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.

Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy

Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications – such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer – clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of anti-tumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of “precision” cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted – and personalized – approach combining DC-based vaccination with adjunctive strategies.

Affiliation

Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA , USA ; Rena Rowen Breast Center, Hospital of the University of Pennsylvania , Philadelphia, PA , USA.

Optimizing Dendritic Cell-Based Approaches for Cancer Immunotherapy

Dendritic cells (DC) are professional antigen-presenting cells uniquely suited for cancer immunotherapy. They induce primary immune responses, potentiate the effector functions of previously primed T-lymphocytes, and orchestrate communication between innate and adaptive immunity. The remarkable diversity of cytokine activation regimens, DC maturation states, and antigen-loading strategies employed in current DC-based vaccine design reflect an evolving, but incomplete, understanding of optimal DC immunobiology. In the clinical realm, existing DC-based cancer immunotherapy efforts have yielded encouraging but inconsistent results. Despite recent U.S. Federal and Drug Administration (FDA) approval of DC-based sipuleucel-T for metastatic castration-resistant prostate cancer, clinically effective DC immunotherapy as monotherapy for a majority of tumors remains a distant goal. Recent work has identified strategies that may allow for more potent “next-generation” DC vaccines. Additionally, multimodality approaches incorporating DC-based immunotherapy may improve clinical outcomes.

Affiliation

Department of Surgery, University of Pennsylvania Perelman School of Medicine, 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.