing with some intracellular parasites [3].On the other hand, the cytokines IL-23, IL-6, TGF-b and IL-1b have each been implicated by various groups [4–9] in promoting the development of IL-17-producing Th17 cells.

These Th17 cells appear highly effective against extracellular bacteria, particularly those that colonize mucosal surfaces [10], and have also been implicated in chronic inflammatory pathology associated with some autoimmune diseases [11,12]. Additional cytokines contribute to the development of other key Th phenotypes including Th2 and Treg [12,13]. It has therefore become increasingly clear that these individual Th phenotypes represent adaptations for dealing with particular types of infection, or otherwise regulating immune responses. In contrast, dysregulation of these differentiation programs could result in ineffective immune responses against pathogens, debilitating autoimmune pathologies, or perhaps even promotion of carcinogenesis [14].

Ductal Carcinoma in situ Carries a Higher Risk of Death than Previously Thought

Women diagnosed with ductal carcinoma in situ (DCIS) are twice as likely to die from breast cancer compared to the general U.S. population, according to a new study led by Dr. Steven Narod.

“Our work shows that DCIS has more in common with small invasive cancers than previously thought,” explains Dr. Narod, a scientist with Women’s College Research Institute and a professor with the Dalla Lana School of Public Health at the University of Toronto. “In these cases, we’ve found that there’s an inherent potential for DCIS to spread to other organs.”

In this sense, DCIS is, in fact, an early form of breast cancer.

“This paper effectively redefines our understanding of the early stages of breast cancer and shows that the cancerous behavior is present very early on,” adds Dr. Narod. “There is a potential for chemotherapy to reduce the rates of death from DCIS but for most women the mortality rate (less than two per cent) is too low to justify toxic therapy.”

The research paper, which was published today in JAMA Oncology, also describes how radiotherapy and mastectomy prevented recurrence but did not diminish breast cancer mortality rates.

In the current study, the researchers looked at data from over 100,000 American women who had been diagnosed with DCIS (a type of stage 0 breast cancer). From the data, the researchers found that:

• About 1.1 per cent of women died of breast cancer within 10 years of being diagnosed with DCIS.
• About 3.3 per cent of women died of breast cancer within 20 years of being diagnosed with DCIS.
• Women diagnosed with DCIS before age 35 were 17 times more likely to die from breast cancer within 10 years, compared to women in the general U.S. population.
• Black women had a higher risk of dying from breast cancer within 20 years of being diagnosed with DCIS, compared to white women.
• Women with DCIS who subsequently developed an invasive form of cancer in the same breast were 18.1 times more likely to die of breast cancer.
• The majority of women with DCIS (54.1 per cent) who died of breast cancer did not have an invasive in-breast recurrence of cancer, prior to death.

About DCIS: Approximately 600,000 women in the United States and 60,000 women in Canada are living with a history of DCIS – some have been told that this is an early cancer and others have been told that this is a precancerous condition. Women under age 40 and black women have the highest chance of dying of DCIS.

DCIS accounts for approximately 20 per cent of breast cancers detected through mammography. Some women with DCIS experience a second breast cancer event – and a small proportion ultimately die of breast cancer. Until now, the impact of various factors (including age at diagnosis, ethnicity and treatment) on mortality rates has not been studied.

Breast Cancer Mortality after a Diagnosis of Ductal Carcinoma in situ (DCIS) 
Steven A Narod, Javaid Iqbal, Vasily Giannakeas, Victoria Sopik

About Women’s College Hospital – For more than 100 years Women’s College Hospital (WCH) has been developing revolutionary advances in healthcare. Today, WCH is a world leader in the health of women and Canada’s leading, academic ambulatory hospital. A champion of health equity, WCH advocates for the health of all women from diverse cultures and backgrounds and ensures their needs are reflected in the care they receive. It focuses on delivering innovative solutions that address Canada’s most pressing issues related to population health, patient experience and system costs. The WCH Institute for Health System Solutions and Virtual Care (WIHV) is developing new, scalable models of care that deliver improved outcomes for patients and sustainable solutions for the health system as a whole.

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