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.

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.

Anti-HER2 CD4(+) T-helper Type 1 Response is a Novel Immune Correlate to Pathologic Response Following Neoadjuvant Therapy in HER2-positive Breast Cancer

A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C.

Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization.
Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C – utilized in 61.5 % – was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p < 0.0001), and cumulative response (148.2 vs. 22.4 SFC/10(6), p < 0.0001) versus non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) – not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2) – phenotypes, and not attributable to non-pCR patients’ immune incompetence, host-level T-cell anergy, or increased immunosuppressive populations. In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination.

Anti-HER2 CD4(+) Th1 response is a novel immune correlate to pathologic response following neoadjuvant T + C. In non-pCR patients, depressed Th1 responses are not immunologically “fixed” and can be restored with HER2-directed Th1 immune interventions. In such high-risk patients, combining HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may improve outcomes and mitigate recurrence.

Affiliation

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA.