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.

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.

Women’s College Research Institute (WCRI) is tackling some of the greatest health challenges of our time. Its scientists are conducting global research that advances the health of women and improves healthcare options for all, and are then translating those discoveries to provide much-needed improvements in healthcare worldwide.

Development of Vaccines for High-Risk Ductal Carcinoma In situ of the Breast

With the widespread use of screening mammography, ductal carcinoma in situ (DCIS) has become the most frequently diagnosed cancerous lesion identified in the breast. Like invasive breast cancer, DCIS is heterogeneous and represents a relatively wide spectrum of diseases.

Low-grade DCIS either rarely develops into invasive disease or progresses slowly to invasiveness over the course of 8 to 10 years. On the other hand, if untreated, high-grade DCIS lesions that display comedonecrosis will likely develop into invasive breast cancers over a 5- to 7-year period. Following current conventional treatment with surgery with wide margins (lumpectomy; ref. 1), lumpectomy plus radiation therapy (2), or mastectomy, the overall prognosis for these patients is excellent. Nonetheless, many patients (at least 30%) require the more aggressive therapeutic option (mastectomy) either because of extensive disease or for fear of cancer recurrence.

The latter remains a significant risk, particularly in younger patients. Fortunately, the relatively long period of latency between the onset of DCIS and development of invasive breast cancer offers an opportunity for novel neoadjuvant interventions. The potential benefits of such neoadjuvant therapies include (a) reduction of risk for subsequent breast cancer, (b) reduction in the psychological effect of the disease related to fear of recurrence, and (c) reduction in the morbidity resulting from surgery and radiation.

The latter would be achieved through diminution in the extent of disease before the application of standard therapies, limiting the need for radiation and decreasing the need for extensive surgical
resections.

Radiation as Immunomodulator: Implications for Dendritic Cell-Based Immunotherapy

The last decade has witnessed significant progress in the field of cancer immunotherapy. This has, in part, been driven by a growing recognition that elements of the innate immune response can be harnessed to induce robust immunity against tumor-associated targets. Nonetheless, as clinically effective immunotherapy for the majority of cancers remains a distant goal, attention has shifted toward multimodality approaches to cancer therapy, sometimes combining novel immunotherapeutics and conventional therapeutics. The traditional view of radiation therapy as immunosuppressive has been challenged, prompting a re-evaluation of its potential as an adjunct to, or even a component of immunotherapy. Radiation therapy may enhance expression of tumor-associated antigens, induce targeting of tumor stroma, diminish regulatory T-cell activity and activate effectors of innate immunity such as dendritic cells through Toll-like receptor (TLR)-dependent mechanisms. Here, we review recent progress in the field of dendritic cell-based immunotherapy, evidence for radiation-induced anti-tumor immunity and TLR signaling and the results of efforts to rationally integrate radiation into dendritic cell-based immunotherapy strategies.

Affiliation

A  Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.

Breast Cancer Developments

Over-expression of the HER2/neu receptor occurs in 20 to 30 percent of breast tumors and is linked to poorer prognosis. The HER2/neu expression status determines whether or not patient will receive trastuzumab-based treatment. In clinical practice, over-expression of HER2/neu is routinely identified using Immunohistochemistry (IHC) or Fluorescence in Situ Hybridization (FISH), both of which are invasive approaches requiring tissue samples. Serum assays for the Extra Cellular Domain of HER2/neu receptor (HER2 ECD) have been reported but the use is very limited due to serum interference factors (e.g. human anti-animal immunoglobulin antibodies) that lead to false test results and inconsistency with tissue Her2 status. We have developed an ELISA based approach using an MBB buffer to eliminate false results and to obtain more accurate assessment of HER2 ECD levels. Using this refined assay we retroactively measured HER2/neu levels from breast cancer patients and controls. Abnormal HER2 ECD levels were detected in about 32% of invasive breast cancer patients but not in controls or patients with benign diseases. In addition, we also showed that patients with elevated serum HER2 levels appeared to have worse survival regardless of treatments. In a small group of 12 Ductal Carcinoma in situ (DCIS) patients who received HER2/neu peptide vaccination and surgery, only one patient showed constantly rising HER2 levels after treatment and this patient had recurrence of HER2 positive tumor within 5 years. Our studies indicate that once the serum interference issue is resolved, serum HER2 ECD can have potential clinical utility to supplement the tissue based tests.

Affiliation

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, U.S.A.